ramon salazar catalan institute of oncology...ramon salazar catalan institute of oncology...

What is best for second lineRamon Salazar

Catalan Institute of Oncology

DisclosuresR Salazar has served in a consultant or advisory role for Amgen Merck

Serono Taihoo MSD Lylli BMS Roche Dx and enjoyed research funding for Roche Dx Roche Pharma and Merck Serono

OralIV fluoropyrimidines

Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Regorafenib

Aflibercept

An

gio

gen

esis

Gro

wth TAS-102dagger

Ramucirumab

Chemo Backbone

bull Slide courtesy of M PeetersFluorouracil (25 mgmL injection) Summary of Product Characteristics Hospira Capecitabine (XELODAreg) Summary of Product Characteristics Roche Raltitrexed (Tomudexreg) Summary of Product Characteristics Hospira Irinotecan (Camptoreg) Summary of Product Characteristics Pfizer Oxaliplatin (Eloxatinreg) Summary of Product Characteristics Sanofi Bevacizumab (Avastinreg) Summary of Product Characteristics Roche Aflibercept (Zaltrapreg) Summary of Product Characteristics Sanofi Regorafenib (Stivargareg) Summary of Product Characteristics Bayer Cetuximab (Erbituxreg) Summary of Product Characteristics Merck Serono Panitumumab(Vectibixreg) Summary of Product Characteristics Amgen PR Newswire 02-03-15 Available at httpwwwprnewswirecouknews-releasestaiho-submits-tas-102-marketing-authorisation-application-to-the-european-medicines-agency-for-the-treatment-of-refractory-metastatic-colorectal-cancer-294606511html Accessed 21-04-15

daggerMarketing Authorisation Application

submitted to the to the European Medicines

Agency in March 2015 for TAS-102

for use in the treatment of refractory mCRC

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer a randomized GERCOR study

FOLFIRIFOLFIRI FOLFOX6FOLFOX6

OXL100 mgm2

R

FOLFOX6FOLFOX6 FOLFIRIFOLFIRI

ProgProg

Prog

Prog

Tournigand C Andreacute T Achille E et alJ Clin Oncol 2004 22 (2)

CPT11 180 mgm2N=226

Logrank

p = 026

Pro

bab

ilid

ad

00

02

04

06

08

10

0 4 8 12 16 20 24 28 32

Median (months)Folfiri85Folfox 80

Months

Pro

bab

ilid

ad

00

02

04

06

08

10

0 6 12 18

Months

Median (months)Folfiri 25Folfox 42

Logrank

p = 0003

EFFICACY VARIABLES

TIME TO 1ST LINE PROG TIME TO 2ND LINE PROG


Overall survival curves

Tournigand C et al JCO 200422229-237

copy2004 by American Society of Clinical Oncology

35

4

FOLFIRIn = 69

63

15

FOLFOXn = 81

4049Absence of progression at 15 months

09215204Median overall survival mos

065

068

p value

115144Median overall TTP mos

8179ORR + SD

5456 ORR (CR)

FOLFOX

n = 111

FOLFIRI

n = 109

Arm A Arm B

V308 EFFICACY ENDPOINTS (5)


Chemo Backbone

Cancer Invest 201634(2)94-104 doi 1031090735790720151104689 Epub 2016 Feb 11XELOX vs FOLFOX in metastatic colorectal cancer An updated meta-analysis

Guo Y1 Xiong BH2 Zhang T3 Cheng Y1 Ma L4

bull Folfiri-Folfox are the preferred optionsbull Simillar PFS and OS

bull Sequence does not influence outcome (Tournigand)

bull Xelox not inferior than Folfox (Phase 3 Meta-analysis)bull But Folfox has prevailed probably because of differential toxicity profiles

bull Pooled analysis revealed that there were no statistical differences between both arms in OS and ORR XELOX arm had a higher incidence of thrombocytopenia hand-foot syndrome and diarrhea whereas neutropenia had a higher incidence in the FOLFOX group For mCRC the effect of XELOX is similar to FOLFOX

bull Xeliri not so popular (toxicity and no Phase 3 data)


Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab

Biological companion






depends on what is used first line and theevidence generated for each Chemo scheme

mCRCmdashSecond-line randomized phase III trials

1

8

Studies Treatment N Prior Bevacizumab OSHR PFSHR

Aflibercept(VELOUR)

FOLFIRI + aflibercept 612 304vs 0817 0758

FOLFIRI + placebo 614 305 P=00032 P=000007

Panitumumab(study 20050181)

2

FOLFIRI + panitumumab 303 18vs 085 0732

FOLFIRI 294 20 P=012 P=00036

Ramucirumab FOLFIRI + ramucirumab vs folfiri

Cetuximab(Study CA225006)

