session 4 - oncologypro · session 4 systemic chemotherapy is not the standard of care in...

SESSION 4

Systemic chemotherapy is NOT the standard of care in

metastatic urothelial cancer

Aristotle Bamias

National & Kapodistrian University of Athens

DISCLOSURE OF INTEREST

Honoraria, Advisory, research funding

Pfizer, Roche, Novartis, BMS, AZ, Ipsen, MSD

WHAT MAKES A THERAPEUTIC OPTION “STANDARD”?

Efficacy

Tolerability

Optimization-patients’ selection

OUTLINE

Efficacy

Tolerability


Durable (?) Responses With Cisplatin-Based CT in UC

Slide credit: clinicaloptions.com

Cisplatin Eligible Cisplatin Ineligible

Gemcitabine + Cisplatin[1,2]

ORR: 49%

CR: 12%

Median OS: 14.0 mos

Dose Dense MVAC[3]

ORR: 72%

CR: 25%

Median OS: 15.1 mos

Gemcitabine + Carboplatin[4]

ORR: 36%

CR: 3%

Median OS: 9.3 mos

1. von der Maase H, et al. J Clin Oncol. 2005;23:4602-4608. 2. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077.

3. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54. 4. De Santis M, et al. J Clin Oncol. 2012;30:191-199.

Pro

po

rtio

n S

urv

ivin

g 1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84

Mos

Patients at Risk, n

203

202

118

125

50

62

36

40

30

34

23

29

7

9

0

1GC

MVAC

GC: median 14.0 mos (12.3-15.5 mos)

MVAC: median 15.2 mos (13.2-17.3 mos)

HR: 1.09 (0.88-1.34)

Log-rank P = .44, Walds P = .66

GC

MVAC

100

80

60

40

20

00 2 4 6 8 10 12

YrsPatients at Risk, nN

129

134

32

45

15

29

11

23

4

8

2

0

Median

5 yrs, %

(95% CI)

M-VAC

HD M-VAC

O

112

101

M-VAC

HD M-VAC

HD M-VAC

15.1 mos

21.8

(14.5-21.9)

M-VAC

14.9 mos

13.5

(7.4-19.6)

Log-rank P = .042

HR: 0.76 (95% CI: 0.58- 0.99)

100

80

60

40

20

00 1 2 3 4 5 6

Yrs

Patients at Risk, nN

119

119

37

44

13

15

7

5

3

2

1

2

M-CAVI

GC

O

108

110

Su

rviv

al

(%)

7

Log-rank test P = .64

M-CAVI

GC

1

1

First-line Therapy for Metastatic UC: Response


DD MVAC[1]

Cisplatin Eligible Cisplatin Ineligible

1. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54. 2. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077.

3. De Santis M, et al. J Clin Oncol. 2012;30:191-199. 4. Vuky J, et al. ASCO 2018. Abstract 4524.

5. Balar AV, et al. ASCO 2018. Abstract 4523.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PR

CR

Atezolizumab[5]Pembrolizumab[4]Gemcitabine +

Cisplatin[2]

Gemcitabine +

Carboplatin[3]

ATEZO VS. CHEMO

DoR

Atezolizumab

Chemotherapy

AND THE WINNER IS……..

ImVigor130 CheckMate901

Nivolumab 1 mg/kg + Chemotherapy

Q3W X 6 cycles

Frontline Checkpoint Inhibition in Cisplatin Ineligible UC:

Updates from Single-Arm Trials

Pembrolizumab (n = 370)

KEYNOTE-52[1]

Atezolizumab (n = 119)

IMvigor 210 Cohort 1[2]

Median follow up, mos 11.5 29

ORR, % 29 24

Median OS, mos 11.5 16.3

12 month OS, % 48 58

Pembrolizumab OS Atezolizumab OS100

80

60

40

20

00 4 8 12 16 20 24

MosPatients at Risk, n

370

28 32

283 223 173 147 86 38 11 11

OS

(%

)

100

80

60

40

20

00 4 8 12 16 20 24

MosPatients at Risk, n

370

28 32

283 223 173 147 86 38 11 11

OS

(%

)

