Advanced Bladder Cancer: Check Mate or Check Point...

Advanced Bladder Cancer: Check Mate or Check Point Inhibitors

Daniel P Petrylak , MD Professor of Medicine and Urology

Director, GU Translational Working Group Co Director, Signal Transduction Program

Smilow Cancer Center, Yale University

Disclosure

•   Consultant: Sanofi Aventis, Celgene, Pfizer, Millineum, Dendreon, Johnson and Johnson, Bayer, Medivation, Roche/Genetech, Bellcium, Tyme

•   Research Support: Roche, Merck, Dendreon, Progenics, Lilly, Medivation, Agenysis, Astra Zenca, GSK, Bayer

•   Stock Tyme, Bellicum

Stromal PD-L1 modulation of T cells

Immune cell modulation of T cells

PD-L1/PD-1-mediated inhibition of

tumor cell killing

IFNg-mediated upregulation of

tumor PD-L1

Priming and activation of T cells

PD-L2-mediated inhibition of TH2 T cells

B7.1

Herbst RS et al. J Clin Oncol . 2013;31(suppl; abstr 3000)

Key Attributes of the Immune System •   Specificity •   Memory •   Adaptive

•   Cancer cells develop many mutations that can make them appear foreign to the immune system

•   T cells can recognize, attack and kill these “foreign” cancer cells

•   Cancer cells can evade immune attack by expressing PD-L1

•   Adaptive tumor expression of PD-L1 turns the immune system OFF

•   Clinically, we want to block PD-1 or PD-L1 to reactivate the immune system

•   PD-L1 plays an important role in dampening the anti-tumor immune response

Mechanism of Immune Checkpoint Inhibitors

Checkpoint Inhibitors Approved for Use in Urothelial Carcinoma

7 US FDA Approvals May 2016-May 2017 Setting Antibody Approval Status First-line (cisplatin-ineligible)

Atezolizumab   Accelerated approval granted in April 2017.

Pembrolizumab   Accelerated approval granted in May 2017.

Platinum-pretreated

Atezolizumab   Accelerated approval granted in May 2016.   In May 2017, the subsequent phase 3

IMvigor211 trial did not meet primary endpoint of overall survival.

Nivolumab   Accelerated approval granted in February 2017. Durvalumab   Accelerated approval granted in May 2017. Avelumab   Accelerated approval granted in May 2017. Pembrolizumab   Full approval granted in May 2017.

Approvals: First-line, Cisplatin-Ineligible

Atezolizumab Pembrolizumab

Apr 2017 May 2017

Above agents are indicated in patients with locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy.

IMvigor210 (Cohort 1)

Balar et al. Lancet. 2017;389:67

Key primary endpoint : •   Confirmed ORR: RECIST v1.1

(per central IRF)

Key secondary endpoints : •   DOR, PFS, OS, safety

Cohort 1 (N = 119): 1L cisplatin-ineligible

IMvigor210: •   Inoperable locally advanced

or metastatic urothelial carcinoma

•   Predominantly UC histology •   Tumor tissue evaluable for

PD-L1 testinga

Cohort 2 (N = 310): Platinum-treated mUC

Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression

Atezolizumab 1200 mg IV q3w until loss of clinical benefit

Cohort 1–specific inclusion criteria •  No prior treatment for mUC (>12 mo since perioperative chemo) •  ECOG PS 0-2 •  Cisplatin ineligibility1 based on ≥1 of the following: −  Renal impairment: GFR <60 and >30 mL/min −  Grade ≥2 hearing loss or peripheral neuropathy −  ECOG PS 2


Balar et al. Lancet. 2017;389:67

•   N = 119 •   ORR = 23% (9% CR) Overall Survival

Secondary Endpoints: DOR, PFS, OS, and ORR in all patients, PD-L1‒positive and PD-L1–high-expressing patients; safety and tolerability

Primary Endpoints: •  Planned interim analysis in first 100 patients

•   Determine the PD-L1–high expression cutpoint •  ORR in all patients and PD-L1‒positive population

Pembrolizumab 200 mg Q3W

Primary Endpoints •  ORR in all patients •  ORR in patients with PD-L1–positive tumors

Patients (N = 350) •  Advanced urothelial cancer •  No prior chemotherapy for metastatic disease •  ECOG PS 0-2 •  Ineligible for cisplatin based on ≥1 of the following:

–   CrCl <60 mL/min –   ECOG PS 2 –   Grade ≥2 neuropathy or

hearing loss –   NYHA class III CHF

KEYNOTE-052: Pembrolizumab as 1st-Line Therapy for Cisplatin-Ineligible Advanced

Urothelial Cancer

Balar et al. ESMO 2016; abstract LBA32_PR.