3

irinotecan + cetuximab 97 NAvs 129 0773

irinotecan 95 NA P=01755 P=00953

Bevacizumab(ECOG 3200)4

FOLFOX + bevacizumab 293 0vs 075 052

FOLFOX 292 0 P=0001 Plt00001

Bevacizumab(ML18147)5

Oxali-Iri-CT + bevacizumab 409 100

vs 083 068

Oxali-Iri-containing CT 411 100 P=00062 Plt00001

1 Van Cutsem et al J Clin Oncol 2012 2 Assessment report for Vectibix Procedure EMEAHC000741II0017 3 Assessment report for Erbitux Procedure EMEAHC000558II0020 4 Assessment report for Avastin Procedure EMEAHC000582II0014 5 Arnold ASCO 2012 Abstract CRA3503

folfiri

folfox

Bevacizumab

E3200

bullObj Primario supervivencia

bullObj Secundario RR

Previously treated metastatic CRC

(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]

Oxaliplatin5-FULV (n=290)

Bevacizumab monotherapy10mgkg every 2 weeks

(n=243)

Oxaliplatin5-FULV + Bevacizumab 10mgkg

every2 weeks(n=289)

PD

PD

PD

Arm closed to enrolment

Giantonio BJ et al J Clin Oncol 200523 (June 1 Suppl)1s (Abstract 2)

E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0

Progression-free survival (months)0 2 4 6 8 10 12 14 16 18 20

HR=064

A vs B plt00001

B vs C plt00001


27 7248

A FOLFOX4 + Bevacizumab

C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal

A FOLFOX4 + Bevacizumab 289 129

B FOLFOX4 290 108

C Bevacizumab 243 102

HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4


FOLFOX4 + Avastin (n=271)

FOLFOX4 (n=271)

Avastin (n=230)

Overall response () 218 92 30

Complete response () 19 07 0

Partial response () 199 85 30

Stable disease () 517 450 291

Estudio E3200 tasa de respuestas

FOLFOX + Bevacizumab versus FOLFOX plt00001

Giantonio BJ et al J Clin Oncol 200523(June 1 Suppl)1s (Abstract 2)

BEV + standard first-line CT (either oxaliplatin or

irinotecan-based)(n=820)

Randomise 11

Standard second-line CT (oxaliplatin or irinotecan-based) until PD

BEV (25 mgkgwk) + standard second-line CT (oxaliplatin

or irinotecan-based) until PD

PD

ML18147 study design (phase III)

CT switch

Oxaliplatin rarr Irinotecan

Irinotecan rarr Oxaliplatin

Study conducted in 220 centres in Europe and Saudi Arabia

Primary endpoint bull Overall survival (OS) from randomisation

Secondary endpoints

included

bull Progression-free survival (PFS)

bull Best overall response rate

bull Safety

Stratification factors bull First-line CT (oxaliplatin-based irinotecan-based)

bull First-line PFS (le9 months gt9 months)

bull Time from last BEV dose (le42 days gt42 days)

bull ECOG PS at baseline (01 2)

Second-line chemotherapy during study Randomised patients

Second-line CT regimen

CT

(n=407)

BEV + CT

(n=407)

Irinotecan-based CT 43 42

FOLFIRI 14 16

LV5FU2 + CPT11 (Douillard regimen1) 7 7

XELIRI 12 12

Other regimens 10 7

Oxaliplatin-based CT 57 58

FOLFOX4 mFOLFOX4 18 19

FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4

1 Douillard et al Lancet 20003551041ndash7

PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42

No at riskCT 410 119 20 6 4 0 0 0BEV + CT 409 189 45 12 5 2 2 0

CT (n=410)BEV + CT (n=409)

41 mo 57 mo

Unstratifieda HR 068 (95 CI (059ndash078)

plt00001 (log-rank test)

Stratifiedb HR 067 (95 CI 058ndash078)


aPrimary analysis method bStratified by first-line CT (oxaliplatin-based irinotecan-based) first-line PFS (le9 months gt9 months) time from last dose

of BEV (le42 days gt42 days) ECOG performance status at baseline (0 ge1)

OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48

No at riskCT 410 293 162 51 24 7 3 2 0BEV + CT 409 328 188 64 29 13 4 1 0

CT (n=410)BEV + CT (n=409)

98 mo 112 mo

Unstratifieda HR 081 (95 CI 069ndash094)

p=00062 (log-rank test)





Median follow-up CT 96 months (range 0ndash455) BEV + CT 111 months (range 03ndash440)

Subgroup analysis of OS ITT population

aPatient population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 when

study was transferred to Roche All patients listed under AIO were included in primary analysis

Category Subgroup n HR (95 CI)

All All 819 081 (069ndash094)

Patient populationa AIO 260 086 (067ndash111)

ML18147 559 078 (064ndash094)

