A Giant Leap in the Treatment Options for Advanced Bladder Cancer

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1 A Giant Leap in the Treatment Options for Advanced Bladder Cancer Yohann Loriot, MD, PhD Department of Cancer Medicine & INSERM U981 Gustave Roussy Villejuif, France

2 Clinical Features of Bladder Cancer Risk factors Smoking +++ Aniline and hydrocarbons Treatment-induced (alkylants, radiation) Age: 70% of patients >65 years old Often have smoking-induced comorbidities Moderate renal failure frequently found in patients Poor health status in metastatic setting Patients classified as fit or unfit 1 1. Galsky MD, et al. Lancet Oncol. 2011;12(3):

3 Overall survival (probability) Cisplatin/Gemcitabine Efficacy in Metastatic Disease Trial/Analysis N ORR (%) Median PFS, Months Median OS, Months Phase III study of classic MVAC vs cisplatin/gemcitabine 405 Classic MVAC: 46 Cisplatin/gemcitabine: 49 HR=0.97 (95% CI: ) P =.51 Classic MVAC: 8.3 Cisplatin/gemcitabine: 7.7 HR=1.09 (95% CI: ) P =.63 Classic MVAC: 15.2 Cisplatin/gemcitabine: 14.0 HR=1.09 (95% CI: ) P = GC MVAC Median OS months with GC vs 15.2 months with MVAC HR=1.09 (log rank P =.44) Time (months) GC, gemictabine/cisplatin; MVAC, methotrexate/vinblastine/doxorubicin/cisplatin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival von der Maase H, et al. J Clin Oncol. 2000;18(17): von der Maase H, et al. J Clin Oncol. 2005;23(21):

4 Consensus Definition of Patients With Metastatic Urothelial Carcinoma Who are Unfit for Cisplatin-Based Chemotherapy Patients meeting at least one of the following are considered unfit WHO or ECOG performance status of 2, or Karnofsky performance status of 60%-70% Creatinine clearance (calculated or measured) less than 1 ml/s CTCAE version 4, grade 2 or above audiometric hearing loss CTCAE version 4, grade 2 or above peripheral neuropathy NYHA class III heart failure 30%-50% of metastatic patients are ineligible ( unfit ) for cisplatin CTCAE, Common Terminology Criteria for Adverse Events; ECOG, Eastern Cooperative Oncology Group; NYHA, New York Heart Association; WHO, World Health Organization Galsky MD, et al. Lancet Oncol. 2011;12(3):

5 EORTC 30986: Gemcitabine/Carboplatin vs M-CAVI in Cisplatin-Ineligible (Unfit) Urothelial Cancer Trial/Analysis N ORR, % Median OS, Months Median PFS, Months Phase III study of gemcitabine/carboplatin vs M-CAVI 626 Gemcitabine/carboplatin: 41.2 M-CAVI: 30.3 P =.08 Gemcitabine/carboplatin: 9.3 M-CAVI: 8.1 HR=0.94 (95% CI: ) P =.64 Gemcitabine/carboplatin: 5.8 M-CAVI: 4.2 HR=1.04 (95% CI: ) P =.78 EORTC, European Organisation for the Research and Treatment of Cancer; M-CAVI, methotrexate/carboplatin/vinblastine De Santis M, et al. J Clin Oncol. 2012;30(2):

6 Metastatic Disease: OS Rates for Patients Receiving Second-Line Vinflunine OS in the ITT population OS in the eligible population* Median OS (ITT) 6.9 months with VFL + BSC (n=253) versus 4.6 months with BSC (n=117) HR=0.88 (log rank P =.2613) Median OS (eligible) 6.9 months with VFL + BSC (n=249) versus 4.3 months with BSC (n=108) HR=0.78 (log rank P =.0227) *The eligible population excludes 13 patients who presented at least one major protocol violation at baseline Bellmunt J, et al. Ann Oncol. 2013;24(6):

7 Powles T, et al. Nature. 2014;515(7528):

8 IMvigor 210: Study Design Locally advanced or metastatic cancer of the bladder, renal pelvis, ureter, or urethra Predominant transitional cell histology Tumor tissue evaluable for PD-L1 testing No autoimmune disease or corticosteroid use Cohort 2 specific criteria: Progression during or following platinum (no restriction on number of prior lines of therapy) Creatinine clearance 30 ml/min ECOG PS 0-1 Cohort 1 (N 100): First-line cisplatin ineligible Cohort 2 (N 300): Disease progression during or following 1 platinumcontaining regimen Atezolizumab 1200 mg IV q 3 w Treatment until loss of clinical benefit (Cohort 2) Response assessment q 9 w (q 12 w after 54 w) Hypothesis: Response rate >10% (historical response rate in 2L) PS, performance status Rosenberg JE, et al. Lancet. 2016;387(10031):