KEYNOTE-052 (ASCO17 Update)

O’Donnell et al. ASCO 2017; Abstract 4502.

N = 370 ORR: 29% CR: 7%

Approvals: Previously-treated Disease

Atezolizumab Nivolumab Durvalumab Avelumab Pembrolizumab

May 2016 Feb 2017 May 2017

Above agents are indicated in patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with (platinum-containing) chemotherapy.


Rosenberg et al. Lancet. 2016; 387:1909.

IMvigor210: •   Inoperable locally advanced

or metastatic urothelial carcinoma

•   Predominantly UC histology •   Tumor tissue evaluable for

PD-L1 testinga

Cohort 1 (N = 119): 1L cisplatin-ineligible

Cohort 2 (N = 310): Platinum-treated mUC

Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression

Atezolizumab 1200 mg IV q3w until loss of clinical benefit

Cohort 2-Specific Inclusion Criteria •  Progression during/following platinum (no restrictions on # prior lines of therapy) •  ECOG PS 0-1 •  CrCl ≥ 30 mL/min

Key primary endpoint : •  Confirmed ORR: RECIST v1.1 (per central IRF)

Key secondary endpoints : •  DOR, PFS, OS, safety


Rosenberg et al. Lancet. 2016; 387:1909.

All patients: •   ORR = 15% (5% CR) •   mOS = 7.9 months

Phase Ia Trial of Atezolizumab in Pretreated Bladder Cancer

Petrylak et al. ASCO 2015; Abstract 4501.

•   N = 92 •   72% with ≥2 prior

systemic therapies •   ORR 50% in PD-L1 high

(IC2/3) •   ORR 17% in PD-L1 low

(IC0/1)

OS by PD-L1 Status


Median Survival by Baseline Characteristics


Patterns of AE Occurrence


IMvigor211 Phase III Trial in Previously-treated Urothelial Cancer

•   Primary endpoint: OS in IHC 2/3à1/2/3àITT •   Secondary endpoints: PFS, ORR, DOR •   FPI: Q4 2014

Atezolizumab 1200 mg IV q3w

Patients with previously treated relapsed UBC

(n = 767 [230 PD-L1+])

Vinflunine, paclitaxel, or docetaxel IV q3w until progression

FPI=first patient in; ITT=intent-to-treat. http://www.clinicaltrials.gov/ct2/show/NCT02108652.

.

Key Eligibility Criteriaa

•  mUC with progression during or following platinum-based chemotherapy

–   ≤ 2 prior lines of therapy •  Measurable disease per RECIST v1.1 •  ECOG PS 0-1 •  Evaluable sample for PD-L1 testing •  TCC histology as primary component

(N = 931)

§ Primary endpoint –  OS, tested hierarchically

in pre-specified populations

20 Powles T, et al. EAS 2017, IMvigor211.

DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer; PRO, patient-reported outcome; q3w, every three weeks; RECIST, Response Evaluation Criteria In Solid Tumors; TCC, transitional cell carcinoma. a ClinicalTrials.gov, NCT02302807. b Defined by time from prior chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dL. c Confirmed response was not required for secondary efficacy endpoints. This analysis reports exploratory confirmed responses.