Gender Female 294 099 (077ndash128)

Male 525 073 (060ndash088)

Age lt65 years 458 079 (065ndash098)

ge65 years 361 083 (066ndash104)

ECOG performance status 0 357 074 (059ndash094)

ge1 458 087 (071ndash106)

First-line PFS le9 months 449 089 (073ndash109)

gt9 months 369 073 (058ndash092)

First-line CT Oxaliplatin-based 343 079 (062ndash100)

Irinotecan-based 476 082 (067ndash100)

Time from last BEV le42 days 630 082 (069ndash097)

gt42 days 189 076 (055ndash106)

Liver metastasis only No 592 081 (067ndash097)

Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2

Best overall response Measurable disease population

aPatients with a best overall response of confirmed complete or partial responsebThis analysis was not prespecifiedcIncludes lsquonot-evaluablersquo or lsquono tumour assessmentrsquo following baseline visit

Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)

p-value (unstratified) 03113

p-value (stratified) 04315

Complete response n () 2 (lt1) 1 (lt1)

Partial response n () 14 (3) 21 (5)

Stable disease n () 204 (50) 253 (63)

Disease control rate n () 220 (54) 275 (68)

p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38

PROGRESIOacuteN DE LA ENFERMEDAD

MUERTE

FACTORES DE ESTRATIFICACIOacuteN

Prior Bevacizumab (YN)ECOG PS (0 vs 1 vs 2)

Pacientes con caacutencer colorrectal metastaacutesico

despueacutes del fracaso de un reacutegimen basado en

oxaliplatino12

R 11

614 pts

612 pts

Aflibercept 4 mgkg IV+ FOLFIRI q 2 semanas

Placebo + FOLFIRIq 2 semanas

1 Clinicaltrialsgov NCT00561470 2 Van Cutsem Ann Oncol 201122(suppl 5) Abstract O-0024 and presentation at ESMO 13th WCGIC June 22-25 2011 Barcelona Spain

Poblacioacuten de estudio1226 randomizados 1216 tratadosAnaacutelisis final de 863 OS eventos

Objetivo primario SG

Objetivos secundarios TR SLP seguridad FC

VELOUR acroacutenimo VEGF Trap(aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen

614 355 171 94 46 24 9

612 420 247 99 43 17 7

VELOUR Progression Free SurvivalITT Population Independent Review Committee

42

Van Cutsem et al Ann Oncol 201122(suppl 5) Abstract O-0024 and presentation at ESMO 13th WCGIC June 22-25 2011 Barcelona Spain

0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK

Stratified HR = 0758 [9999 CI 0578ndash0995]Log-rank P = 000007

Censor

AfliberceptFOLFIRI median = 69 monthsPlaceboFOLFIRI median = 467 months

10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont

hs) Cut-off date May 6 2011

43

1 Van Cutsem et al Ann Oncol 201122(suppl 5) Abstract O-0024 and presentation at ESMO 13th WCGIC June 22-25 2011 Barcelona Spain 2 Joulain et al ASCO 2012 abstract 36023 Tabernero et al Eur J Cancer 201147(2) Abstract 6LBA and presentation at ESMO 2011 EMCC September 23ndash27 2011 Stockholm Sweden

10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)

Fecha de corte Febrero 7 2011

Seguimiento mediano 2228 meses

PROBABILIDAD DE SUPERVIVEacuteNCIA3

Estratificado HR=0817[9534 CI 0713ndash0937]

Log-rank P=00032

AfliberceptFOLFIRImediana SGsup1=135 mesesmedia SGsup2=232 meses75 quartile 2559 (2201ndash3170)

PlaceboFOLFIRImediana SGsup1=121 mesesmedia SGsup2=203 meses75 quartile 2103 (1892ndash2280)

791 503 309 187 120

819 561 385 280 223 AfliberceptFOLFIRI

PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39

El beneficio absoluto en supervivencia del estudio se incrementa con el tiempo de seguimiento mdash la mejora en supervivencia a los 2 antildeos fue del 50 (280 con aflibercept vs 187 con

placebo) Y casi el doble a los 30 meses (223 vs 120)

EVALUABLE POPULATION () PLACEBO (N=530) AFLIBERCEPT (N=531)

BEST OVERALL RESPONSE

Complete response 04 0

Partial response 108 198

Stable disease 649 659

Progressive disease 215 104

Not evaluable 25 40

OVERALL RESPONSE RATE

CR or PR 111 198

95 CI 85ndash138 164ndash232

P-value 00001

VELOUR Response Rate Independent Review Committee

44


Evaluable population Patients with measurable target lesions that have agreed for third party reviewStratified Cochran Mantel test

POBLACIOacuteN ITT () PLACEBO (N=614) AFLIBERCEPT (N=612)

