La realidad de la inmunoterapia en el tratamiento de 1ª y 2ª línea del cáncer de vejiga

Transcription

1 La realidad de la inmunoterapia en el tratamiento de 1ª y 2ª línea del cáncer de vejiga Daniel Castellano Oncología Médica. Unidad de Tumores Genito-Urinarios Hospital Universitario 12 de Octubre. I + 12 Research Institute

2 Outline Rationale for immunotherapy in urothelial cancer PD-L1/PD-1 inhibitors in urothelial cancer

3 Bladder cancer Major cause of morbidity and mortality worldwide 430,000 new cases and 165,000 deaths per year Antoni et al. Eur Urol 2017;71: Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30.

4 First-line randomised trials in advanced transitional cell carcinoma Author Treatment N RR (%) MDS (months) Best arm Loehrer Logothetis Von der Maase Sternberg Bamias Dreicer Bellmunt MVAC CDDP MVAC CISCA MVAC GC HD-MVAC + G-CSF MVAC MVAC + GCSF DC + GCSF MVAC PC PCG GC MVAC > CDPP MVAC > CISCA MVAC ~ GC HD-MVAC MVAC MVAC > DC MVAC > PC PCG ~ GC Better patient selection, earlier diagnosis and screening, better supportive care (growth factors)

5 Overall survival (probability) Overall survival (probability) Phase III trial of vinflunine + BSC vs BSC OS in the ITT population OS in the eligible population* 1.0 VFL + BSC BSC 1.0 VFL + BSC BSC 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=0.2868) 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=0.0403) Time (months) Time (months) *The eligible population excludes 13 patients who presented at least one major protocol violation at baseline Bellmunt et al. J Clin Oncol 2009;27: ; Bellmunt et al. Ann Oncol 2013;24:

6 ESMO Guidelines for diagnosis, treatment and follow-up Management of metastatic disease First line FIT CISPLATIN-based combination UNFIT CARBOPLATIN-based regimen Patients with poor comorbid status or impaired renal function unfit Carboplatin-based regimens or single-agents: taxane, gemcitabine PS 2 plus poor renal function Clinical trial Cisplatin-based combination chemotherapy (e.g. MVAC, GC, HDMVAC, PCG) Subsequent lines Vinflunine Taxane-based Platinum rechallenge Best supportive care Progression <12 months Second-line chemotherapy 1. Vinflunine 2. Taxane-based 3. Clinical trial Progression >12 months 1. Platinum-based rechallenge Bellmunt et al. Ann Oncol 2014;25 Suppl 3:iii40 8

7 Rhabdoid tumour Ewing sarcoma Thyroid AML Medulloblastoma Carcinoid Neuroblastoma Prostate CLL Low-grade glioma Breast Pancreas Multiple myeloma Kidney clear cell Kidney papillary cell Ovarian Glioblastoma multiforme Cervical DLBCL Head and neck Colorectal Oesophageal adenocarcinoma Stomach Bladder Lung adenocarcinoma Lung squamous cell carcinoma Melanoma Somatic mutation frequency (/Mb) High mutational load in bladder cancer n= , Bladder tumours along with other malignancies such as lung and melanoma display a high number of somatic mutations rendering these tumours more immunogenic Lawrence et al. Nature 2013;499:214 8

8 Germ cell tumour Soft-tissue sarcoma Prostate cancer Thyroid cancer Biliary cancer Ovarian cancer Renal cell carcinoma Pancreatic cancer Breast carcinoma Head and neck carcinoma Glioma Esophagogastric carcinoma Endometrial cancer Non-small-cell lung cancer Colorectal cancer Melanoma Bladder cancer Somatic mutation burden (mut/mb) High mutational burden in bladder cancer Mutational Burden (13,8 mut./mb) Zehir et al. Nat Med 2017;23:

9 Immune Response Is Regulated by a Balance of Co-stimulation and Co-inhibition Acting at Different Steps Activating receptors + OX40 CD28 CTLA-4 PD-1 Inhibitory receptors GITR CD137 CD27 HVEM T cell TIM-3 BTLA VISTA LAG-3 Adapted from Mellman I, et al. Nature. 2011;480(7378): T-cell activation or inhibition

10 PD-L/PD-1 binding prevents inhibits effector T cell function: T cell break Tumor antigen TCR MHC CD8 T cell PD-1 PD-L1 Tumour cell PD-1 PD-L2 Programed cell death receptor 1 (PD-1) is a negative co stimulatory receptor expressed primarily on activated T cells Expression of PDL-1 on tumour cells and macrophages suppresses immune surveillance and permits neoplastic growth

11 PD-L1 Is Expressed in a Range of Tumor Types Examples of tumor types with strong PD-L1 staining ( 10% of cells): Breast1 Bladder2 Lung cancer3 Melanoma4 Reprinted from J Transl Med. 14:173. Sun WY, Lee KY, Koo JS, Expression of PD-L1 in triple-negative breast cancer based on different immunohistochemical antibodies, Sun WY, Lee KY, Koo JS Ovarian5 SCCHN3 Adapted by permission from Macmillan Publishers Ltd: Nature Rev Cancer Topalian SL, et al. Nat Rev Cancer. 2016; 16: , Copyright Adapted from Oncotarget 7(2) Darb-Esfahani S, et al. Prognostic impact of programmed cell death-1 (PD-1) Pages ,2016 Impact Journals, LLC. 1. Sun WY, et al. J Transl Med. 2016;14: Massard C, et al. J Clin Oncol. 2016;34(suppl): Abstract Rebelatto MC, et al. J Clin Oncol. 2015;33(suppl): Abstract Topalian SL, et al. Nat Rev Cancer. 2016; 16: Darb-Esfahani S, et al. Oncotarget. 2015;7:

12 Regulatory status Publications Evolution of systemic therapy for urothelial cancer Pembrolizumab (1L cis-ineligible) 11 Docetaxel 2 Gemcitabine + cisplatin 3 Pembrolizumab (prior platinum) 10 Nivolumab (prior platinum) 9 Standard MVAC HD-MVAC 4 Paclitaxel 5 Vinflunine 6 Atezolizumab (prior platinum) 7 Atezolizumab (1L cis-ineligible) Cisplatin FDA approval 1978 Gemcitabine EU approval Vinflunine EU approval Atezolizumab FDA approval prior platinum 18 May 2016 Durvalumab FDA BLA prior platinum 09 December 2016 Nivolumab FDA approval prior platinum 02 February 2017 BLA, Biologics License Application Sternberg et al. Cancer 1989;64: ; 2. McCaffrey et al. J Clin Oncol 1997;15: von der Maase et al. J Clin Oncol 2005;23:4602 8; 4. Sternberg et al. J Clin Oncol 2001;19: Vaughn et al. J Clin Oncol 2002;20:937 40; 6. Bellmunt et al. J Clin Oncol 2009;27: Rosenberg et al. Lancet 2016;387: ; 8. Balar et al. Lancet 2017;389: Sharma et al. Lancet Oncol 2017; doi: /S (17) Bellmunt et al. N Engl J Med 2017; doi: /NEJMoa Balar et al. J Clin Oncol 2017;35(suppl 6S):Abstract 284 Atezolizumab FDA BLA 1L cis-ineligible 09 January 2017 Pembrolizumab FDA BLA 1L cis-ineligible AND prior platinum 03 February 2017 Avelumab FDA BLA prior platinum 28 February 2017

13 Immunotherapy in urothelial cancer: what compounds? PD-L1 inhibitors Atezolizumab Durvalumab Avelumab PD-1 inhibitors Nivolumab Pembrolizumab