IMvigor211 Study Design 20

Atezolizumab 1200 mg q3w

R 1:1

No crossover permitted per protocol

Survival follow-up

Loss of clinical benefit

RECIST v1.1 progression

Stratification Factors •   No. of risk factorsb (0 vs. 1/2/3) •   Liver metastases (yes vs. no) •   PD-L1 status (0/1 vs. 2/3) •   Chemotherapy (vinflunine vs. taxanes)

§  Additional endpoints –   Efficacy: RECIST v1.1 ORR, PFS and DORc

–   Safety –   PROs: EORTC QLQ-C30

Chemotherapy (investigator’s choice)

•  Vinflunine q3w •  Docetaxel q3w •  Paclitaxel q3w

Key secondary endpoints: ORR, then PFS

Primary endpoint: OS

OS: IC2/3

OS: IC1/2/3

OS: ITT

PFS: IC2/3

PFS: IC1/2/3

PFS: ITT

ORR: IC2/3

ORR: IC1/2/3

ORR: ITT

2-sided = 0.05

21 Powles T, et al. EAS 2017, IMvigor211. HR, hazard ratio.

OS Analysis: IC2/3 Population

HR = 0.87 (95% CI: 0.63, 1.21) P = 0.41

Events/ Patients

Median OS (95% CI)

12-mo OS Rate (95% CI)

Atezolizumab 72/116 11.1 mo (8.6, 15.5) 46% (37, 56)

Chemotherapy 88/118 10.6 mo (8.4, 12.2) 41% (32, 50)

No. at Risk Atezolizumab 116 100 85 77 71 58 51 39 27 19 11 6 0

Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1

80

60

0

10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Sur

viva

l

100

Months


OS Analysis: IC1/2/3 Population

Events/ Patients

Median OS (95% CI)


Atezolizumab 220/316 8.9 mo (8.2, 10.9) 40% (35, 46)

Chemotherapy 232/309 8.2 mo (7.4, 9.5) 33% (28, 39)

HR = 0.87 (95% CI: 0.71, 1.05) P = 0.14


Chemotherapy 309 273 228 188 153 121 95 66 46 31 15 7 1

80

60

0

10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Sur

viva

l

100

Months

§ Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo) 23 Powles T, et al. EAS 2017, IMvigor211.

OS Analysis: ITT Population

Events/ Patients

Median OS (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) 80

60

0

10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Sur

viva

l

100

Months

80

60

0

10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Sur

viva

l

100

Months

HR = 0.85 (95% CI: 0.73, 0.99) P = 0.038


Chemotherapy 464 397 330 268 219 175 140 99 60 42 17 7 1

§ OS was also examined in subgroups based on chemotherapy type at randomization –   Improved OS was observed

with atezolizumab vs. taxanes


OS by Chemotherapy Type

ITT With Taxane


Taxane 214 179 147 122 94 74 58 35 20 16 4 3 1

80

60

0 10 12 14 16 18 20 2 4 6 8 0 24 22

20

40

Ove

rall

Sur

viva

l 100

Months

HR = 0.73 (95% CI: 0.58, 0.92) Subgroup

Median OS (95% CI)

Atezolizumab 8.3 mo (6.6, 9.8)

Taxane 7.5 mo (6.7, 8.6)

Open-label, single-arm, phase II study

aPatients were required to have an evaluable tumor tissue sample for PD-L1 expression testing at screening, but were not excluded based on PD-L1 status. bPatients could have been treated beyond progression under protocol-defined circumstances.

Treat until progressionb or

unacceptable toxicity

Nivolumab 3 mg/kg IV

Q2W

N = 270

Blinded independent review committee (BIRC) assessment of response using

RECIST v1.1

•  Metastatic or locally advanced mUC

•  Disease progression on a prior platinum-based therapy

•  Evaluable PD-L1 tumor tissue samplea

Treatment Patients

Adapted from Galsky et al. ESMO 2016.

CheckMate 275: Study Design

Sharma et al. Lancet Oncol. 2017;18:312-322.

CheckMate 275

ORR = 20% (2% CR)

Study 1108: Durvalumab Dose-escalation and Dose-expansion Study

Powles et al. ASCO GU 2017; Abstract 286.

Study 1108 (Durvalumab) – ASCO17 Update

Hahn et al. ASCO 2017; Abstract 4525.

