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
IMvigor210 (Cohort 1)
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.
IMvigor210 (Cohort 2)
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
IMvigor210 (Cohort 2)
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
Petrylak et al. ASCO 2015; Abstract 4501.
Median Survival by Baseline Characteristics
Petrylak et al. ASCO 2015; Abstract 4501.
Patterns of AE Occurrence
Petrylak et al. ASCO 2015; Abstract 4501.
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
22 Powles T, et al. EAS 2017, IMvigor211.
OS Analysis: IC1/2/3 Population
Events/ Patients
Median OS (95% CI)
12-mo OS Rate (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
No. at Risk Atezolizumab 316 274 232 198 175 141 122 97 64 41 23 9 1
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)
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) 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
No. at Risk Atezolizumab 467 405 327 280 245 201 177 138 90 59 34 13 1
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
24 Powles T, et al. EAS 2017, IMvigor211.
OS by Chemotherapy Type
ITT With Taxane
No. at Risk Atezolizumab 215 186 153 125 106 89 81 66 45 34 19 7 0
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
Presented by: Daniel P. Petrylak
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
Presented by: Daniel P. Petrylak
Investigator-Assessed Response in Patients with mUC on Enfortumab Vedotin
Presented by: Daniel P. Petrylak
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
Presented by: Daniel P. Petrylak
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.
Response in mUC Patients with Prior CPI, Taxane Treatment, or Liver Metastases on Enfortumab Vedotin
Presented by: Daniel P. Petrylak
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.
Response in mUC Patients with Prior CPI, Taxane Treatment, or Liver Metastases on Enfortumab Vedotin
Presented by: Daniel P. Petrylak
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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