36

1-yr OS: 58% (95% CI: 49-67)

2-yr OS: 41% (95% CI: 32-50)

Median OS: 16.3 mo (95% CI: 10.4-24.5)

1. Vuky J, et al. ASCO 2018. Abstract 4524. 2. Balar AV, et al. ASCO 2018. Abstract 4523.

Carbo/Gem1 MCAVI1 VFL/Gem2* VFL/Carbo2* Pembro3 Atezolizumab4

n 89 89 34 35 374 119

PS 2 44% 45% 0% 0% 42% 20%

Visceral 46% 55% 53% 46% 85% 66%

RR 38% 20% 44% 28% 24% 23%

CR 3% 3% 6% 11% 6% 9%

mOS 9.3 8.1 14 12.8 11.5 16.3 mos

INELIGIBLE-FOR-CISPLATIN ADVANCED UROTHELIAL CANCER PATIENTS

1. De Santis et al. J Clin Oncol 2009; 2 De Santis et al Ann Oncol 2016; 3. Balar et al. lancet Oncol 2017; 4. Balar et al. Lancet 2017

14.3-15.1

FDA-Approved Checkpoint Inhibitors for 1st-line UC

1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017.

3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018.

5. Pembrolizumab [package insert]. June 2018.


Agent Target Schedule FDA Approval Type by Setting

Post-Platinum Frontline Cisplatin Ineligible

Atezolizumab[1] PD-L1 Q3W Accelerated Accelerated

Avelumab[2] PD-L1 Q2W Accelerated --

Durvalumab[3] PD-L1 Q2W Accelerated --

Nivolumab[4] PD-1 Q4W Accelerated --

Pembrolizumab[5] PD-1 Q3W Level 1 Accelerated

Overall survival: Total

Median (95% CI)

Events HR (95% CI) p

Pembro 155 0.73 (0.59-0.91) 0.0022

Chemo 179

Bellmunt et al. New Engl J Med 2017

OS Analysis in ITT Population

Reprinted from The Lancet, Powles T,

et al. 2017 Dec 18. [Epub], © 2017,

with permission from Elsevier

OS: IC2/3

OS: IC1/2/3

OS: ITT

Events/

PatientsMedian OS

(95% CI)

12-mo OS Rate(95% CI)

Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44)

Chemotherapy 350/464 8.0 mo (7.2, 8.6) 32% (28, 37)

Post-Platinum UC

OS at 12 Mos


CT: ~

26%

Atezolizumab[1]

OS

(%

, 9

5%

CI)

39.2 54.3 46.6 40.3 43.90

10

20

30

40

50

60

70

Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]

1. Powles T, et al. Lancet. 2017 2. Patel M, et al. Lancet Oncol 2018 3. Powles T, et al. JAMA Oncol 2017 4. Sharma P, et al. Lancet Oncol. 2017 5. Bellmunt J, et al. N Engl J Med. 2017

FDA-Approved Checkpoint Inhibitors for relapsed

mUC

1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017.

3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018.

5. Pembrolizumab [package insert]. June 2018.


Agent Target Schedule FDA Approval Type by Setting

Post-Platinum Frontline Cisplatin Ineligible

Atezolizumab[1] PD-L1 Q3W Accelerated Accelerated

Avelumab[2] PD-L1 Q2W Accelerated --

Durvalumab[3] PD-L1 Q2W Accelerated --

Nivolumab[4] PD-1 Q4W Accelerated --

Pembrolizumab[5] PD-1 Q3W Level 1

OUTLINE

Efficacy

Tolerability


PEMBRO VS. CHEMO

ATEZO VS. CHEMOAtezolizumab Chemotherapy

OUTLINE

Efficacy

Tolerability


Phase I Data: Assays for Measurement of PD-L1 Expression in Advanced Urothelial Cancer

1. Petrylak DP, et al. J Clin Oncol. 2015;33(suppl): Abstract 4501. 2. Sharma P, et al. J Clin Oncol. 2016;34(suppl): Abstract 4501. 3. Plimack ER, et al. J Clin Oncol. 2015;33(suppl): Abstract 4502. 4. Massard C, et al. J Clin

Oncol. 2016;34(suppl): Abstract 4502. 5. Apolo AB, et al. J Clin Oncol. 2016;34(suppl): Abstract 4514.