All Patients (N = 191)

≥2nd-line (N = 182)

ORR CR

18% 4%

18% 3%

mOS 18.2 mo -

mPFS 1.5 mo -

DANUBE Phase 3 Study Design

Treatment-naïve patients •  Unresectable •  Stage IV (ie, T4b, any N; or any T, N2-N3; or M1) •  Transitional cell carcinomaa

Durvalumab + tremelimumab

N = 335

Follow-up for

OS

Objective disease

progression

Durvalumab monotherapy

N = 335

Standard of care

N = 335

Randomization N = 1005

aTransitional cell and mixed transitional/nontransitional cell histologies of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra). Powles T, et al. J Clin Oncol. 2016;34:(suppl; abstr TPS4574).

Phase Ib JAVELIN Solid Tumor Trial of Avelumab: Trial Schema

•   Open-label, multicenter phase Ib study in pts with confirmed solid tumors

§  Primary endpoint: ORR, safety

§  Secondary endpoints: PFS, OS, and association of PD-L1 expression on tumor cells with clinical activity of avelumab

Advanced UC Cohort: Pts with histology or cytology confirmed

metastatic UC after progression on or ineligible for platinum-based chemotherapy for metastatic

disease; ECOG PS 0-1 (N = 241)

Avelumab 10 mg/kg IV Q2W

Treated until PD, unacceptable AE, or investigator decision

Patel M, et al. ASCO GU 2017. Abstract 330.

Phase Ib JAVELIN Solid Tumor Trial of Avelumab (ASCO17 Update)

ORR in patients with ≥6 months follow-up (N = 161): 17% (6% CR)

Apolo, et al. ASCO17; Abstract 4528.

N = 242

mOS 7.4 mo

mPFS 1.5 mo (6.6 wk)

KEYNOTE-045: Phase III Study Design

CPS, combined positive score; PD, progressive disease. Bellmunt et al. SITC 2016; Abstract 02.

Bajorin et al. ASCO 2017, Abstract 4501.

Pembrolizumab Chemotherapy

ORR CR

21% 8%

11% 3%

Median OS HR P Value

Pembro 10.3 mo 0.70 .0004

Chemo 7.4 mo

Data cutoff: Jan 18, 2017 Median follow-up: 18.5 mo

Median PFS HR P Value

Pembro 2.1 mo 0.96 .32

Chemo 3.3 mo

Future Directions

Combinations Adjuvant therapy

Biomarkers

Addition of Ipilimumab to Nivolumab at

Progression •   10 patients who evidenced progression of

disease on nivolumab. •   1 PR, 4 SD after addition of ipilimumab. •   Modest increase in grade 3/4 toxicities.

Callahan et al. ASCO GU 2017; Abstract 384.

Epacadostat (IDO1 Inhibitor) + Pembrolizumab in Advanced UC (Phase 1/2 ECHO-202/KEYNOTE-037)

•   N = 40 •   Prior treatments for advanced disease:

–   0-1: 80% –   ≥2: 20%

Smith et al. ASCO 2017; Abstract 4503.

All Patients (N = 40)

0-1 Prior Lines

(n = 32)

≥2 Prior Lines (n = 8)

PD-L1 ≥1%

(n = 11)

PD-L1 <1%

(n = 8)

ORR 35% 38% 25% 64% 13%

CR 8% 9% 0 0 0

Grade 3/4 AEs N = 40

Rash 8%

Hyperglycemia 5%

Fatigue 3%

ALT increase 3%

Lipase increase 3%

Rationale for VEGF Blockade in Bladder Cancer

•   Antiangiogenic agents, particularly anti-VEGFR-2 monoclonal antibodies (MAbs), may be capable of acting as chemosensitizing agents when given in combination with docetaxel, since this effect was demonstrated in mice when an anti-VEGFR-2 MAb, DC101, was combined with paclitaxel.

•   Anti-VEGFR-1 MAbs may inhibit metastasis, based on the observed impact of the anti-VEGFR-1 MAb, MF1, on VEGFR-1-positive circulating hematopoietic progenitor cells in mice.

