asco updates 2011 lung cancer heather wakelee, m.d. assistant professor of medicine,oncology...

ASCO Updates 2011

Lung Cancer

Heather Wakelee, M.D. Assistant Professor of Medicine,Oncology

Stanford University and Stanford Cancer Institute

Abstracts to be discussed• Metastatic NSCLC

– Maintenance• CRA7510 - pemetrexed, LBA7511 – gefitinib

– Targeted Therapy• LBA7512- motesanib, 7502-vadimezan, CRA7506-driver

mutations, 7503- EURTAC, 7505- MetMab, 7507-crizotinib, 7500-ganetespib

• Early Stage NSCLC• 7002-TREAT, 7013-E1505

• Small Cell Lung Cancer • 7000-amrubicin

Abstracts to be discussed

• Metastatic NSCLC– Maintenance

• CRA7510 - pemetrexed, LBA7511 - gefitinib





Recent Maintenance Trials

• Docetaxel early vs. late– PFS benefit– Strong trend OS benefit

• Pemetrexed vs placebo– PFS + OS benefit

• Erlotinib vs placebo - Saturn– PFS + small OS benefit

• Erlotinib vs placebo + Bevacizumab (ATLAS) - ~ early vs late (unblinding at PD)– PFS benefit– Trend OS benefit

Continuation Maintenance

• Study/Yr Induction Maintenance MTTP/MPFS

Med OS toxicity

Belani 2003

Carbo/Tax

Paclitaxel wkObs

38 wk29 wk

75 wk60 wk

45% Gr 3/4

Brodowicz 2006

Cis/Gem Gem d1,8Obs

6.6 mo5.0 moP<.001

13 mo11 mo

Heme tox in 20%+

Belani 2010

Carbo/Gem

Gem d1,8Obs

7.4 mo7.7 mo

8 mo9.3 moNS

<20% Heme

Perol 2010

Cis/Gem Gem d1,8Obs

3.8 mo1.9 moP<.001

NR 28% Gr 3/4

Fidias/Novello JCO Dec 2010

Clear benefit of continuation in PFS in 3/4, and trend in OS in 2/3 trialsPFS matters if we will never return to the 1st line drugs which were stopped

Continuation Maintenance• Bevacizumab, cetuximab, erlotinib are

ALWAYS given w/ maintenance approach

• Patel’s phase II study of carboplatin/pemetrexed/bevacizumab w/ continuation of pem/bev was very promising

• We never stop 2nd or 3rd line therapy while it is working, so why do we stop 1st line?

PARAMOUNT: Phase III Study of Maintenance Pemetrexed (Pem) Plus Best Supportive Care (BSC) Versus Placebo Plus BSC Immediately Following Induction Treatment with Pem Plus Cisplatin for Advanced Nonsquamous NSCLCCRA 7510

L. G. Paz-Ares1, F. de Marinis2, M. Dediu3, M. Thomas4, J.L. Pujol5, P. Bidoli6, O. Molinier7, T.P. Sahoo8, E. Laack9, M. Reck10, J. Corral1, S. Melemed11, W. John11, N. Chouaki12, A. H. Zimmermann11, C. Visseren-Grul13, C. Gridelli14

1

PARAMOUNT: Background

Pemetrexed is active nonsquamous NSCLC:

─ In first-line doublet 3

─ As maintenance agent following a non-pem platinum doublet 4

JMEN: after 4 cycles non-pem platinum doublet pem vs placebo

Non-squamous pt results: OS HR .07, p.002

Pemetrexed maintenance has not been studied following pemetrexed-platinum induction in a phase III setting (continuation maintenance)

1 http://seer.cancer.gov/statfacts/html/lungb.html; 2Azzoli CG et al. J Clin Oncol 2009; 27:6251–6266 3Scagliotti GV et al. J Clin Oncol 2008;26:3543-51.; 4Ciuleanu T et al. Lancet 2009;374:1432-40.

Paz-Ares PASCO 2011, LBA7510

http://seer.cancer.gov/statfacts/html/lungb.html

PARAMOUNT: Study Design

Randomized, placebo-controlled, double-blind, phase III study

Folic acid and vitamin B12 administered to both arms

Study Treatment PeriodProgression

Induction Therapy (4 cycles)

Maintenance Therapy (Until PD)

21 to 42 Days

500 mg/m2 Pemetrexed +75 mg/m2 Cisplatin, d1, q21d

CR, PR, SD

PD

Placebo + BSC, d1, q21d

500 mg/m2 Pemetrexed + BSC, d1, q21d

2:1 Randomization

Patients enrolled if:•Nonsquamous NSCLC•No prior systemic treatment for lung cancer•ECOG PS 0/1 Stratified for:

•PS (0 vs 1) •Disease stage (IIIB vs IV) prior to induction•Response to induction (CR/PR vs SD)


Time (Months)

0 3 6 9 12 15

Su

rviv

al

Pro

ba

bil

ity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PARAMOUNT: Investigator Assessed PFS (from Maintenance)

Pemetrexed: median =4.1 mos (3.2-4.6)Placebo: median =2.8 mos (2.6-3.1)Log-rank P=0.00006Unadjusted HR: 0.62 (0.49-0.79)