Discontinuacioacuten del tratamiento de estudio 974 969

Progresioacuten de enfermedad 712 498

Acontecimiento adverso 121 266

Otro 03 05

Peticioacuten del paciente 70 126

Decisioacuten del investigador 34 33

Cirugiacutea metaacutestasis 16 20

Otras causas 21 26

Tratamiento de estudio en curso 18 23

VELOUR treatment interruption

48

Van Cutsem et al Ann Oncol 201122(suppl 5) Resumen O-0024 y presentacioacuten en ESMO 13th WCGIC 22-25 de junio de 2011 Barcelona Espantildea

Otras causas incluyen retirada del consentimiento peacuterdida en el seguimiento incumplimiento y otras razones no clasificadas

Drug related Dearhs (23 vs 07)The adverse events (all grades) leading most frequently to permanent discontinuation of study treatment were asthenicconditions (38 v 13 respectively) infections (34 v 17) diarrhea (23 v 07) and hypertension (23 v 0)

Ramucirumab

bull RAISE phase 3 trial second line

bull disease progression during or within 6 months of the last dose of first-line therapy withbevacizumab oxaliplatin and a fluoropyrimidine for metastatic disease

bullTabernero J Yoshino T Cohn A Obermannova R Bodoky G Garcia-Carbonero R et al

(2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with

metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab

oxaliplatin and a fluoropyrimidine (RAISE) a randomised double-blind multicentre phase III

study Lancet Oncol 16 499ndash508 [PubMed]

Response Rate134 vs 125

Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U

PDisease assessments

every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan

FranceBelgiumThe NetherlandsGermanySwitzerlandAustriaItalyCzech RepublicSlovakiaPolandLithuania

Australia

Enrollment Target

1100 patients

Randomization stratification

bull ECOG score 0-1 vs 2

bullPrior oxaliplatin exposure for mCRC

bullPrior bevacizumab exposure for mCRC

S

C

R

E

E

N

I

N

G

UkraineRomaniaBulgariaUnited KingdomIrelandPortugalSpainNorwaySwedenFinland

181 TRIAL Study Schema and Stratification

Peeters M et al Eur J Cancer 20097(3S)14LBA oral presentation

20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)

Log-rank p-value = 0004

Eventsn ()

Median (95 CI) months

Panitumumab + FOLFIRI

178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)

WT KRAS Significant Improvement of Progression-Free Survival


10

Panitumumab

+ FOLFIRIFOLFIRI alone

Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)

WT KRAS Trend for Overall Survival Benefit


Subsequent Use of EGFR mAb 10 pmab arm vs 31 FOLFIRI arm

62

Trend for greater efficacy of 1st line panitumumab + FOLFOX vs FOLFOX in left- vs

right-sided tumors (RAS wt)12

Panitumumab trialsTumor location analyses ndash RAS WT

Trial(line)

TreatmentsTumorlocation

Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)

Phase III PRIME(1st line)

Pani + FOLFOX4 vs FOLFOX4

Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)

Phase II PEAK (1st line)3

Pani + mFOLFOX6 vs bev + mFOLFOX6

Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)

Phase III Study 181 (2nd line)4

Pani + FOLFIRI vs FOLFIRI

Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)

1 Peeters M et al Oral presentation at ESMO 20162 Boeckx C et al ESMO 2016 (Abstract No 89P)

3 Rivera F et al ECC 2015 (Abstract No 2014)4 Peeters M et al Clin Cancer Res 2015215469ndash5479

Bev bevacizumab pani panitumumab Adjusted for BRAF status prior adjuvant CT and ECOG PS

Significant increase in OS and PFS only in the left-sided subgroup of PRIME

NO APPARENT SIDE INTERACTION IN SECOND LINE

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS

No Benefit or Detrimental Effect in Patients with KRAS Mutant Tumors


Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)

Objective response rate (95 CI)

35(30 ndash 41)

10(7 ndash 14)





All responses were confirmed no earlier than 28 days after the

response criteria were first met

WT KRAS Objective Response (Central Review)

Peeters M et al ASCO-GI 2010 282 oral presentation

1For wt KRAS subset p lt 0001(descriptive) exact test of odds ratio stratified by randomization factors

Radiological Response By Tumor Side

Trial(line)

Treatments Tumor location Patients n ORR

Phase III PRIME(1st line)12


Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462

Phase III Study181 (2nd line)4


Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS

Seymour et alLancetOncology2013 14 749-759

CetuximabEPIC TRIAL

bull within 6 months of the last-dose of

bull first-line fluoropyrimidine and oxaliplatin treatment for metastatic disease was required

bull Previous irinotecan or anti-EGFR therapies were excluded

bull prior bevacizumab was allowed

bull NO KRAS SELECTION OR ANALYSIS

bull NO TUMOR SIDE ANALYSIS

PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001

ERBITUX in pretreated mCRC EPIC Progression free survival amp response rate

4

46

16

61

0

10

20

30

40

50

60

70

Response rate Disease Control

()