Binding of Ramucirumab to VEGFR-2 and Icrucumab to VEGFR-1 Inhibits Subsequent Signaling

Figure 2. Decreased Tumor Burden in Urothelial Carcinoma Patients (RECIST 1.1)

ITT Population Cohort D

N = 24 Objective response rate 3 (13)a

Disease control rateb 12 (50)

Median duration of response, mo (95% CI) NR (4.6-NR)

Median time to response, mo (95% CI) 2.8 ( 1.3-5.5)

Duration of stable disease 2.8 (1.9-NR) Best overall response, n (%) Complete response (CR) - Partial response (PR) 3 (13) Stable disease (SD) 9 (38) Progressive disease (PD) 11 (46) Not evaluable 1 (4)

aAll responders were PD-L1 positive. bPatients with best response of CR, PR, or SD. NR= not reached. Presented by Petrylak DP et al.

48% of evaluable patients experienced a decrease in target lesion

Ramucirumab + Docetaxel in Platinum-Pretreated, Advanced Bladder Cancer

(RANGE)

May 31, 2017: Primary endpoint of PFS met.

•   Primary endpoint: PFS •   Secondary endpoints: OS, ORR, DOR

Placebo + Docetaxel

•   Patients with locally advanced or unresectable or metastatic urothelial carcinoma progressing on or after platinum-based therapy

•   ≤1 prior chemotherapy for relapsed or metastatic disease

•   N=531

Ramucirumab + Docetaxel

ClinicalTrials.gov ID: NCT02426125.

Summary of Selected IO Combination Studies in Previously-treated Patients Sponsor/name Arms Line of therapy N Phase ClinicalTrials.gov

Identifier BMS CA209-032 Nivolumab +/- ipilimumab 2nd line 1150 I/II NCT01928394 NCI - Center for Cancer Research

Nivolumab +/- ipilimumab in combination with cabozantinib

2nd line 66 I/II NCT02496208

BMS CA224-020 Anti-LAG-3 With and Without nivolumab 2nd line 360 I NCT01968109

CDX1127-06 Combination of varlilumab (CDX1127) and atezolizumab

2nd line 55 I NCT02543645

CPI-444-001 CPI-444 +/- atezolizumab

2nd line 534 I NCT02655822

Plexxikon Combining a CSF1R, KIT, FLT3 Inhibitor (PLX3397) and pembrolizumab

2nd line 400 I/II NCT02452424

PsiOxus Therapeutics Enadenotucirev (oncolytic virus) +/- nivolumab 2nd line 30 I NCT02636036

UC Davis Pembrolizumab (MK3475) + docetaxel or gemcitabine in platinum pre-treated urothelial cancer

2nd line 38 I NCT02437370

Yale Ramucirumab, VEGFR2 inhibitor, + pembrolizumab 2nd line 155 I NCT02443324

USC Combination Therapy with pembrolizumab and sEphB4-HSA

2nd line 60 II NCT02717156

AstraZeneca Biomarker-driven treatment: combinations with durvalumab and inhibitors of FGFR, PARP, Wee1

2nd line/ 3rd line

110 I NCT02546661

•   What are the studies evaluating checkpoint inhibition therapy as adjuvant treatment post cystectomy? What is the optimal patient population?

NCI Trial - Pembrolizumab Eligibility •  Histologically confirmed UC •  Radical cystectomy, ureterectomy, and/or nephrectomy performed ≤ 16 wk prior to registration •  High-risk disease •  No invasive cancer at the surgical margins •  No evidence of residual cancer or metastasis after surgery •  No adjuvant systemic therapya

Stratification •   Site of disease: upper tract vs.

bladder cancer primary •   Neoadjuvant chemotherapy:

yes vs. no •   Pathologic Stage: pT2/3N0 vs

pT4N0/pTanyN1-3 •   PD-L1 status: positive vs.

negative

Endpoints Dual primary objectives To determine DFS and OS in patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant pembrolizumab vs. observation. Secondary endpoints •  OS and DFS in PD-L1 positive subjects and PD-L1 negative subjects •  To characterize the safety and tolerability of pembrolizumab when administered in the adjuvant setting

aPatients should be counseled appropriately and document refusal of cisplatin chemotherapy if eligible or be ineligible for cisplatin.