Atezolizumab1 Nivolumab2 Pembrolizumab3 Durvalumab4 Avelumab5

Detection antibody SP142 28-8 22C3 SP263 73-10

IHC platform Ventana Dako Dako Ventana Dako

Cell types scored for urothelial cancer

IC TC TC IC and TC IC and TC

Cut-off definitions for

urothelial cancer

PD-L1+ (IHC 2/3) as ≥5% of ICs PD-L1+

PD-L1+ ≥1% TC expression

PD-L1+ ≥1% TC stainingPD-L1+ as ≥25% of ICs and TCs with membrane

PD-L1 staining

PD-L1+ as ≥5% TC staining or ≥10% IC

staining

Estimated PD-L1 prevalence

in urothelial cancer trials

PD-L1+ ORR(phase I trials)

~37%2 ~62%3 ~65%4 ~36%5~32%1

0

50

100

OR

R (

%)

DX+1 DX+2 DX+3 DX+4 DX+5

50.0 24.0 29.0 46.0 53.8

FDA and EMA warn of decreased survival with first-line atezolizumab or pembrolizumab in

cisplatin-ineligible patients with low PD-L1, as assessed by an appropriate companion

diagnostic test

Checkpoint inhibition in the context of the cancer immunity cycle

Trafficking

Antigen presentation

Infiltration

Antigen release

DC maturation

Migration to lymph node

IL-12

Costimulation

T cell activation & proliferation

Elimination

Peptide

MHC-I

T cell with specific TCR

Recognition

Antigen release


Infiltration

Elimination

ImmuneCheckpoints

CTLA-4

PD-L1

PD-L1

PD-1

One has to determine the interruption point

Combination therapy

Cancer immunophenotypes

IMvigor210: TCGA Subtype in mUC

Response by TCGA Molecular Subtype

1. Balar AV et al. Lancet 2017; 389:67-76. 2. Rosenberg JE, et al. Lancet. 2016;387(10031):1909-1920.

Atezolizumab 2nd-line2Atezolizumab 1st-line1

Response by TCGA Molecular Subtype

1.Sharma P, et al. Lancet Oncol. 2017;18(3):312-322.

Nivolumab 2nd-line1

BLC2001: Antitumor Activity

� Tumor shrinkage observed in 76% of evaluable patients receiving erdafitinib 8 mg QD

� Reponses were durable

Siefker-Radtke AO, et al. ASCO 2018. Abstract 4503. Slide credit: clinicaloptions.com

Response,*† n (%) Patients (N = 99)

ORR

� CR

� PR

40 (40.4)

3 (3.0)

37 (37.4)

SD 39 (39.4)

PD 18 (18.2)

Median TTR, mos 1.4

Median DoR, mos 5.6

Response, %

Patient Subgroups

CT Naive

(n = 12)

PD/Relapse After CT

(n = 87)

Visceral Mets

(n = 78)

No Visceral Mets

(n = 21)

Prior IO

(n = 22)

ORR to erdafitinib 41.7 40.2 38.5 47.6 59.0

ORR to prior IO -- -- -- -- 5

*Investigator-assessed response confirmed with second scan ≥ 6 wks

after first observation of response. †Response unknown, n = 2.

3 cancer immunophenotypes

Trafficking

Antigen presentation

Infiltration

Antigen release

DC maturation

Migration to lymph node

IL-12

Costimulation


Elimination

Peptide

MHC-I

T cell with specific TCR

Recognition

Antigen release


Infiltration

Elimination

IMMUNE EXCLUDED

INFLAMED

IMMUNE DESERT

Combinationwith chemo?

� Immunotherapy is the new standard in metastatic urothelial cancer

� If chemotherapy remains a standard, it will be with immunotherapy

CONCLUSIONS

session 4 - oncologypro · session 4 systemic chemotherapy is not the standard of care in...

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