Patients at Risk

Pem + BSC N=359 132 57 21 4 0

Placebo + BSC

N=180 52 15 5 0 0

Pem + BSC

Placebo + BSC

JMEN: PFS 4.4 mo vs 1.8 mo, HR 0.47, p<.00001


Efficacy and tolerability data from a randomized, placebo-controlled, parallel-group

study of gefitinib as maintenance therapy in patients with locally advanced or metastatic

NSCLC (INFORM) (C-TONG 0804)

L Zhang, SL Ma, XQ Song, BH Han, Y Cheng, C Huang, SJ Yang, XQ Liu,

YP Liu, MZ Wang, XW Zhang on behalf of the INFORM investigators

# LBA 7511

INFORM: Study design

Gefitinib(250 mg/day)

Placebo(once daily)

1:1 randomization

EGFR, epidermal growth factor receptor; PD, progressive diseasePS, performance status; WHO, World Health Organization

Patients• Age ≥18 years • Completed 4 cycles of first-line platinum-based chemotherapy without PD or unacceptable toxicity

• Life expectancy≥12 weeks

• WHO PS 0-2• Measurable Stage IIIB/IV disease

Endpoints

Primary• Progression-free survival (PFS)

Secondary• Objective response rate (ORR)• Disease control rate (DCR)• Overall survival (OS)• Quality of life• Safety and tolerability

Exploratory• Biomarkers

– EGFR mutation

Zhang PASCO LBA7511

INFORM: PFS (ITT population)

†Estimated using the Kaplan-Meier method‡Primary Cox analysis with covariates

HR‡ (95% CI) = 0.42 (0.33, 0.55); p<0.0001

Gefitinib(n=148)

Placebo(n=148)

Median PFS,† months6-month PFS rate, %12-month PFS rate, %No. events, n (%)

4.847.333.2

124 (83.8)

2.615.02.9

144 (97.3)

GefitinibPlacebo

0 16 40 56 72 96 1120

10

40

60

80

100P

rob

abil

ity

of

PF

S (

%)

Patients at risk :

20

30

50

70

90

8 24 32 48 64 80 88 104

148 46 10 4 2 0 082 26 16 6 3 2 2 0148 82 56 42 31 6 0109 70 65 49 38 20 15 1

Time since randomization (weeks)

Zhang PASCO LBA7511

INFORM PFS by EGFR mut status

†Estimated using the Kaplan-Meier method

HR (95% CI) = 0.17 (0.07, 0.42)

Gefitinib (n=15) Median PFS†, 16.6 months No. events, 9 (60.0%)Placebo (n=15) Median PFS†, 2.8 months No. events, 15 (100.0%)

EGFR mutation-positive

HR (95% CI) = 0.86 (0.48, 1.51)

Gefitinib (n=25) Median PFS†, 2.7 months No. events, 25 (100.0%) Placebo (n=24) Median PFS†, 1.5 months No. events, 24 (100.0%)

EGFR mutation-negative

0

20

40

60

80

100

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

PF

S (

%)

Time (weeks)

15 9 5 3 3 2 1 1 1 1 1 1 0 0 0

15 15 14 14 13 11 10 18 7 7 5 3 1 0 0

Placebo

Gefitinib

No. of patients at risk

0

20

40

60

80

100

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

PF

S (

%)

Time (weeks)

24 9 5 3 2 0 0 0 0 0 0 0 0 0 0

25 14 6 3 3 1 0 0 0 0 0 0 0 0 0

Placebo

Gefitinib

No. of patients at risk

Zhang PASCO LBA7511

INFORM OS: (ITT population)

0 16 40 56 72 96 1120

10

40

60

80

100O

vera

ll s

urv

ival

(%

)

20

30

50

70

90

8 24 32 48 64 80 88 104 120 128

Time (weeks)

Placebo

Patients at risk:

148 136 97 78 37 0 0147 115 107 91 66 13 6 0148 129 102 84 39 0 0141 114 108 90 75 18 4 0

4756

127119Gefitinib

HR (95% CI) = 0.84 (0.62, 1.14); p=0.2608

Gefitinib(n=148)

Placebo(n=148)

Median OS, months6-month survival rate, %12-month OS rate, %No. events, n (%)

18.782.268.8

79 (53.4)

16.984.966.0

93 (62.8)

HR <1 implies a lower risk of death on gefitinib

Conclusions – Switch Maintenance

• PFS improved in ALL switch maintenance studies• OS significantly improved w/ PEM in JMEN and

erlotinib in Saturn but not gefitinib in INFORM• OS strongly trended in favor of early docetaxel• Patients receiving delayed 2nd line Rx MAY live

just as long IF they receive the effective agent• BUT we miss at least 1/3 of them• 2nd line therapy works, we should not deny our

patients 2nd line therapy

Abstracts to be discussed• Metastatic NSCLC

– Maintenance• CRA7510 - pemetrexed, LBA7511 - gefitinib

– Targeted Therapy• LBA7512- motesanib, 7502-vadimezan,CRA7506-driver



• Small Cell Lung Cancer • 7000-amrubicin, 7001-obatoclax

E4599: Bevacizumab Efficacy

RR: 15% for Carboplatin (CbP) vs 35% for CbP + Bevacizumab

P = .003; HR: 0.79 Median OS: 12.3 mos vs

10.3 mos1-yr OS: 51% vs 44%2-yr OS: 23% vs 15%

Pat

ien

ts S

urv

ivin

g (

%)