Phase III Randomized “Adjuvant study of peMBrolizumAb in muScle invaSive and locAlly aDvanced urOthelial carcinoma” (AMBASSADOR )

versus Observation

Pembrolizumab 200mg q3W

1 year

Observation q3W

RANDOMIZE

Eligibility §  MIBC or UTUC

§  h/o cystectomy or nephrectomy within 16 weeks

§  pT2-4aNx or pTxN+ post neoadjuvant chemotherapy OR pT3-4Nx or pN+ post surgery with no chemotherapy

DISEASE FREE S U R V I V A L

Stratify §  PDL1 +/-

§  Bladder vs upper-tract §  Neoadjuvant chemotherapy

yes/no §  Pathologic

stage: pT2/3/4aN0 vs pT4bNx orN1-3

1:1

OVERAL L S U R V I V A L

N = 739

Co-primary

Other Adjuvant Trials

Agent (Trial)

Phase N Setting Treatment Arms Primary Endpoint(s)

ClinicalTrials.gov ID

Atezolizumab (IMvigor010)

III 700 Post-resection, high riska

Atezolizumab vs observation

DFS NCT02450331

Nivolumab (CheckMate 274)

III 640 Post-resection, high riska

Nivolumab vs placebo

DFS NCT02632409

Durvalumab (DUART)

I/II 42 Locally advanced, unresectableb

Durvalumab + RT Safety, PFS, DCR

NCT02891161

aPatients who have not received prior neoadjuvant platinum-based chemotherapy may enroll if cisplatin ineligible. bCisplatin-ineligible patients may enroll.

Biomarkers •   In bladder cancer, PD-L1 staining appears to be

associated with higher response rate, and may be linked to overall survival;1 however, multiple assays exist and are under evaluation in bladder cancer.

•   Other biomarkers beyond PD-L1 are needed. –   Data in multiple cancer types suggests that mutation load is associated

with treatment outcome with immune checkpoint blockade.2,3 –   Gene expression subtypes may be predictive of ORR with

immunotherapy.4,5 1. Petrylak et al. ASCO 2015; Abstract 4501; 2. Snyder et al. N Engl J Med. 2014;371:2189-2199; 3. Rizvi et al. Science. 2015;348:124-128; 4. Rosenberg et al. ASCO 2016; Abstract 104; 5. Choi et al. Nat Rev Urol. 2014;11:400-410.

Examples of Different Staining Patterns and Antibodies

Massard C, et al. J Clin Oncol. 2016;34(26):3119-2125.

IC2/3

≥ 5%

IC1

≥ 1 but < 5%

IC0

< 1%

Rosenberg et al. ESMO 2016 Abstract

SP-142

SP263 22C3

c/o E. Plimack

Other Biomarkers Beyond PD-L1 IHC are Needed

•   Bladder cancer has high mutation burden, second only to lung cancer and melanoma1

•   Data in multiple cancer types suggests that mutation load is associated with treatment outcome with immune checkpoint blockade2,3

1.  Alexandrov LB, et al. Nature. 2013;500(7463):415-421. 2.  Snyder A, et al. N Engl J Med. 2014;371(23):2189-2199. 3.  Rizvi NA, et al. Science. 2015;348(6230):124-128.

II III Luminal Basal

IV All (n = 150)

Mut

atio

n Lo

ad/M

B

I 0

10 20

30

40

IC0/1 IC2/3

0

10 20

30

40

50

Mut

atio

n Lo

ad/M

B

Responder Non-responder

RECIST v1.1 response

Estimated Mutation Load Associated with Higher Objective Responses with Atezolizumab in

Platinum-pre-treated Patients

•  Estimated using a targeted panel •  Focuses on non-hotspot alterations •  Extrapolates from 3% of genome covered in assay

Rosenberg JE, et al. Lancet. 2016;387(10031):1909-1920.

Biomarkers Beyond PD-L1: Mutation Load is Associated with OS in

Patients Treated with Atezolizumab

•   Mutation load associated with ORR

•   Quartile-split mutation load was associated with OS in platinum-treated patients (cohort 2)

•   Similar results were seen for 1L cisplatin-ineligible patients (cohort 1)

–   In both cohorts, patients with the highest median mutation load (Q4) had significantly longer OS versus those in Q1-Q3a

Rosenberg JE, et al. Presented at: ASCO 2016; June 3-7, 2016; Chicago, IL. Abstract 104.