Irinotecan (N=650) ERBITUX + irinotecan (N=648)

Response Rate

Sobrero et al AACR 2007

p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712

ERBITUX + IRINOTECAN N = 648

Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36

ERBITUX in pretreated mCRC EPIC Overall Survival

MONTHS

Recommendation 20 Second-line combinations with targeted agents

Patients who are bevacizumab naiumlve should be considered for treatment with an antiangiogenic (bevacizumab or aflibercept) second-line [I A] The use of aflibercept should be restricted to combination with FOLFIRI for patients progressing on an oxaliplatin-containing regimen [I A]

Patients who received bevacizumab first-line should be considered for treatment with

bull Bevacizumab post-continuation strategy [I A]

bull Aflibercept or ramucirumab (in combination with FOLFIRI) when treated in first line with oxaliplatin [I A]

bull EGFR antibodies in combination with FOLFIRIirinotecan for patients with RAS wild-type (BRAF wild-type) disease

bull Relative benefit of EGFR antibodies is similar in later lines compared with second-line [II A]

Patients who are fast progressors on first-line bevacizumab-containing regimens should be considered for treatment with aflibercept or ramucirumab (only in combination with FOLFIRI) [II B] and - in the case of patients with RAS wild-type disease and no pre-treatment with anti-EGFR therapy - EGFR antibody therapy preferably in combination with chemotherapy [II B]

Van Cutsem E Cervantes A Arnold D et al ESMO Consensus 2016

Online Ann Oncol July 2016

Treatment of metastatic disease












ldquoSPECTAColor Platform for Molecular Analysisrdquo

Results with Potential Implications for Novel Therapeutic Approaches

Genetic Alteration Prevalence Potential TreatmentRASRAF mutation

co-present

Multi-gene sequencing

BRCA12 mutation 10457 (22) PARP inhibitor 510 (50)

TSC12 mutation 6457 (13) mTOR inhibitor 46 (67)

IDH12 mutation 4457 (09) IDH inhibitor 34 (75)

ERBB2 (HER2) amplification 4146 (27) HER2 MAb 04 (0)

FGFR12 amplification 4146 (27) FGFR inhibitor 24 (50)

Gene fusion (2x ROS2 1x ALK) 3251 (12) ROS1 inhibitor 13 (33)

PCR QC amp IHC MMR

RAS 55 NO EGFR inhibitor 0BRAF 5 EGFR + BRAF inhibitor 0

MSI3 PD1 inhibitor (50)

328-Gene Panel in the First 457 Tumor Samples (440 patients)

Sanger 14G UK Lab Analysis Dresden Molecular Pathology Lab

Microsatellites

bull Microsatellites are repeats of 1 to 10 nucleotides variable in length (from 5 to 50 repeats)

bull A A A A A A A -gt 7 poly-A microsatellite

bull GT GT GT GT -gt 4 poly-GT microsatellite

bull ACGTCC-ACGTCC-ACGTCC -gt 3 poly ACGTCC

bull Localized in coding or non-coding regions of DNA

Biologic importance of microsatellites

bull Microsatellites cause DNA polymerase slips in the replicative fork causing DNA mismatches and ultimately protein mutations

bull Zones of accumulations of mutations

bull Commonly frame shifts

Vilar E Nat Clin Oncol 2010

DNA mismatch repair system

bull Evolution endowed eukaryotic cells with a dedicated system to repair mismatches in DNA

The loss of mismatch repairsystem causes mutationsand ultimately cancer


n = 13

n = 9CACACACACACACACACACACACACA

CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci

Microsatellite instability

Therapeutic implications of MSI status

bull The higher mutational tumor load the higher immune activation and T lymphocyte infiltrates

Dung T lee ASCO 2015

MSI tumor

MSS tumor

Therapeutic implications of MSI statusbull MSI tumors have significant high mutation tumor load amp

mutation ldquoof qualityrdquo

Chen DS amp Mellman I Immunity 2013

Giannakis M ASCO 2015MSI tumors haverdquo high qualityrdquo mutationsrdquoStadler Z JCO 2016