OS

0

20

40

60

80

100

Pat

ien

ts W

ith

PF

S (

%)

0 6 12 18 24 30 36Mos

P < .001; HR: 0.66 Median PFS: 6.2 mos vs

4.5 mos6-mos PFS: 55% vs 33%

1-yr PFS: 15% vs 6%

PFS

CbPCbP + bevacizumab

.

CbPCbP + bevacizumab

Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

0

20

40

60

80

100

0 6 12 18 24 30 36Mos

Promising Small Molecule Inhibitors of VEGFR and Their Targets

Inhibitor VEGFR-1 VEGFR-2 VEGFR-3 PDGFR cKIT EGFR Other

Sunitinib + + - + + - FGFR

Valatanib + + + + + - cFms

Vandetanib - + + +/- - + ret

Cediranib + ++ + + - -

Pazopanib + + + -

Sorafenib - + + + + - Raf

Axitinib + + + + + -

Cabozantinib + + + + Met

Motesanib + + + + +

BIBW1120 + + + + FGFR

VEGFR-TKI activity in NSCLC

• Vandetanib improved symptoms combination w/ 2nd line chemo– Improved PFS with docetaxel, but no FDA approval

• Cediranib with 1st line chemo promising (BR.24)– Press release that phase III trial halted for toxicity

• Sorafenib single agent promising results, but toxic w/ carbo/taxol (ESCAPE trial)

An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC)

• 1090 chemo-naïve pts with stage IIIB/IV NSCLC

• Randomized to 6 cycles of carboplatin/paclitaxel

+ motesanib 125 mg QD (Arm A) or placebo QD (Arm B)

• OS was NOT significantly improved w/ motesanib– 13 mo vs 11 mo, HR .9, p.14, primary endpoint

• PFS was improved w/motesanib– HR .79, p.0006

• ORR was significantly improved with motesanib– 40% vs 26%, p<.0001

• Incidence of grade 3 AEs in Arms +/- m was 73%/59%

Scagliotti LBA#7512

Aflibercept in combination with docetaxel for 2nd-line treatment of locally advanced or metastatic NSCLC: Final results of a multinational placebo-controlled phase III trial (VITAL)

• Aflibercept novel fusion protein binding VEGF-A, -B and PIGF acting as a decoy receptor

• 913 pts w/ stage IIIB/IV NSCLC s/p 1 prior chemo– randomized to docetaxel + aflibercept or placebo

• 83% adenoCA, Med age 60 yo, 66% male• OS 10.4 vs 10.0 mo, HR 1.0 w aflibercept, primary endpoint• PFS HR .82, p.0035• RR 9% vs 23%, p<.0001

Novello, WCLC 2011, O43.06

Study Design

Ran

dom

izat

ion

1:1

Paclitaxel + carboplatin + placebo

Paclitaxel + carboplatin + ASA404

N=1200

• Stage IIIB/IV NSCLC

• All histologies

• First-line chemotherapy-naïve

• PS 0 or 1

• Stratification:• Sex• Squamous vs

non-squamous • Paclitaxel 200 mg/m2, carboplatin AUC 6, and ASA404 1800 mg/m2 or placebo

• Day 1, q3w, up to six cycles• ASA404 maintenance treatment (after

completion of six cycles of ASA404 + P/C up to progression)

Lara abstr 7502

ASA404 (vadimezan): a small molecule vascular disrupting agent;Causes breakdown of vasculature and hemorrhagic tumor necrosis

ATTRACT1: Overall Survival

Arm ASA404 + PC Placebo + PC

Median survival (95% CI)

13.4 months (11.4, 16.6)

12.7 months (11.3, 14.4)

Lara abstr 7502

Anti-Angiogensis in NSCLCNo biomarkers, small steps forward

• Bevacizumab increases RR and PFS when added to 1st line chemotherapy for NSCLC, improved OS in 1/2 trials

• No VEGFR-TKI to date has improved the efficacy of chemotherapy, including motesanib at ASCO 2011

• Decoy receptor-aflibercept – No OS benefit with chemotherapy• Vascular disrupting agent ASA404 failed to improve outcomes

when added to chemotherapy• Single agent promise seen with sorafenib, sunitinib, others, but

no confirmatory phase III trial data to date• Novel agents in development – other VDAs, other antibodies• Predictive and prognostic markers are in development to help

guide patient selection- but none validated to date– ICAM, VEGF levels, VEGF polymorphisms, C/AFs…