9 What is the Response Rate? IC0 Group IC2/3 Group Response rate in unselected population: 15% PD-L1 expression on immune cells is associated with response But PD-L1 expression is not discriminant enough in advanced metastatic UBC UBC, urothelial bladder cancer Rosenberg JE, et al. Lancet. 2016;387(10031):

10 Is There Any Survival Improvement? The responses are durable Rosenberg JE, et al. Lancet. 2016;387(10031):

11 PD-1/PD-L1 Race Atezolizumab PD-L1 Phase III Durvalumab PD-L1 Phase I Avelumab PD-L1 Phase I Pembrolizumab PD-1 Phase III Nivolumab PD-1 Phase II

12 Patients With CR or PR at Best Response OS SLD Change From PD (%) 100 Similar Efficacy Plots for all of Them Atezolizumab Time Time Time CR, complete response; PD, progressive disease; PR, partial response; SLD, sum of the longest diameters Loriot Y. Unpublished data

13 Patients With CR or PR at Best Response OS SLD Change From PD (%) Similar Efficacy Plots for all of Them Durvalumab Time Time Time Loriot Y. Unpublished data

14 Patients With CR or PR at Best Response OS SLD Change From PD (%) Similar Efficacy Plots for all of Them Nivolumab Time Time Time Loriot Y. Unpublished data

15 Phase Where Are We? Atezolizumab Nivolumab Pembrolizumab Avelumab Durvalumab Phase III randomized trial Phase II single arm Phase III randomized trial Phase Ib Phase I/II Number of patients (153 patients 6 month follow-up 191 (103 eligible for efficacy analysis) Dosing 1200 mg q 3 w 3 mg/kg q 2 w 200 mg q 3 w 100 mg/kg q 2 w 10 mg/kg q 2 w ORR (ITT) 13.4% 19.6% 21.1% 17.6% 20.4% Duration of response 63% of responses ongoing at median follow-up of 17.3 months 77% of responses ongoing at median follow-up of 7 months 72% of responses ongoing at median follow-up of 14.1 months 89% of responses ongoing at median follow-up of 7.3 months 81% of responses lasting 6 months Median OS 8.6 months (ITT) 8.7 months 10.3 months Not reached (6-month OS = 54.5%) 14.1 months Median PFS 2.1 months 2.0 months 2.1 months 1.5 months 2.2 months Rate of grade 3/4 treatment-related AEs 20% 18% 13.5% (15% G3-5) 7.5% 6.8% AE, adverse event Powles T, et al. Abstract presented at: EACR-AACR-SIC Special Conference 2017; June 24-27, 2017: Florence, Italy. Abstract 606. Sharma P, et al. Lancet Oncol. 2017;18(3): Bellmunt J, et al. N Engl J Med. 2017;376(11): National Institutes of Health. Accessed November 23, Powles T, et al. J Clin Oncol. 2017;suppl 6S(35):Abstract 286.

16 KEYNOTE-045: Study Design DOR, duration of response; RECIST, Response Evaluation Criteria in Solid Tumors Bellmunt J, et al. N Engl J Med. 2017;376(11):

17 KEYNOTE-045: Baseline Characteristics Bellmunt J, et al. N Engl J Med. 2017;376(11):

18 KEYNOTE-045: Overall Survival Bellmunt J, et al. Presented at: SITC 2016; November 9-13, 2016: National Harbor, Maryland, United States. Abstract 470.

19 KEYNOTE-045: Response Rate Bellmunt J, et al. Presented at: SITC 2016; November 9-13, 2016: National Harbor, Maryland, United States. Abstract 470.

20 KEYNOTE-045: Treatment-Related Adverse Events Bellmunt J, et al. N Engl J Med. 2017;376(11):

21 IMvigor211: Atezolizumab vs Chemotherapy for Post-Platinum Advanced UC An open-label, 2-arm, randomized phase III trial Patients with metastatic or locally advanced UC after recurrence or progression following platinum-based chemotherapy; ECOG PS 0-1; evaluable tumor tissue for PD-L1 testing (N = 932) Atezolizumab 1200 mg q 3 w Investigator s Choice Paclitaxel 175 mg/m 2 q 3 w or Docetaxel 75 mg/m 2 q 3 w or Vinflunine 320 mg/m 2 q 3 w Treated until PD, unacceptable AE, or investigator decision Treated until PD or unacceptable AE Primary endpoints: OS Secondary endpoints: ORR, PFS, safety, pharmacokinetics UC, urothelial cancer National Institutes of Health. NCT Accessed November 23, 2017.

22 IMvigor211: Overall Survival for IC2/3 Population Events / Patients Median OS (95% CI) 12-Month OS Rate (95% CI) Atezolizumab 72/ months (8.6, 15.5) 46% (37, 56) Chemotherapy 88/ months (8.4, 12.2) 41% (32,50) IC, immune cell Powles T, et al. Abstract presented at: EACR-AACR-SIC Special Conference 2017; June 24-27, 2017: Florence, Italy. Abstract 606.