14 Immunotherapy in urothelial cancer: what compounds? Prior platinum 1L cis-ineligible PD-L1 inhibitors Atezolizumab N=932 (phase III) N=119 Durvalumab N=103 Avelumab N=153 PD-1 inhibitors Nivolumab N=270 Pembrolizumab N=542 (phase III) N= Rosenberg et al. Lancet 2016;387: ; 2. Powles et al. J Clin Oncol 2017;35(Suppl 6S):Abstract Patel et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 330; 4. Sharma et al. Lancet Oncol 2017; doi: /S (17) Bellmunt et al. N Engl J Med 2017; doi: /NEJMoa ; 6. Balar et al. Lancet 2017;389: Balar et al. J Clin Oncol 2017;35(suppl 6S):Abstract 284

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

16 IMvigor210 Cohort 2: study design Inoperable locally advanced or metastatic urothelial carcinoma Predominantly UC histology Tumour tissue evaluable for PD-L1 testing a Cohort 1 (N=119): 1L cisplatin ineligible Cohort 2 (N=310): Platinum-treated muc Atezolizumab 1,200mg IV q3w until RECIST v1.1 progression Atezolizumab 1,200mg IV q3w until loss of clinical benefit Co-primary endpoints ORR (confirmed) per RECIST v.1.1 (central independent review) Investigator-assessed ORR per modified RECIST Primary endpoints met if null hypothesis (ORR of 10%) rejected at significance level (α) of 5% Key secondary endpoints PFS, DOR, OS, safety Data previously published in The Lancet 1, longer follow-up presented at ESMO (21.0 months vs 11.7 months) IRF, independent review facility. ClinicalTrials.gov ID: NCT a PD-L1 prospectively assessed by a central laboratory, with patients and investigators blinded b Cockcroft-Gault formula 1. Rosenberg et al. Lancet 2016;387: ; 2. Loriot et al. Ann Oncol 2016;27(suppl_6):783P

17 IMvigor210 Cohort 2: ORR IC2/3 (n=100) IC1/2/3 (n=207) All patients (N=310) IC1 (n=107) IC0 (n=103) ORR per IRF RECIST v1.1 a, % (95% CI) 28 (19, 38) 19 (14, 25) 16 (12, 20) 11 (6, 19) 9 (4, 16) CR rate per IRF RECIST v1.1, % (95% CI) 14 (8, 22) 8 (5, 13) 6 (4, 9) 3 (1, 8) 2 (0, 7) ORR per immune-modified RECIST b, % (95% CI) 29 (20, 39) 24 (18, 30) 20 (15, 25) 19 (12, 27) 12 (6, 19) Median treatment duration was 12 weeks (range, 0 to 104) 137 patients were treated beyond RECIST v1.1 progression Durable clinical benefit also observed Disease control rate (IRF RECIST v1.1 CR + PR + SD 24 weeks) of 21% (95% CI, 17% to 26%) in all patients IRF, independent review facility Median follow-up: 21.0 months; data cut-off: July 4, 2016 Loriot et al. Ann Oncol 2016;27(suppl_6):783P

18 Overall survival (%) IMvigor210 Cohort 2: overall survival 100 IC0/1 (n=210) IC2/3 (n=100) All patients (N=310) Median OS, months (95% CI) 12-month OS rate, % (95% CI) 6.7 (5.4, 8.0) 31 (24, 37) 11.9 (9.0, NE) 50 (40, 60) 7.9 (6.7, 9.3) 37 (31, 42) Time (months) Number at risk All patients Median follow-up: 21.0 months; data cut-off: July 4, 2016 Loriot et al. Ann Oncol 2016;27(suppl_6):783P

19 CheckMate 275: study design and objectives Open-label, single-arm, phase II study Patients Treatment 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 sample Nivolumab 3mg/kg IV q2w N=270 Treat until progression or unacceptable toxicity Primary endpoint: ORR based on blinded independent review committee (BIRC) (RECIST v1.1) evaluation in all patients and in patients with tumour PD-L1 expression 1% and 5% NCT Sharma et al. Lancet Oncol 2017; doi: /S (17)