• CRA7510 - pemetrexed, LBA7511 - gefitinib




• Small Cell Lung Cancer • 7000-amrubicin, 7001-obatoclax

Lung Cancer Mutation Consortium Kris ASCO 2011, CRA7506

51682

294

172

Mutation profiling FISH

Pending analysis

Lung Cancer Mutation Consortium

Number analyzed for mutation and FISH

Total study group as of 13 May 11

1064

Kris ASCO 2011, CRA7506

Lung Cancer Mutation Consortium

Incidence of Single Driver Mutations

Mutation found in 54% (280/516) oftumors completely tested (CI 50-59%)

Kris ASCO 2011, CRA7506

IPASS: Progression-free survival in EGFR mutation + vs - patients

EGFR mutation-positive EGFR mutation-negative

Treatment by subgroup interaction test, p<0.0001

HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001

No. events gefitinib, 97 (73.5%)No. events C/P, 111 (86.0%)

Gefitinib (n=132)Carboplatin/paclitaxel (n=129)

HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001

No. events gefitinib, 88 (96.7%)No. events C/P, 70 (82.4%)

132 71 31 11 3 0129 37 7 2 1 0

108103

0 4 8 12 16 20 24

GefitinibC/P

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of p

rogr

essi

on-f

ree

surv

ival

At risk:91 4 2 1 0 085 14 1 0 0 0

2158

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of p

rogr

essi

on-f

ree

surv

ival

Gefitinib (n=91)Carboplatin/paclitaxel (n=85)

Months Months

Mok et al 2008Incidence of EGFR mutation: 261/437 = 59.7%

Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial

174 patients in Europe w/ EGFR mut randomized to receive erlotinib or platinum-based CT as first-line therapy

CT Erlotinib P value

Response rate 10.5% 54.5% <0.0001

PFS, mo 5.2 (95% CI, 4.4-5.8) 9.4 (95% CI, 7.9-12.3) HR: 0.42, P<0.0001

Median survival, mo 18.8 22.9 HR: 0.80, P=0.42

Most common toxicities Asthenia: 68.9%Anemia: 45.9%Nausea: 40.5%Neutropenia: 36.5%

Diarrhea: 57.3%Asthenia: 53.3%Rash: 49.3%

Rosell PASCO 2011, abstr 7503

EURTAC: PFS in ITT population P

FS

pro

babi

lity

Erlotinib (n=86)Chemotherapy (n=87)

HR=0.37 (0.25–0.54)Log-rank p<0.0001

Time (months)

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

Patients at risk

Erlotinib 86 63 54 32 21 17 9 7 4 2 2 0 Chemo 87 49 20 8 5 4 3 1 0 0 0 0

Data cut-off: 26 Jan 2011

1.0

0.8

0.6

0.4

0.2

09.75.2

Study Response Rate PFS

EURTAC 58% vs 14.9% 9.7 vs 5.2 months (HR 0.37)

OPTIMAL 83% vs 36% 13.1 vs 4.6 months (HR 0.16)

NEJ 002 74% vs 31% 10.8 vs 5.4 months (HR 0.30)

WJTOG 3405 62% vs 31% 9.2 vs 6.3 months (HR 0.49)

Tony Mok, ASCO discussant 2011

Final overall survival results of NEJ002, a phase III trial comparing gefitinib to carboplatin (CBDCA) plus paclitaxel (TXL) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations

• 228 patients w/ EGFR+ adv NSCLC were treated with gefitinib or carboplain/paclitaxel

• Results: MST= 27.7 mo for gef vs. 26.6 mo for C/P

– 2-year survival: 58% for gef vs. 54% for C/P

• Eurtac OS: HR=0.80 (0.47–1.37), Log-rank p=0.4170

• None of the EGFR-TKI vs chemo as 1st line therapy trials in EGFR mut pts have shown a significant OS benefit

Inoue PASCO 2011, abstr 7519Rosell PASCO 2011 abstr 7503

EGFR Resistance Overview Unfortunately resistance to EGFR TKIs develops T790M ~50% of acquired resistance Approachs like irreversible* EGFR-TKIs in development

– Afatinib, HKI272*, PF00299804*, BMS690514*

Met amplification ~20% of acquired resistance Multiple drugs in development, mostly + an EGFR-TKI

– XL184 (cabozatinib), MetMab, ARQ197

Other resistance mutations in EGFR reported– T854A, D761Y…

Kobayashi. NEJM 2005;352:786; Engelman. Science 2007;316:1089; Balak. CCR 2006;12:6494;Bean. CCR 2008;14:7519

MetMAb (15 mg/kg IV Q3W)

+

erlotinib(150 mg daily)

Phase II: Erlotinib +/- MetMAb in2nd/3rd-line NSCLC

RANDOMIZATION

1:1

n=137*

n=69

n=68

Arm A

Arm B

PD

n=27

Key eligibility:• Stage IIIB/IV NSCLC• 2nd/3rd-line NSCLC• Tissue required• PS 0–2

Stratification factors:• Tobacco history • Performance status • Histology

Placebo (IV Q3W)

+

erlotinib(150 mg daily)

Add MetMAb

Co-primary objectives:

• PFS in ‘Met Diagnosticpositive’ patients (est. 50%)

• PFS in overall ITT population

5

Spigel PASCO 2011, 7505

MetMAb + erlotinib - ITT population

Time to progression (months)