23 IMvigor211: Overall Survival for ITT Population Events / Patients Median OS (95% CI) 12-Month OS Rate (95% CI) Atezolizumab 324/ months (7.8, 9.6) 39% (35,44) Chemotherapy 350/ months (7.2, 8.6) 32% (28, 37) Median follow-up duration in ITT population: 17.3 months (range, 0 to 24.5 months) Powles T, et al. Abstract presented at: EACR-AACR-SIC Special Conference 2017; June 24-27, 2017: Florence, Italy. Abstract 606.

24 IMvigor211: Safety Summary AE, n(%) Atezolizumab (N = 459) All Cause Chemo (N = 443) Atezolizumab (N = 459) Treatment-Related Chemo (N = 443) All Grade AEs 438 (95%) 435 (98%) 319 (70%) 395 (89%) Grade 3 or 4 AEs 233 (51%) 249 (56%) 91 (20%) 189 (43%) Grade 5 AEs 17 (4%) 18 (4%) 1 (1%) 8 (2%) All Grade AESIs 139 (30%) 98 (22%) - - Grade 3 or 4 AESIs 37 (8%) 13 (3%) - - Grade 5 AESIs 0 1 (<1%) - - SAEs 188 (41%) 191 (43%) 72 (16%) 110 (25%) AEs leading to treatment disc 34 (7%) 78 (18%) 16 (3%) 63 (14%) AEs leading to dose modification, delay, or intertuption 134 (29%) 210 (47%) - - Rates of treatment-related AEs and AEs leading to discontinuation (any cause) were numerically lower in the atezolizumab arm AESI, adverse event of special interest; SAE, serious adverse event Powles T, et al. Abstract presented at: EACR-AACR-SIC Special Conference 2017; June 24-27, 2017: Florence, Italy. Abstract 606.

25 Open Questions How to identify responders? How to identify superprogressors? When should we treat patients? How long should we treat patients? How should we give ICI for frail patients? How to explain resistance and to overcome resistance? ICI, immune checkpoint inhibitor

26 Biomarker Assay Endpoint Drug Results IHC dako kit (22C3 clone) IHC Ventana (SP263) PD-L1 on IC Key Biomarkers Currently Assessed in UC to Predict Response to PD-1 or PD-L1 Blockade 1% of cell stained 25% of cell stained Pembrolizumab Durvalumab Higher expression associated with response Higher expression associated with response PD-L1 on TC IHC dako kit (22C3 clone) IHC dako kit (28-8) IHC Ventana (SP263) 1% of cell stained 1% vs 5% of cell stained 25% of cell stained Pembrolizumab Nivolumab durvalumab Higher expression associated with response Higher expression associated with response Higher expression associated with response T CD8 infiltration IHC Atezolizumab High T CD8 infiltration associated with response CD8 expression Gene expression High vs low Nivolumab High CD8 expression associated with response CXCL9 / CXCL10 expression Gene expression High vs low Nivolumab High expression associated with response Mutational load Exome sequencing Number of mutations/megabase Atezolizumab High mutation load associated with response TCGA classification Gene expression Luminal vs basal Atezolizumab Nivolumab Luminal 2 associated with better response to atezolizumab Basal 1 associated with better response to nivolumab INF-ɣ signature 25 gene expression High vs low Nivolumab Better response to nivolumab TCR sequencing DNA sequencing of the CDR3 region of the TCR beta chain Clonal dominance, clonal expansion and T-cell fraction Atezolizumab high T cell infiltration and clonality in the tumor plus peripheral expansion of dominant tumor-resident TCR clones associated with response No biomarker validated so far

27 Future Strategies for Immunotherapy Targeting several immune checkpoints Enhancing neoantigen expression Combination with targeted therapies, chemo, or IR Targeting T-cell metabolism and microenvironnement Reprogramming host microbiome Use earlier IR, ionizing radiation

28 Phase I/II Ongoing Second-Line Trials D4190C00010 (NCT ) Progression or recurrence of urothelial cancer following a first-line platinumcontaining regimen N = 167 Primary endpoints: Safety; Secondary Endpoints: ORR, PFS, DOR, and OS Durvalumab + tremelimumab STRONG (NCT ) Progression or recurrence of urothelial cancer following At least one first-line platinum-containing regimen Urothelial and non-urothelial N = 1200 R Durvalumab Durvalumab + tremelimumab Primary endpoint: Safety; Secondary endpoint: OS BISCAY (NCT ) Progression or recurrence of urothelial cancer following a firstline platinum-containing regimen PD-1 and PD-L1 naive N = 110 Somatic DNA Sequence R Control FGFR3 mut DDR+ Durvalumab Durvalumab + AZD4547 Durvalumab + olaparib Primary endpoints: Safety; secondary endpoints ORR and PFS