20 OS estimate CheckMate 275: overall survival Median OS, months (95% CI)* All treated 8.74 (6.05 NR) PD-L1 <1% 5.95 ( ) PD-L1 1% (8.74 NR) ORR and median OS in all patients were 19.6% and 8.7 months Number at risk Time (months) All patients 265 (0) 198 (3) 148 (4) 63 (71) 5 (125) 0 (130) *Similar results were seen using the 5% PD-L1 tumour expression cut-off Sharma et al. Lancet Oncol 2017; doi: /S (17)

21 KEYNOTE-045: study design and objectives Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra Transitional cell predominant PD after 1 2 lines of platinum-based chemotherapy or recurrence within 12 months of perioperative platinum-based therapy ECOG PS 0 2 Provision of tumour sample for biomarker assessment N=542 Paclitaxel 175mg/m 2 IV q3w or docetaxel 75mg/m 2 IV q3w or vinflunine 320mg/m 2 IV q3w Co-primary endpoints: OS and PFS in total and PD-L1 CPS 10% populations Secondary endpoints: ORR and DOR in total and PD-L1 CPS 10% populations; safety in total population NCT Bellmunt et al. N Engl J Med 2017; doi: /NEJMoa R Stratification factors ECOG PS (0/1 vs 2) Hemoglobin level (<10 vs 10 g/dl) Liver metastases (yes vs no) Time from last chemotherapy dose (<3 vs 3 months) Pembrolizumab 200 mg IV q3w

22 KEYNOTE-045 Trial Follow-Up Data cutoff: Jan 18, 2017 Median duration of follow-up: 18.5 months Bajorin DF et al. ASCO Data cutoff: October 26, 2017 Median follow-up: 27.7 months Enrollment Nov 2014-Nov Data cutoff: Sept 7, 2016 Median duration of follow-up: 14.1 months Bellmunt J et al. NEJM Data cutoff: May 19, 2017 Median duration of follow-up: 22.5 months de Wit R et al. ESMO Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q Bellmunt J et al. N Engl J Med. 2017;376: Bajorin DF et al. J Clin Oncol. 2017;35(suppl 15): de Wit R et al. Ann Oncol. 2017;28(suppl 5):v605-v649.

23 Baseline Characteristics n (%) Age, median (range), y Men Pembro (N = 270) 67 (29-88) 200 (74.1) Chemo (N = 272) 65 (26-84) 202 (74.3) n (%) Liver metastases Hemoglobin <10 g/dlb Pembro (N = 270) 91 (33.7) 43 (15.9) Chemo (N = 272) 95 (34.9) 44 (16.2) Upper tract disease 38 (14.1) 37 (13.6) Time since completion of most recent prior therapy Lower tract disease ECOG PSa 232 (85.9) 235 (86.4) 3 months <3 months 167 (61.9) 103 (38.1) 168 (61.8) 104 (38.2) (44.4) 106 (39.0) Setting of most recent prior therapy 1 2 Visceral disease Disease in lymph node only 142 (52.6) 3 (1.1) 241 (89.3) 28 (10.4) 158 (58.1) 4 (1.5) 235 (86.4) 37 (13.6) Neoadjuvant Adjuvant First line Second line Third line 19 (7.0) 12 (4.4) 184 (68.1) 55 (20.4) 0 22 (8.1) 31 (11.4) 158 (58.1) 59 (21.7) 2 (0.7) amissing for 5 patients in the pembrolizumab arm and 4 patients in the chemotherapy arm. bmissing for 7 patients in the pembrolizumab arm and 4 patients in the chemotherapy arm. Data cutoff date: October 26, 2017.