0 3 6 9 12 15 18

Pro

bab

ilit

y o

f p

rog

ress

ion

fre

e

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

7.4

41

MetMAb +erlotinib

8.9

34

Median (mo)HR

(95% CI)Log-rank p-value

No. of events

Overall survival (months)

0 3 6 9 12 15 18 21

Pro

bab

ilit

y o

f su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

2.6

56

MetMAb +erlotinib

2.2

48

Median (mo)HR


No. of events

PFS: HR=1.09 OS: HR=0.8

8

1.09(0.73–1.62)

0.69

0.80(0.50–1.28)

0.34


MetMAb plus erlotinib in Met Dx+ pts

Time to progression (months)

0 3 6 9 12 15 18

Pro

bab

ilit

y o

f p

rog

ress

ion

fre

e

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

3.8

26

MetMAb +erlotinib

12.6

16

Median (mo)HR


No. of events

Overall survival (months)

0 3 6 9 12 15 18 21

Pro

bab

ilit

y o

f su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

1.5

27

Median (mo)HR


No. of events

PFS: HR=0.53 OS: HR=0.37

9

MetMAb +erlotinib

2.9

20

0.53(0.28–0.99)

0.04

0.37(0.19–0.72)

0.002


Afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib.

• Background: T790M resistance common, combined afatinib+ cetuximab may overcome resistance

• Methods: 61 NSCLC with “acquired resistance” received oral afatinib 40 mg qd + biweekly cetuximab 250 or 500 mg/m2

• Results (of 55 evaluable): – 100% disease control w/500 mg/m2 dose: 51% PR– 11/35 PR in T790M+ pts– No dose-limiting toxicities, 8% Gr 3 rash

• Conclusions: Cetuximab/afatinib combination is tolerable with encouraging clinical activity- study expansion

• 1st documented activity in T790M population

Janjigian PASCO 2011, abstr 7525; Horn WCLC 2011, abstr O19.07

Tumor Regression by T790M Mutation Status

Horn WCLC 2011, abstr O19.07

60

40

20

0

–20

–40

–60

–80

–100

Progressive disease

Stable disease

Confirmed partial response

Confirmed complete response

Max

imum

cha

nge

in tu

mor

siz

e (%

)

–30%

Marked Activity of Crizotinib in Patients with Advanced, ALK-positive NSCLC (N=82)

Kwak et al. NEJM 2010;363:1693–703; Bang et al. JCO 2010;28:18S abstract 3

*

Impact of crizotinib on survival in patients with advanced, ALK+ NSCLC compared with historical controls

• 82 ALK+ patients enrolled phase 1 trial of crizotinib were compared to 37 ALK+ patients not treated with crizotinib (many of whom were not trial eligible which was confounder) and 252 ALK-/EGFR- patients

• Results:

OS in ALK+ patients treated with crizotinib did not differ with gender, ethnicity, smoking history, or age

• Conclusions: in patients with ALK+ NSCLC, crizotinib therapy resulted in a higher OS than that of crizotinib-naïve controls , but confounded by selection of control population

ALK+ Crizotinib-treated

ALK+ not treated with crizotinib ALK-/EGFR-

1-y OS 77% 73% 49%

2-y OS 64% 33% 33%

Median OS Not reached 20 mo Not reached

Shaw PASCO 2011 abstr 7507

An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC)

• 73 pts 2nd line+ NSCLC - ganetespib (200 mg/m2 qwk 3/4)

– Mutation status: group A=EGFR; group B=KRAS; group C=EGFR & KRAS wt

• Results: AEs reported in ≥20%

– diarrhea, fatigue, nausea, anorexia, constipation, and dyspnea (all generally grade 1-2)

• Group C: durable PR, and 7 SD; expansion continues

• Responses seen exclusively in ALK+ patients (all 4 PRs ALK+)• Disease stabilization noted in EGFR and KRAS mutated patients

Wong PASCO 2011 abstr#7500

Hsp90: Background

• Heat shock proteins represent 1-2% of all cellular proteins

• Facilitate protein-folding and stabilization

• Induced under stress, hypoxia and oxidative damage

Soti et al, J Biol Chem, 2002.Ramalingam discussion

http://www.jbc.org/content/277/9/7066/F10.large.jpg

Clinical Results: HSP90 Inhibition in ALK+ NSCLC

-60

-50

-40

-30

-20

-10

0

10

20

30

Res

pons

e(%

cha

nge

from

bas

elin

e)

Patients

IPI-504

STA-9090

N=11

*simulated waterfall plotbased on reported results

*Durability of responses not reported

Ramalingam discussion ASCO 2011

Hsp90 Inhibtion in ALK + NSCLC

• There is now clear evidence of robust anti-cancer effects with Hsp90 inhibitors in ALK+ NSCLC– Durability of responses is not established yet

• Next steps– Combination of Crizotinib with Hsp90 inhibitors– Hsp90 inhibition in Crizotinib-resistant ALK +NSCLC

Ramalingam discussion ASCO 2011

Targeted Therapy: Summary• The VEGFR-TKI inhibitors show promise, but not with

chemotherapy today, and not without biomarkers• Other angiogenesis approaches like Aflibercept and