29 Phase I/II Ongoing Second-Line Trials CHECKMATE-032 (NCT ) 1 Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen N = 196 Primary endpoint: ORR; secondary endpoints PFS and safety SAUL Study Design (NCT ) DANUBE (NCT ) Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen No more than 2 prior lines of systemic chemotherapy N = 1000 R R n = 78 n = 26 n = 104 Nivolumab 3 mg/kg Nivolumab 1 mg/kg Ipilimumab 3 mg/kg Nivolumab 3 mg/kg Ipilimumab 1 mg/kg Atezolizumab Estimated timelines Estimated completion: May 2022 ORR = 26.5% ORR = 38.5% mpfs = 4.3m mos = 10.2m ORR = 26% mpfs = 2.6m mos = 7.3 Primary endpoint: Safety; secondary endpoints: ORR, OS, PFS, and quality of life MK (NCT ) Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen PD-1 and PD-L1 naive N = 1200 R Pembrolizumab Pembrolizumab + epacadostat Primary endpoint: OS; Secondary endpoints: PFS and safety 1. Sharma P, et al. Presented at: SITC 2016; November 9-13, 2016: National Harbor, Maryland, United States. Abstract 449.

30 Current / Future Clinical Trials in UC NMIBC MIBC Metastatic UC 1 ère ligne Low Grade High Grade neoadjuvant Adjuvant fit unfit BCG refractory DANUBE (durvalumab, tremelimumab) MK (pembrolizumab) IMVIGOR 130 (atezolizumab CA (nivolumab, ipilimumab) Pembro + Epacadostat (KN672, phase III) Maintenance Avelumab (JAVELIN, phase III) 2 nde line Platinum-resistant Pembrolizumab (KEYNOTE 045, Phase III) Atezolizumab (IMVIGOR 211, Phase III) Pembrolizumab + Epacadostat (phase III)

31 A New Standard in First-Line? Imvigor 210: Overall Survival Investigator-Assessed Objective Response Rates Balar AV, et al. Lancet. 2017;389(10064):67-76.

32 KEYNOTE-052: Pembrolizumab as First-Line Patients (N = 370) Locally advanced/muc No prior chemotherapy ECOG PS 0-2 Ineligible for cisplatinbased chemotherapy: - CrCI <60 ml/min - ECOG PS 2 - Grade 2 neuropathy - NYHA class III Pembrolizumab 200 mg IV/Q3W Primary endpoints ORR ORR in PD-L1 + ORR = 29% in the whole cohort 370 patients ORR = 51% in PD-L1 expressing patients (PD-L1 >10%) INF-gamma Signature (18 genes) associated with ORR muc, metastatic urothelial cancer Balar AV, et al. Lancet Oncol Sep 26. [Epub ahead of print].

33 Ongoing First-Line Trials IMvigor130 (NCT ) 1L cisplatin-ineligible, locally advanced/metastatic ECOG PS 2 N = 1200 Co-primary endpoints: PFS and OS DANUBE (NCT ) 1L unresectable stage IV Eligible / ineligible for cisplatin-based chemotherapy N = 1004 Primary endpoint: OS R R Atezolizumab Platinum based chemo + atezolizumab Cisplatin + gemcitabine or carboplatin + gemcitabine Durvalumab + tremelimumab Durvalumab Cisplatin + gemcitabine or carboplatin + gemcitabine KEYNOTE-361 (NCT ) 1L unresectable or metastatic ECOG PS 2 N = 990 Co-primary endpoints: PFS and OS R Pembrolizumab + cisplatin/gemcitabine or Pembrolizumab + carboplatin/gemcitabine Pembrolizumab Cisplatin + gemcitabine or carboplatin + gemcitabine

34 Ongoing First-Line Trials CHECKMATE 901 (NCT ) Metastatic urothelial cancer Unfit or fit patients No chemotherapy in metastatic setting N = 897 R Nivolumab + ipilimumab Nivolumab + chemotherapy SOC Platinum-based chemotherapy Primary endpoint: OS and PFS in unfit patients; secondary endpoints: OS in all patients, ORR, safety JAVELIN (NCT ) Metastatic urothelial cancer CR, PR, SD upon 4-6 platinum-based chemotherapy N = 668 R Avelumab SOC: BSC Primary endpoint: OS; secondary endpoints: PFS, ORR, DOR, Safety Estimated completion: 2020 SOC, standard of care

35 Conclusions Immune checkpoint inhibitors approved in both first- and second-line therapy Level 1 evidence for pembrolizumab in second-line No data from randomized trials in first-line to date ~20% achieved response with PD-1/PD-L1 inhibitors Many combinations currently investigated