24 Baseline Characteristics n (%) Pembro (N = 270) Chemo (N = 272) n (%) Pembro (N = 270) Chemo (N = 272) Prior platinum therapy Risk Factorsc Cisplatin Carboplatin 199 (73.7) 70 (25.9) 214 (78.7) 56 (20.6) (20.0) 96 (35.6) 45 (16.5) 97 (35.7) Othera 1 (0.4) 2 (0.7) 2 66 (24.4) 80 (29.4) Smoking statusb (16.7) 45 (16.5) Never 104 (38.5) 83 (30.5) Former 136 (50.4) 148 (54.4) Current 29 (10.7) 38 (14.0) PD-L1 CPS 10% 74 (27.4) 90 (33.1) aoxaliplatin, nedaplatin. bmissing for 1 patient in the pembrolizumab arm and 3 patients in the chemotherapy arm. cincludes Bellmunt risk factors of ECOG performance status >0, hemoglobin level <10 g/dl, and liver metastases (J Clin Oncol. 2010;27: ) + time from prior chemotherapy <3 months (Eur Urol. 2013;63: ). Missing for 8 patients in the pembrolizumab arm and 5 patients in the chemotherapy arm. Data cutoff date: October 26, 2017.

25 OS, % Overall Survival: Total 14.1 months of follow-up1 100 Pembro Chemo Events, n HR (95% CI)a 0.73 ( ) Pb % 29.8% 27.0% 14.3% Pembro Chemo 27.7 months of follow-up Events, n HR (95% CI)a ( ) Pb Median (95% CI): 10.3 months ( ) 7.3 months ( ) No. at risk Time, months Pembro % at 24 months in the chemotherapy arm received an immunotherapeutic agent, including those who received pembrolizumab as part of the cross over. Chemo abased on Cox regression model with treatment as a covariate stratified by ECOG performance status (0/1 vs 2), liver metastases (yes vs no), hemoglobin (<10 vs 10 g/dl), and time from completion of chemotherapy (<3 vs 3 months). bone-sided P value based on stratified log-rank test. Data cutoff date: October 26, Bellmunt J et al. N Engl J Med. 2017;376:

26 Patients, % (95% CI) Remaining In Response, % Objective Response and Response Duration Objective Response Rates Time to Response, median (range) Duration of Response, median (range) % CR PR Pembro Chemo 2.1 mo ( ) 2.1 mo ( ) NR (1.6+ to mo) 4.4 mo (1.4+ to 29.9+) % (7.0%) 11.0% % (14.1%) 2.9% (3.3%) 8.1% Pembrolizumab N = 270 Chemotherapy N = Time, months Pembro Assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: October 26, Chemo

27 Treatment-Related AEs Occurring in 10% of pts Pembrolizumab Chemotherapy Grade 1-2 Grade 3-5 Pruritus Fatigue Pruritus Fatigue Grade 1-2 Grade 3-5 Nausea Decreased appetite Diarrhea Asthenia Anemia Constipation Peripheral sensory neuropathy Peripheral neuropathy Decreased neutrophils Neutropenia Alopecia Nausea Decreased appetite Diarrhea Asthenia Anemia Constipation Peripheral sensory neuropathy Peripheral neuropathy Decreased neutrophils Neutropenia Alopecia Patients, % Patients, % aof patients in either treatment arm. 7.5% febrile neutropenia in the chemotherapy arm. Data cutoff date: October 26, AEs, adverse events Data cutoff date: October 26, 2017

28 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/m2 q 3 w/ Docetaxel 75 mg/m2 q 3 w/ Vinflunine 320 mg/m2 q 3w unacceptable AE, or investigator decision Treated until PD or unacceptable AE Treated until PD Primary endpoints: OS Secondary endpoints: ORR, PFS, safety, pharmacokinetics UC, urothelial cancer National Institutes of Health. NCT Accessed November 23, 2017.

29 IMvigor211: Overall Survival for IC2/3 Population Atezolizumab Chemotherapy Events / Patients 72/116 88/118 Median OS (95% CI) 12-Month OS Rate (95% CI) 11.1 months (8.6, 15.5) 46% (37, 56) 10.6 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.