ASA404 unfortunately negative to date• Driver mutations identified in >50% of adenocarcinomas• EGFR-TKI therapy is appropriate first-line therapy for pts

with known EGFR activating mutations• Strategies to overcome EGFR-TKI promising

– MetMab, Afatinib/cetuximab

• EML4-ALK fusion protein inhibitor crizotinib shows great promise in selected patients

• HSP90 inhibitors may overcome crizotinib resistance

Time Lag- Target Recognition to Drug Therapy

BCR-ABL 41 yrsBCR-ABL 41 yrs

EGFR 26 yrsEGFR 26 yrs

BRAF 8 yrsBRAF 8 yrs

ALK 3 yrs

ALK 3 yrs

1960 1978 1998 2001 2002

KIT 3 yrsKIT 3 yrs

2004 2010

Gerber and Minna Cancer Cell: 18: 548, 2010

2007

Govindan Discussion ASCO 2011



• CRA7510 - pemetrexed, LBA7511 – gefitinib





Lace Meta-analysis trials

NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; Lancet Onc 2006

Trial Stage n Chemo Survival

ALPI I-III 1209 Cis/MVd NoBLT I-III 381 Cis/4 options NoIALT I-III 1867 Cis/Vinca or VP16 Yes

NCIC IB-II 482 Cis/Vin Yes

ANITA I-IIIA 840 Cis/Vin Yes

NCCN Guidelines

• Adjuvant Chemotherapy, NSCL-D

• Includes 5 published cisplatin regimens– Cis 50 d 1,8 + vin 25 d 1, 8, 15, 22 q 28– Cis 100 d 1 + vin 30 d 1,8,15, 22 q 28 – Cis 75-80 d 1 + vin 25-30 day 1,8 q 21– Cis 100 d 1 + etop 100 day 1-3, q 28– Cis 80 d 1 + vinblastine 4 q wk - q 2 wk q 21

• Includes 3 other regimens – all cis 75 q 21– Gem 1250 d 1,8: Doce 75 d 1, Pem 500 d 1

M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N. M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N.

Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn,

T. Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas T. Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas

on behalf of the TREAT investigatorson behalf of the TREAT investigators

Kreuter PASCO abstr 7002

TREAT Design

Cisplatin / Vinorelbine (CVrb)

Cisplatin / Pemetrexed (CPx)

50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4

75 mg/m2 d1 / 500 mg/m2 d1 q d 22 x 4

R0Winton et al., N Engl J Med (2005) 352: 258

InclusionInclusion • NSCLC stages IB, IIA, IIB, T3N1M0

• ≤ 42 days postoperatively, R0, systematic LN-dissection

• ECOG 0, 1

• amenable to Cisplatin treatment

StratificationStratification • Center

• Nodal status (N0 versus N1)

• Surgical procedure (lobectomy versus pneumonectomy)

400 mg/m2 over 16 wks

300 mg/m2 over 12 wks

Kreuter PASCO 2011 abstr 7002

• CPx safe and feasible less toxicity compared to CVb; Gr 3/4 heme

• Very high dose delivery on cis/pem– 90% of cisplatin or 271 mg/m2 (mean)

• On cis/vin dose delivery lower– 66% of cisplatin still 263 mg/m2 (mean)

• Dose density improved with cis/pem

• CVb –Vb delivery d15, d22 difficult

• Efficacy: longer follow up to be awaited; but 38% stage IB and 45% squamous cell

TREAT Kreuter PASCO 2011 abstr 7002

Which Chemotherapy in the Adjuvant Setting?

• Metastatic disease:• Carboplatin/paclitaxel =

cisplatin/paclitaxel = cisplatin/docetaxel = cisplatin/gemcitabine

• Cisplatin/docetaxel > cisplatin/vinorelbine• Cisplatin/pemetrexed >

cisplatin/gemcitabine for non-squam histology

Schiller NEJM 346:92, 2002; Fossela JCO 21:3016, 2003; Scagliotti JCO 26:3543, 2008

Wakelee Discussion ASCO 2011

A simple proof in adjuvant chemotherapy

• So IF in metastatic disease:• Cis/Vin < Cis/Doce• Cis/Doce = Cis/Gem• Cis/Gem < Cis/Pem (non-squam)• Then: either cis/doce, cis/gem or

cis/pem (non-squam) > cis/vin for adjuvant therapy

• But this is BIOLOGY, not simple math

Wakelee Discussion ASCO 2011

ECOG 1505 Adjuvant Chemo +/- Bevacizumab

RANDOM IZE

ChemotherapyX 4 cyclesELIGIBLE:

N=1500

Resected IB-IIIA(1B 4cm)

Chemotherapyx 4 cycles +

BevacizumabX 1 year

* Investigator Choice : Cis/Vinorelbine, Cis/Docetaxel, Cis/Gem, Cis/Pem

Overall SurvivalPrimary Endpoint

Table 4: E1505 - PreliminaryChemotherapy Administered

Total Arm A Arm B (BEV)

Cisplatin + 636 320 316

Vinorelbine 170(27%) 82(26%) 88(28%)