Clinical data of MSI tumor and immunotherapy

bull Pembrolizumab in MSI-H tumors

Dung T lee NEJM 2015

Overman M ASCO 2016


bull NIVOLUMAB in MSI-H CRC

Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27

Immunotherapy in unselected CRC population

Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012

Patnaik Clin Can Res 2015

Herbst R ASCO 2013

Next steps in CRC immune-therapies

bull Increase the benefit from immunotherapy (fight resistance or adaptation)

bull Increase the of patients that benefit from immunotherapy

MSS

MSIH

Overman ASCO 2016

Future directions

bull Nivolumab plus Ipilimumab in MSI-H CRC

POLE EDM TCGA

ICO LrsquoHospitalet

Adapted from Becht E et al Oncoimmunology 2015

Immune vs Transcriptomic subtypes of CRC

Supervised immune infiltration analysis

Redefining mCRC

The Consensus

Molecular Subtypes Perspective CONSENSUS SUBTYPES

Proposed taxonomy of colorectal cancer

Inmune checkpointsblockade +

BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications

(almost all) molecular subtypes of CRC have MEK over-activation

Biomarkers CD8 T-cell Accumulation and MHC I Expression

Presented By Johanna Bendell at 2016 ASCO Annual Meeting

MEK activation lead to decrease on MHC-1

expression and therefore impairs antigen

presentation (2)

FUTURE DIRECTIONS

Examples of anti-PDL1PD1 therapies currently under investigation in CRC

Target Therapy Phase Trial Design Trial ID

Anti-PDL1

Atezolizumab (engineered IgG1

no ADCC)

I Solid tumours NCT01375842

Ib Solid tumours (+ bevacizumab plusmn FOLFOX) NCT01633970

II mCRC (+ bevacizumab + fluoropyrimidine) NCT02291289

MEDI4736(modified IgG1

no ADCC)II mCRC NCT02227667

Anti-PD1

Nivolumab(IgG4)

III mCRC (plusmn ipilimumab) (CheckMate 142) NCT02060188

III Solid tumours (+INCB24360) NCT02327078

III Solid tumours (+ chemotherapy) NCT02423954

III Solid tumours (+ varlilumab) NCT02335918

Pembrolizumab(IgG4 humanised)

I Solid tumours (+ aflibercept) NCT02298959

III GI cancers (+mFOLFOX6) NCT02268825

III WT mCRC (+ cetuximab) NCT02318901

II mCRC (+ radiotherapy or ablation) NCT02437071

II mCRC (+ chemotherapy) NCT02375672

II mCRC (+ azacitidine andor romidepsin) NCT02512172

II MSI-positive-negative CRC NCT01876511

bull Recruiting studies bull Clinicaltrialsgov

DisclosuresR Salazar has served in a consultant or advisory role for Amgen Merck

Serono Taihoo MSD Lylli BMS Roche Dx and enjoyed research funding for Roche Dx Roche Pharma and Merck Serono


Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Regorafenib

Aflibercept

An

gio

gen

esis

Gro

wth TAS-102dagger

Ramucirumab

Chemo Backbone








OXL100 mgm2

R


ProgProg

Prog

Prog


CPT11 180 mgm2N=226

Logrank

p = 026

Pro

bab

ilid

ad

00

02

04

06

08

10

0 4 8 12 16 20 24 28 32


Months

Pro

bab

ilid

ad

00

02

04

06

08

10

0 6 12 18

Months


Logrank

p = 0003

EFFICACY VARIABLES






35

4

FOLFIRIn = 69

63

15

FOLFOXn = 81



065

068

p value


8179ORR + SD

5456 ORR (CR)

FOLFOX

n = 111

FOLFIRI

n = 109

Arm A Arm B



Chemo Backbone









Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab









1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)















Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Regorafenib

Aflibercept

An

gio

gen

esis

Gro

wth TAS-102dagger

Ramucirumab

Chemo Backbone








OXL100 mgm2

R


ProgProg

Prog

Prog


CPT11 180 mgm2N=226

Logrank

p = 026

Pro

bab

ilid

ad

00

02

04

06

08

10

0 4 8 12 16 20 24 28 32


Months

Pro

bab

ilid

ad

00

02

04

06

08

10

0 6 12 18

Months


Logrank

p = 0003

EFFICACY VARIABLES






35

4

FOLFIRIn = 69

63

15

FOLFOXn = 81



065

068

p value


8179ORR + SD

5456 ORR (CR)

FOLFOX

n = 111

FOLFIRI

n = 109

Arm A Arm B



Chemo Backbone









Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab









1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)
















OXL100 mgm2

R


ProgProg

Prog

Prog


CPT11 180 mgm2N=226

Logrank

p = 026

Pro

bab

ilid

ad

00

02

04

06

08

10

0 4 8 12 16 20 24 28 32


Months

Pro

bab

ilid

ad

00

02

04

06

08

10

0 6 12 18

Months


Logrank

p = 0003

EFFICACY VARIABLES






35

4

FOLFIRIn = 69

63

15

FOLFOXn = 81



065

068

p value


8179ORR + SD

5456 ORR (CR)

FOLFOX

n = 111

FOLFIRI

n = 109

Arm A Arm B



Chemo Backbone









Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab









1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Logrank

p = 026

Pro

bab

ilid

ad

00

02

04

06

08

10

0 4 8 12 16 20 24 28 32


Months

Pro

bab

ilid

ad

00

02

04

06

08

10

0 6 12 18

Months


Logrank

p = 0003

EFFICACY VARIABLES






35

4

FOLFIRIn = 69

63

15

FOLFOXn = 81



065

068

p value


8179ORR + SD

5456 ORR (CR)

FOLFOX

n = 111

FOLFIRI

n = 109

Arm A Arm B



Chemo Backbone









Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab









1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)

