30 IMvigor211: Overall Survival for ITT Population Atezolizumab Chemotherapy Events / Patients 324/ /464 Median OS (95% CI) 12-Month OS Rate (95% CI) 8.6 months (7.8, 9.6) 39% (35,44) 8.0 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.

31 IMvigor211: Safety Summary All Cause Treatment-Related AE, n(%) Atezolizumab (N = 459) Chemo (N = 443) Atezolizumab (N = 459) Chemo (N = 443) All Grade AEs Grade 3 or 4 AEs Grade 5 AEs All Grade AESIs Grade 3 or 4 AESIs Grade 5 AESIs SAEs AEs leading to treatment disc AEs leading to dose modification, delay, or intertuption 438 (95%) 233 (51%) 17 (4%) 139 (30%) 37 (8%) (41%) 34 (7%) 134 (29%) 435 (98%) 249 (56%) 18 (4%) 98 (22%) 13 (3%) 1 (<1%) 191 (43%) 78 (18%) 210 (47%) 319 (70%) 91 (20%) 1 (1%) (16%) 16 (3%) (89%) 189 (43%) 8 (2%) (25%) 63 (14%) - 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.

32 Durvalumab and avelumab in prior platinum urothelial cancer: summary of antitumour activity Durvalumab 1 N=103 Confirmed ORR, % (95% CI) 17.8 (13.1, 29.5) CR, % 3.9 Median duration of follow-up, 8.4 months PD-L1-high expression defined as 25% of tumour cells (TCs) or immune cells (ICs) staining for PD-L1; PD-L1-low/negative expression defined as <25% of both TCs and ICs staining for PD-L1 Avelumab 2 N=153 Confirmed ORR, % (95% CI) 17.6 (12.0, 24.6) CR, % 5.9 Clinical cut-off, 19 March Median duration of follow-up, 7.3 months 1. Powles et al. J Clin Oncol 2017;35(Suppl 6S):Abstract Patel et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 330

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35 Immunotherapy in urothelial cancer: what compounds? Prior platinum 1L cis-ineligible PD-L1 inhibitors Atezolizumab N=310 N=119 Durvalumab N=103 Avelumab N=153 PD-1 inhibitors Nivolumab N=270 Pembrolizumab N=542 (phase III) N= Rosenberg et al. Lancet 2016;387: ; 2. Powles et al. J Clin Oncol 2017;35(Suppl 6S):Abstract Patel et al. J Clin Oncol 2017;35(Suppl 6S):Abstract 330; 4. Sharma et al. Lancet Oncol 2017; doi: /S (17) Bellmunt et al. N Engl J Med 2017; doi: /NEJMoa ; 6. Balar et al. Lancet 2017;389: Balar et al. J Clin Oncol 2017;35(suppl 6S):Abstract 284

36 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):

37 IMvigor210 Cohort 1: study design Inoperable locally advanced or metastatic urothelial carcinoma Predominantly UC histology Tumour tissue evaluable for PD-L1 testing a Cohort 1 (N=119): 1L cisplatin ineligible Cohort 2 (N=310): Platinum-treated muc Atezolizumab 1,200mg IV q3w until RECIST v1.1 progression Atezolizumab 1,200mg IV q3w until loss of clinical benefit Primary endpoint Confirmed ORR: RECIST v1.1 (per central IRF) Key secondary endpoints DOR, PFS, OS, safety IRF, independent review facility. ClinicalTrials.gov ID: NCT a PD-L1 prospectively assessed by a central laboratory, with patients and investigators blinded b Cockcroft-Gault formula Balar et al. Lancet 2017;389:67 76