Docetaxel 207(33%) 105(33%) 102(32%)

Gemcitabine 158(25%) 82(26%) 76(24%)

Pemetrexed* 99(16%) 50(16%) 49(16%)

*option only since 2009, non-squamous histology only

Wakelee abstr 7013, ASCO 2011

Interim E1505 Toxicity Differences

Arm A n=341Gr 3 /4

Arm B (Bev) n=329Gr 3/4

P value

Neutropenia 57(17%) / 69(21%) 68(21%)/ 76(24%) 0.05

Lymphopenia 3(0.9%)/0 10(3.1%)/1(0.3%) 0.03

Hypertension 7(2.1%) / 0(0%) 64(20.1%)/ 3(0.9%) <0.001

Proteinuria 2 (0.6%) / 0 8(2.5%) / 1 (0.3%) 0.03

Abdominal pain 1 (0.3%) / 0 12 (3.8%) / 2 (0.6%) <0.001

Hyponatremia 21(6.3%)/1(0.3%) 31(9.7%)/5(1.6%) 0.04

Hypoxia 1(0.3%)/0 6(1.9%)/0/1 gr 5 (0.3%) 0.03

Worst grade - any 130 (38%) / 95 (28%) 160 (50%) / 107 (34%) <0.001

Grade 5 8 (2.4%) 10 (3.1%) NS

Enrollment goal: 1500 pts w/ resected stage 1B-IIIA NSCLC; pts are randomized to chemo (cis+vin, doce, gem, or pem) alone or chemo+ bevacizumab

Wakelee PASCO 2011. Abstr #7013

Adjuvant Chemotherapy Choices

• Strongest evidence for adjuvant chemotherapy in NSCLC is w/ cis/vinorelbine

• TREAT-improved drug delivery/toxicity w/ cis/pem• Substitutions of other regimens common• Data on other regimens coming; E1505• The future will include more directed therapy

based on results of prospective biomarker driven adjuvant trials

• For now we all have to decide how much “proof” we need to use alternative regimens

Prospective Chemotherapy Biomarker Adjuvant Trials

Stage Therapy Marker

SWOG 0720

I (>2cm) +/- Chemotherapy

(Cis/Gem)

ERCC1

/RRM1

ITACA I-IIIA Cisplatin/Pemetrexed ERCC1/TS

TASTE I-IIIA Cisplatin / Erlotinib ERCC1/

EGFR mut

SCAT I-IIIA Platinum / Docetaxel BRCA1/ RAP80

RRMI > 40.5

AND

ERCC1> 66.0

Active Monitoring

All Others

(RRM1< 40.5 OR

ERCC1 < 66.0 )

Cisplatin-Gemcitabine

Assignment, stage I >2cm

S0720: Pharmacogenomic-directed Adjuvant Therapy of NSCLC

Primary Endpoint: Feasibility measured as % of patients in whom treatment assignment can be made (>75%=success)

Phase II Pharmacogenomics-Based Adjuvant Therapy Trial in Pts with Stage I NSCLC:S0720

Started Accrual April 2009. 85 pts enrolled. 83 eligible• Met Primary Endpoint of Feasibility • Expression analysis for all 83 eligible pts • 72/83 (87%) treatment assignment met requirements • Pre-specified target was at least 85%• 64/83 (77%) evaluated pts assigned to chemo (95% CI: 67%-86%) Expected: 70% • 14/64 pts (22%) declined treatment assignment

Zinner WCLC 2011

RRM1 and ERCC1 (AQUA) 64/83 (77%) eligible for chemor = 0.40 (p = 0.0002)

ERCC1 <65

RRM1 <40

S0720 Conclusions

Met Primary Endpoint of Feasibility• 72/83 (87%) treatment assignments met

requirements • 64/83 (77%) evaluated pts assigned to chemo• 14/64 pts (22%) declined treatment assignment

Biomarker• RRM1 and ERCC1 levels correlated with each

other• Neither correlated with gender, age, histology

Zinner WCLC 2011



• CRA7510 - pemetrexed, LBA7511 – gefitinib





Randomized Phase 3 Trial of Amrubicin versus Topotecan as Second-line

Treatment for Small Cell Lung Cancer (SCLC)

R. Jotte1, J. von Pawel,2 D.R. Spigel,3 M. Socinski,4 M.E.R. O’Brien,5 E. Paschold,6 J. Mezger,7 M. Steins,8 L. Bosquée9, J. Bubis,10 K. Nackaerts,11 J.M.