35

4

FOLFIRIn = 69

63

15

FOLFOXn = 81



065

068

p value


8179ORR + SD

5456 ORR (CR)

FOLFOX

n = 111

FOLFIRI

n = 109

Arm A Arm B



Chemo Backbone









Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab









1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Chemo Backbone









Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab









1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)















Irinotecan

Oxaliplatin

Raltitrexed

Bevacizumab

Cetuximab

Panitumumab

Aflibercept

An

gio

gen

esis

Gro

wth

Ramucirumab









1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)















1

8


Aflibercept(VELOUR)




2


FOLFIRI 294 20 P=012 P=00036



3





FOLFOX 292 0 P=0001 Plt00001



vs 083 068



folfiri

folfox

Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Bevacizumab

E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














E3200




(n=822)

mainly bolus

irinotecan + 5-

FU + LV [IFL]



(n=243)


every2 weeks(n=289)

PD

PD

PD



E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














E3200 PFS

Pro

babili

ty o

f bein

g p

rogre

ssio

n f

ree

10

08

06

04

02

0


HR=064

A vs B plt00001

B vs C plt00001


27 7248


C Bevacizumab

B FOLFOX4

E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














E3200 SG

MedianTotal


B FOLFOX4 290 108


HR = hazard ratio

Pro

babili

ty o

f su

rviv

al

10

08

06

04

02

0

Time (months)

HR=076

A vs B p=00018

B vs C p=095

102 129

108

0 3 6 9 12 15 18 21 24 27 30 33 36


C Bevacizumab

B FOLFOX4



FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)















FOLFOX4 (n=271)

Avastin (n=230)










Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)
















Randomise 11




PD


CT switch





Secondary endpoints

included



bull Safety







CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)
















CT

(n=407)

BEV + CT

(n=407)


FOLFIRI 14 16


XELIRI 12 12

Other regimens 10 7



FOLFOX6 13 16

FUFOX 9 6

XELOX 11 14

Other regimens 6 4


PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














PFS ITT population

PFS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42


CT (n=410)BEV + CT (n=409)

41 mo 57 mo







OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














OS ITT population

OS

est

imat

e

Time (months)

10

08

06

04

02

00 6 12 18 24 30 36 42 48


CT (n=410)BEV + CT (n=409)

98 mo 112 mo












All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)


















All All 819 081 (069ndash094)


ML18147 559 078 (064ndash094)


Male 525 073 (060ndash088)


ge65 years 361 083 (066ndash104)


ge1 458 087 (071ndash106)






gt42 days 189 076 (055ndash106)


Yes 226 079 (059ndash105)

No of organs

with metastasis

1 307 083 (064ndash108)

gt1 511 077 (064ndash094)

HR 0 1 2



Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)
















Outcome

CT

(n=406)

BEV + CT

(n=404)

Respondersa n () 16 (39) 22 (54)





Stable disease n () 204 (50) 253 (63)


p-valueb lt00001

PD n () 142 (35) 87 (22)

Missingc n () 44 (11) 42 (10)

Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Aflibercept

VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














VELOUR trial

38


MUERTE





oxaliplatino12

R 11

614 pts

612 pts








614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














614 355 171 94 46 24 9

612 420 247 99 43 17 7


42


0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK


Censor


10

09

08

07

06

05

04

03

02

01

00

KA

PLA

N-M

EIE

RE

ST

IMA

TE

TIM

E(m

ont


43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














43


10

09

08

07

06

05

04

03

02

01

00

KA

PL

AN

-ME

IER

ES

TIM

AT

E

TIEMPO (meses)





Log-rank P=00032



791 503 309 187 120


PlaceboFOLFIRI

Censor

Δ=14 months2

Δ=26 months2

Δ=44 months2

0 3 6 9 12 15 18 21 24 27 30 33 36 39









Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)




















Not evaluable 25 40


CR or PR 111 198


P-value 00001


44







Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)


















Otro 03 05




Otras causas 21 26



48




Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Ramucirumab









Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)