38 IMvigor210 Cohort 1: efficacy Response to atezolizumab (IRF RECIST v1.1) IC2/3 (n=32) ORR a, % 28 (95% CI) (14, 47) IC1/2/3 (n=80) 24 (15, 35) All patients (N=119) 23 (16, 31) IC1 (n=48) 21 (10, 35) IC0 (n=39) 21 (9, 36) CR, % Durable clinical benefit also observed Disease control rate (CR + PR + SD 24 weeks) of 30% (95% CI, 22% to 39%) in all patients With a median follow-up of 17.2 months, median DOR was not yet reached in any PD-L1 subgroup (median DOR range, 3.7 to 21.0 months), and 70% of responses were ongoing a Includes 19 patients with missing/unevaluable responses. All treated patients had measurable disease at baseline per investigator-assessed RECIST v1.1. PD-L1 IC status: IC2/3 ( 5%), IC1 ( 1% and <5%), IC0 (<1%). Data cut-off: 14 March 2016 Balar et al. Lancet 2017;389:67 76

39 Overall survival (%) IMvigor210 Cohort 1: efficacy Overall survival (median and landmark 12-month OS) Subgroup Median OS (95% Cl) 12-month OS (95% Cl) All (N=119) 15.9 months (10.4, NE) IC0/1 (n=87) IC2/3 (n=32) 19.1 months (9.8, NE) 12.3 months (6.0, NE) 57% (48 66) 59% (48 70) 52% (35 70) Number at risk Time (months) All patients Data cut-off: 4 July 2016 Balar et al. Lancet 2017;389:67 76

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45 Pembrolizumab as first-line therapy in eldery patients with poor performance status with cisplatin-ineligible advanced urothelial cancer: results from KEYNOTE-052 Daniel Castellano, 1 Petros Grivas, 2 Elizabeth Plimack, 3 Arjun V. Balar, 4 Peter H. O Donnell, 5 Joaquim Bellmunt, 6 Thomas Powles, 7 Noah Hahn, 8 Ronald de Wit, 9 Dean Bajorin, 10 Misoo Chung Ellison, 11 Tara Frenkl, 11 Stephen M. Keefe, 11 Jaqueline Vuky 12 1 Hospital Universitario 12 de Octubre, Madrid, Spain; 2 Cleveland Clinic, Cleveland, OH, USA; 3 Fox Chase Cancer Center, Philadelphia, PA, USA; 4 Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA; 5 The University of Chicago Medical Center, Chicago, IL, USA; 6 Dana-Farber Cancer Institute, Boston, MA, USA; 7 Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; 8 Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; 9 Erasmus MC Cancer Institute, Rotterdam, Netherlands; 10 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 11 Merck & Co., Inc., Kenilworth, NJ, USA; 12 Oregon Health & Science University, Portland, OR, USA

46 ORR, % (95% CI) Results, Safety, and Conclusions Objective Response Rate Safety CR Age Age/ECOG PS % 7% 22% 27% 5% 22% 29% 6% 24% 32% 6% 26% PR 29% 7% 22% n (%) Treatmentrelated AE, any grade Treatmentrelated AE, grades n = (68) 59 (20) 75 n = (68) 33 (18) 65 ECOG 2 n = ECOG 2 n = 78 Total Populati on n = (59) 50 (64) 243 (66) 24 (20) 15 (19) 70 (19) 5 Conclusions 0 65 years (n=302) 75 years (n=179) Age Subgroups 65 years ECOG PS 2 (n=119) 75 years ECOG PS 2 (n=78) Age/ECOG PS 2 Subgroups Total Population (N=370) First-line pembrolizumab elicits clinically meaningful responses in cisplatin-ineligible, senior patients with advanced urothelial cancer consistent with those of the overall study population No new safety signals for pembrolizumab were identified, and the safety profile was consistent in senior patients, including those with poor performance status Pembrolizumab provides a new treatment option for patients with advanced urothelial cancer who may not tolerate any chemotherapy