OS

Pro

babi

lity

100%

75%

50%

25%

0%

Days 0 100 200 300 400 500 600

Cohort 1 1L cisplatin-ineligible mUC

P = 0.0079a

Median load quartile (range)

Q4: ( > 13.5 to ≤ 46.8) Q3: ( > 9.0 to ≤ 13.5) Q2: ( > 5.4 to ≤ 9.0) Q1: (≥ 0 to ≤ 5.4)

OS

Pro

babi

lity

Days 0 100 200 300 400 500 600

100%

75%

50%

25%

0%

Cohort 2 Platinum-treated mUC

P = 0.0012a

Median load quartile (range)

Q4: ( > 16.0 to ≤ 62.2) Q3: ( > 8.1 to ≤ 16.0) Q2: ( > 5.4 to ≤ 8.1) Q1: (≥ 0.9 to ≤ 5.4)

Q4 Q4

Luminal

Basal

Urothelium

Biomarkers Beyond PD-L1: Expression Subtype Associated with ORR

•   Gene expression data used to classify IMvigor210 tumor samples recapitulated TCGA subtypes1,2

•   Responses occurred in all subtypes, but ORR was significantly higher in luminal II versus other subtypes (P=.0072)

•  What might be the drivers of this subtype-specific response?

1. Rosenberg JE, et al. J Clin Oncol. 2016;34(suppl):Abstract 104. 2. Choi W, et al. Nat Rev Urol. 2014;11(7):400-410.

•   TCGA, The Cancer Genome Atlas. Data cutoff: March 14, 2016. 1. Cancer Genome Atlas Research Network. Nature. 2014;507(7492):315-322. 2. Rosenberg JE, et al. Lancet. 2016;387(10031):1909-1920.

PD SD PR CR

RECIST v1.1 response

0

25

50

75

100

OR

R, %

I II III IV

n = 73 n = 52 n = 38 n = 36

Luminal Basal

•   Luminal I tumors have low Teff expression

•   Luminal II tumors have high Teff and low stromal gene expression

•   Basal tumors have high Teff and high stromal gene expression

Luminal

Basal

Urothelium

Luminal I: Immune desert

Luminal II: Inflamed

Basal: Immune suppressed

Increased responses

Biomarkers Beyond PD-L1

Rosenberg JE, et al. Presented at: ASCO 2016; June 3-7, 2016;

Chicago, IL. Abstract 104.

16.625.4

21.7

15.1

22.7

30.939.1

24.2

59.1

41.830.4

60.6

0%

25%

50%

75%

100%

Cluster 1 (Luminal 1) n=66

Cluster 2 (Luminal 2) n=55

Cluster 3 (Basal 1) n=23

Cluster 4 (Basal 2) n=33

P<0.001

CR/PR/SD PD

Response

2

1

0

-1

-2 Si

gnat

ure

scor

e

Signature score, 25-gene interferon-γ signature expression Basal 2 CR, 0%; luminal 1 CR,1.5%; luminal 2 CR, 1.8% Molecular Subtype

Complete Responsea

Partial Response

Stable Disease

Progressive Disease

8.7

Association Between UC Molecular Subtype, 25-gene Interferon-γ Signature, and Response to Nivolumab

•   Basal 1 and luminal 2 have higher response rates versus the other 2 subtypes •   Interferon-γ genes are enriched in responders/SD versus those with progressive disease (P<.01)

c/o Galsky, ESMO 2016

Luminal 2 (Cluster 2)

n=55

Basal 1 (Cluster 3)

n=23

Basal 2 (Cluster 4)

n=33

Luminal 1 (Cluster 1)

n=66

Enfortumab Vedotin: Proposed Mechanism of Action

Presented by: Daniel P. Petrylak

Enfortumab Vedotin is being co-developed by Seattle Genetics, Inc. and Astellas Pharma Inc.