Trigo,12 P. Clingan,13 W. Schuette,14 P. Lorigan,15 M. Reck,16 M. Domine,17 F. Shepherd,18 R McNally,19 MF Renschler19

Jotte PASCO 2011, abstr 7000

Phase III 2nd-line SCLC: ACT-1

AMR IVAMR IV40 mg/m40 mg/m22 1x daily on 1x daily on d 1-3 q 3 w d 1-3 q 3 w

• Small Cell Lung Cancer (SCLC)Small Cell Lung Cancer (SCLC)

• Extensive or Limited DiseaseExtensive or Limited Disease

• Sensitive or refractory disease Sensitive or refractory disease (Progression ≥ 90 or <90 days after (Progression ≥ 90 or <90 days after completion of 1completion of 1stst line chemotherapy, line chemotherapy, Response to 1Response to 1stst line chemo) line chemo)

• 1 prior chemotherapy regimen1 prior chemotherapy regimen

• ECOG performance status 0-1ECOG performance status 0-1

• Stratified: Sensitive/Refractory; Stratified: Sensitive/Refractory; Extensive/LimitedExtensive/Limited

RRAANNDDOOMMIIZZEE

2 2 toto11

Topotecan IVTopotecan IV1.5 mg/m1.5 mg/m22 1x daily on1x daily on

d 1-5 q 3 w d 1-5 q 3 w

• Primary endpoint: Overall Survival• Secondary endpoints: ORR, PFS, TTP, quality of life, safety, sparse PK• Analyses: Interim (deaths = 294), Final (deaths = 490)


OS – ITT Population

AMR Topo HRP

Value*

N/Events 424/336 213/175

Median OS

(months)7.5 7.8 0.880 0.1701

95% CI 6.8 – 8.5 6.6– 8.50.733 – 1.057

* Unstratified log-rank testSur

viva

l Pro

bab

ility

Time (months)

AmrubicinTopotecan

# at risk343164

250122

10977

9443

5022

328

174

71

31

10

00

Amrubicin

Topotecan

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

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


Median OS in Sensitive and Refractory Patient Subgroups

Sur

viva

l Pro

bab

ility

Time (months)

Amrubicin

Topotecan

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 3 6 9 12 15 18 21 24 27

Sur

viva

l Pro

bab

ility

Time (months)

Amrubicin

Topotecan

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 3 6 9 12 15 18 21 24 27 30 33

AMR Topo HRP

Value*

N/events 199/168 96/86

OS (mo)

6.2 5.7 0.7660.0469

95% CI 5.5-6.7 4.1-7.00.589 – 0.997

* Unstratified log-rank test

Sensitive Patients

Refractory Patients

AMR Topo HRP

Value*

N/events 225/168 117/89

OS (mo)

9.2 9.9 0.9360.6164

95% CI 8.5-10.68.5-11.5

0.724 – 1.211


PFS – ITT Population

Amrubicin

N=424

Topotecan

N=213HR P Value*

N/ Events 424/367 213/167

Median PFS (months)

4.1 3.5 0.802 0.0182

95% CI 3.5– 4.3 2.9 – 4.20.667 – 0.965* Unstratified log-rank test

Sur

viva

l Pro

bab

ility

Time (months)

AmrubicinTopotecan

# at risk236102

10532

366

131

60

30

00

AmrubicinTopotecan

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21


Conclusions

• Primary endpoint of OS in ITT 7.5 mo Amrubicin vs. 7.8 mo topotecan, HR 0.880, p=0.1701

• All secondary endpoints favored Amrubicin– ORR (31.1 vs. 16.9%, p=0.0001)– PFS (median 4.1 mo vs. 3.5, HR 0.802, p=0.0182) – Enhanced symptom control and quality of life

• OS in refractory patients improved (6.2 mo Amrubicin vs. 5.7 mo topotecan, HR 0.766, p=0.0469)

• Safety profile of Amrubicin is acceptable– Increased infections; Fewer transfusions– No evidence of significant cumulative cardiotoxicity

Jotte PASCO 2011 abstr 7000

Negative trials in orphan diseases

• RPhII Carboplatin/etoposide +/- obatoclax– ES-SCLC; 165 pts– RR 65% vs 54%; PFS 6.0 vs 5.4 mo; OS 10.6 vs

9.9 mo all NS

• RPhIII maintenance thalidomide post chemo – Mesothelioma; 222 pts– PFS HR 1.0; OS HR 0.78 favor placebo

Langer PASCO 2011; abstr 7001Baas PASCO 2011; abstr 7006

Abstracts discussed• Metastatic NSCLC

– Maintenance• CRA7510 - pemetrexed, LBA7511 – gefitinib

• Continuation maintenance with pemetrexed promising; await survival results

• Switch maintenance gefitinib feasible

Abstracts discussed• Metastatic NSCLC- Targeted Therapy

– LBA7512- motesanib, 7502-vadimezan, CRA7506-driver mutations, 7503- EURTAC, 7505-MetMab, 750-crizotinib, 7500-ganetespib

• Chemo + motesanib, vadimezan, aflibercept – all negative trials

• Driver mutations found in >50% adenoCA• EGFR mut tumors do well with EGFR TKI 1st line• EGFR resistance better understood

– Promise w/MetMab and afatinib/cetuximab

• ALK resistance better understood - ?HSP 90

Abstracts discussed• Early Stage NSCLC

• 7002-TREAT, 7013-E1505

• Adjuvant chemotherapy substitutions with some data in support

• E1505 enrollment ongoing


• Small steps in small cell and mesothelioma– Hope for amrubicin in refractory SCLC pts

asco updates 2011 lung cancer heather wakelee, m.d. assistant professor of medicine,oncology...

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