Panitumumab

Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Tx Arm 1

Panitumumab

60 mgkg Q2W +

FOLFIRI Q2W

E

N

R

O

L

L

M

E

N

T

E

N

D

O

F

T

R

E

A

T

M

E

N

T

L

O

N

G

T

E

R

M

F

O

L

L

O

W

U


every 8 weeks

Tx Arm 2

FOLFIRI Q2W

Study

20050181

Countries

United

States

RussiaJapan


Australia

Enrollment Target

1100 patients





S

C

R

E

E

N

I

N

G




20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














20181614121086420

00

01

02

03

04

05

06

07

08

09

10

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

Months

HR = 073 (95 CI 059 090)


Eventsn ()



178303 (59) 59 (55-67)

FOLFIRI 203294 (69) 39 (37-53)



10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














10

Panitumumab


Patients at risk

89303 288 264 235 217 189 168 147 65111

74294 278 249 223 187 166 146 121 5893

1843 929

1646 726

0 04

1 05

20181614121086420

01

02

03

04

05

06

07

08

09

Months

323028262422 34

Su

rv iva

l P

rob

ab

ility

00

HR = 085 (95 CI 070 104)


EventsN ()



200 (66) 145 (130 - 160)

FOLFIRI alone 207 (70) 125 (112 - 142)




62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














62




Trial(line)


Patients n ORR

PFS OS

Median months

HR (95 CI)

Median months

HR (95 CI)



Left 169 vs 159 68 vs 53 129 vs 92072

(057ndash090)303 vs 236

073 (057ndash093)

Right 39 vs 49 42 vs 35 75 vs 70080

(050ndash126)111 vs 154

087 (055ndash137)



Left 53 vs 54 64 vs 57 146 vs 115068

(021ndash200)434 vs 320

077 (022ndash327)

Right 22 vs 14 63 vs 50 87 vs 126 104

(018ndash379)175 vs 210

067 (008ndash249)



Left 150 vs 148 50 vs 13 80 vs 58088

(069ndash112)201 vs 166

096 (074ndash123)

Right 31 vs 39 13 vs 3 48 vs 24075

(045ndash127)103 vs 81

114 (068ndash189)






00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20

Pro

gre

ssio

n-f

ree

Pro

ba

blil

ity

HR = 085 (95 CI 068 106)


Eventsn ()



162 238 (68) 50 (38 - 56)

FOLFIRI 161 248 (65) 49 (36 - 56)

00

01

02

03

04

05

06

07

08

09

10

Months

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Su

rv iva

l P

rob

ab

ility

Eventsn ()



181 238 (76) 118 (104 - 133)

FOLFIRI 193 248 (78) 111 (103 - 124)

HR = 094 (95 CI 076 115)


PFS OS



Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Panitumumab

+ FOLFIRI

(n = 297)

FOLFIRI

(n = 285)


35(30 ndash 41)

10(7 ndash 14)











Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)















Trial(line)




Left 156 vs 148 703 vs 548

Right 26 vs 32 520 vs 412



Left 52 vs 53 635 vs 585

Right 13 vs 13 692 vs 462



Left 143 vs 144 507 vs 135

Right 22 vs 26 190 vs 38



PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














PICCOLO TRIAL

WT

mut

OS

OS

PFS

PFS


CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














CetuximabEPIC TRIAL







PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

MONTHS

00

02

04

06

08

10

0 3 6 9 12 15 18

40 mo

26 mo

HR = 069

p lt 00001


4

46

16

61

0

10

20

30

40

50

60

70


()


Response Rate


p lt 00001

p lt 00001

PFS

PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














PR

OP

OR

TIO

N A

LIV

EHR = 0975

p = 0712


Median OS = 107 mo

IRINOTECAN N = 650

Median OS = 100 mo

00

01

02

03

04

05

06

07

08

09

10

0 3 6 9 12 15 18 21 24 27 30 33 36


MONTHS


























co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)







































co-present








PCR QC amp IHC MMR





Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Microsatellites















n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)























n = 13


CACACACACACACACACA

N T TN

MSI phenotype

TN

Normal

TN

LOH

MSI

MSI

Microsatellite Loci





MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)

















MSI tumor

MSS tumor








Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)





















Overman M ASCO 2016



Report ORR

Pembro ASCO 2015 60

Pembro NEJM 2015

40

NivoASCO 2016

27


Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)















Drug ORR

Nivolumab 0

Pembrolizumab 0

Atezolizumab 0

Topalian NEJM 2012


Herbst R ASCO 2013




MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)

















MSS

MSIH

Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














Overman ASCO 2016

Future directions


POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














POLE EDM TCGA





Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)

















Redefining mCRC

The Consensus




BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)
















BEVACIZUMAB

TGF-

inhibition+ Inmune

checkpointblockade

Prognosis

Drugresponse

prediction

Metabolismamp

DNA damage

Oncogenedrivers

Amplifications






presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)



















presentation (2)

FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














FUTURE DIRECTIONS



Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)
















Anti-PDL1


no ADCC)






Anti-PD1

Nivolumab(IgG4)














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