Screening of Nectin-4 Expression in mUC

•   At screening, patients with mUC had samples that were centrally assessed by immunohistochemistry (IHC) for Nectin-4

–   Almost all patient (97%) samples showed Nectin-4 expression

–   Expression of Nectin-4 was high (median H-score 280 out of a 300 maximum score)

•   Due to the above findings, pre-screening for Nectin-4 is no longer an eligibility requirement for subjects with mUC


0

50

100

150

200

250

300

H-‐score

Pa+ents Gray bars indicate patients with Nectin-4 H-score <150 Blue bars indicate patients with H-scores of ≥150 Note: data cutoff November 2016, N=186

Maximum Reduction from Baseline in Total Tumor Burden in Patients with mUC on Enfortumab Vedotin


Investigator-Assessed Response in Patients with mUC on Enfortumab Vedotin


0.5 mg/kg (n=2)

0.75 mg/kg (n=12)

1.0 mg/kg (n=27)

1.25 mg/kg (n=30)

Total (N=71)a

CR, n (%) 0 0 2 (7) 1 (3) 3 (4)

PR, n (%) 1 (50) 4 (33) 6 (22) 15 (50) 26 (37)

SD, n (%) 1 (50) 6 (50) 9 (33) 6 (20) 22 (31)

PD, n (%) 0 2 (17) 6 (22) 6 (20) 14 (20)

NE, n (%) 0 0 4 (15) 2 (7) 6 (9)

ORRb (95% CI) (unconfirmed)

50 (1.3, 98.7)

33 (9.9, 65.1)

30 (13.8, 50.2)

53 (34.3, 71.7)

41 (29.3, 53.2)

DCRb (95% CI) 100

(15.8, 100) 83

(51.6, 97.9) 63

(42.4, 80.6) 73

(54.1, 87.7) 72

(59.9, 81.9)

Orange box indicates recommended phase 2 dose. CR, complete response; SD, stable disease; PR, partial response; DCR, disease control rate (DCR=CR+PR+SD); ORR (unconfirmed), overall response rate (ORR=CR+PR). aPatients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. b95% CI based on the Clopper-Pearson method.

Response in mUC Patients with Prior CPI, Taxane Treatment, or Liver Metastases on Enfortumab Vedotin


Prior CPI Treatmenta Prior Taxane Treatment Liver Metastases

1.25 mg/kg (n=17)

All Dosesb

(N=32) 1.25 mg/kg

(n=10) All Dosesb

(N=29) 1.25 mg/kg

(n=5) All Dosesb

(N=19)

CR, n (%) 0 1 (3) 1 (10) 1 (3) 0 1 (5)

PR, n (%) 8 (47) 13 (41) 5 (50) 11 (38) 3 (60) 8 (42)

SD, n (%) 5 (29) 9 (28) 0 (0) 8 (28) 1(20) 4 (21)

ORRc (95% CI)

(unconfirmed) 47

(23.0, 72.2) 44

(26.4, 62.3) 60

(26.2, 87.8) 41

(23.5, 61.1) 60

(14.7, 94.7) 47

(24.4, 71.1)

DCRc (95% CI) 77 (50.1, 93.2)

72 (53.3, 86.3)

60 (26.2, 87.8)

69 (49.2, 84.7)

80 (28.4, 99.5)

68 (43.4, 87.4)

Data cut-off date April 28, 2017. Data presented as n (%), unless otherwise indicated. CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); NE, not evaluable; PD, progressive disease; PR, partial response; ORR (unconfirmed), overall response rate (ORR=CR+PR); SD, stable disease. aNo patients with prior CPI treatment received 0.5 mg/kg enfortumab vedotin. bEvaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. cData presented as % (95% confidence interval [CI]); 95% CI based on the Clopper-Pearson method.

Conclusions

•   Checkpoint inhibition therapy demonstrates significant antitumor activity in advanced urothelial carcinoma: –   As initial therapy in cisplatin-ineligible patients. –   In patients with cisplatin-pretreated disease.

•   Trials are ongoing to explore immunotherapy-based combinations and the use of immunotherapy in earlier stages of disease.

•   A thorough understanding of the markers of resistance and response will help to designing future trials in earlier disease.

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