47 Open Questions How to identify responders? When and 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

48 Key Biomarkers Currently Assessed in UC to Predict Response to PD-1 or PD-L1 Blockade Biomarker PD-L1 on IC PD-L1 on TC T CD8 infiltration CD8 expression CXCL9 / CXCL10 expression Mutational load Assay Endpoint IHC dako kit (22C3 clone) IHC Ventana (SP263) 1% of cell stained 25% of cell stained IHC dako kit (22C3 clone) IHC dako kit (28-8) 1% of cell stained IHC Ventana (SP263) 1% vs 5% of cell s. 25% of cell stained IHC Gene expression Gene expression Exome sequencing TCGA classification Gene expression INF-ɣ signature TCR sequencing High vs low High vs low Number of mutations/megabase Luminal vs basal Drug Pembrolizumab durvalumab Pembrolizumab Nivolumab durvalumab Atezolizumab Nivolumab Nivolumab atezolizumab Atezolizumab nivolumab 25 gene expression High vs low nivolumab DNA sequencing of the Clonal dominance, clonal CDR3 region of the TCR expansion and T-cell atezolizumab beta chain fraction Results Higher expression associated with response Higher expression associated with response Higher expression associated with response Higher expression associated with response Higher expression associated with response High T CD8 infiltration associated with response High CD8 expression associated with response High expression associated with response High mutation load associated with response Luminal 2 associated with better response to atezolizumab Basal 1 associated with better response to nivolumab Better response to nivolumab 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

49 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

50 Ongoing First-Line Trials CHECKMATE 901 (NCT ) Metastatic urothelial cancer Unfit or fit patients R No chemotherapy in metastatic setting N = 897 Nivolumab 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

51 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

52 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

53 BACKUP

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

55 Phase I/II Ongoing Second-Line Trials CHECKMATE-032 (NCT )1 Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen R N = 196 Progression (NCT ) or recurrence of urothelial cancer following a first-line platinum-containing regimen R No more than 2 prior lines of systemic chemotherapy N = 1500 Nivolumab 3 mg/kg Primary endpoint: Safety; secondary endpoints: ORR, OS, PFS, and quality of life MK (NCT ) n = 78 n = 26 n = 104 Primary endpoint: ORR; secondary endpoints PFS and safety SAUL Study Design (NCT ) 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 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; Novem 2016: National Harbor, Maryland, United States. Abs

56 MB: 62-year-old male with Stage IV TCC and extensive RP lymph node mts after adjuvant GC, paclitaxel-carbo, vinflunine, gemcitabine alone and anthracycline based-ct. Atezolizumab 1.200mg q3w initiated on study on September 2014 (> 40 cycles) Baseline 08/2014 PS 1 Back pain PR 11/2014 PS 0 Excellent tolerance PR 01/2015 CR 03/2015 Adverse events: G1 flu-like syndrome, and G1-2 asthenia. Hospital 12 de Octubre: IMvigor 210 STUDY

57 CM: 68-year-old female with metastatic TCC after GC and vinflunine Nivolumab 3mg/kg q2w initiated on study on July 2015 July 2015 September 2015 April 2016 Courtesy C. Sternberg/ San Camilo Hospital: CheckMate 275

58 MB: 62-year-old female with Stage IV TCC with lung and liver and bladder cancer after GC Pembrolizumab 200mg q3w initiated on study on 30 June 2015 June 2015 October 2015 December 2016 Courtesy C. Sternberg/ San Camilo Hospital: KEYNOTE-045

59 MB: 62-year-old female with Stage IV TCC with lung and liver and bladder cancer after GC Pembrolizumab 200mg q3w initiated on study on 30 June 2015 June 2015 October 2015 December 2016 San Camilo Hospital: KEYNOTE-045

60 75-year-old male with upper tract UCC and bone, liver and LN mts after nephroureterectomy + lymphadenectomy Pembrolizumab 200mg q3w initiated on study on September 2015 Baseline 09/2015 PS 2 Cis-inelegible CR 09/2016 PS 0 Hospital 12 de Octubre: KEYNOTE cycles Excellent tolerance