Immunotherapy in GU Cancers. Dr Ravindran Kanesvaran Medical Oncologist National Cancer Centre Singapore

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1 Immunotherapy in GU Cancers Dr Ravindran Kanesvaran Medical Oncologist National Cancer Centre Singapore 1

2 Disclosures Speaker Bureau: Pfizer, J&J, Sanofi, Novartis, MSD Advisory Board/ Consultant: GSK, Novartis, Bayer, J&J, Mundipharma, Astellas, MSD, BMS Research support: Sanofi, J&J, Astellas 2

3 Outline Introduction Immunotherapy in mbc Immunotherapy in mrcc Summary 3

4 Bladder and Kidney Cancers Singapore Singapore Cancer Registry Interim Annual Report Trends in Cancer Incidence in Singapore

5 Metastatic Bladder Cancer Approximately 25% of patients will have muscle-invasive disease and either present with or later develop metastases 5

6 6 Current Treatment : Chemotherapy

7 7 Current first line treatment

8 Carboplatin in patients unfit for cisplatin Data suggests that CDDP > carbo in terms of efficacy MA Galsky Annals 2011 : CDDP > Carbo wrt CR, ORR Multiple phase II studies reveal CDDP > Carbo in terms of ORR EORTC (ASCO 2010) G/Carbo vs M-CAVI (M, V and Carbo) in pts CCT 30-60, PS 2 OS same (about 8.5 mths); G/Carbo better tolerated Definition of pts unfit for CDDP (Galsky, JCO June 2011) ECOG 2 CCT < 60 G2 hearing loss or G2 neuropathy NYHA III CCF 8

9 9 Current Treatment: Immunotherapy

10 Role of immune system in advanced bladder cancer High mutational load may correlate with immunogenicity, and provides valuable prognostic information Martincorena I, Campbell PJ. Science. 2015;349:

11 IMvigor 210: Study Design Single-arm phase II study with 2 cohorts Pts with inoperable advanced or metastatic UC, predominantly TCC histology, evaluable tumor tissue for PD-L1 testing Cohort 1 Previously untreated, cisplatin ineligible Cohort 2 Prior platinum treatment Atezolizumab 1200 mg IV Q3W until PD Atezolizumab 1200 mg IV Q3W until loss of benefit Primary endpoints: confirmed ORR by RECIST v1.1 (per central review), ORR per immunemodified RECIST (per investigator) Secondary endpoints: DoR, PFS, OS, safety Rosenberg JE, et al. Lancet. 2016;387:

12 Post platinum Responses Responses seen in all PD-L1 IC subgroups; higher response seen with higher PD-L1 status After a median follow-up of 11 7 months, the median duration of response was not yet reached in any of the PD-L1 subgroups (range months) At the time of the updated data cutoff, ongoing responses were reported in 38 (84%) of the 45 responding patients The median time to response was 2 1 months (95% CI ) 12

13 Post platinum Conclusion Targeting PD-L1 with atezolizumab is effective in heavily pretreated patients with locally advanced or metastatic urothelial carcinoma Responses were seen in all PD-L1 expression subgroups Higher response rates in patients with higher levels of PD-L1 expression on immune cells Data led to FDA accelerated approval of atezolizumab for advanced or metastatic UC after PD during or following platinum-based therapy 13

14 Cohort 1 (Previously untreated and cisplatin ineligible) Many patients are cisplatin ineligible due to poor performance status, impaired renal function, or comorbidities Non-cisplatin based regimens associated with short response duration, lack of survival benefit, high discontinuation rate Many patients do not end up receiving systemic treatment 14

15 Cisplatin ineligible Survival No clear difference in OS between PD-L1 subgroups Median OS was not reached in patients with no risk factors 13 4 months in patients with one risk factor (either visceral metastases or ECOG 2) 6 2 months in patients with two risk factors 19 1 months median OS reported in the stable disease subgroup 15

16 Cisplatin ineligible Conclusion Durable responses to atezolizumab in previously untreated cisplatinineligible patients metastatic urothelial carcinoma Responses seen in all PD-L1 subgroup Survival to date appears favourable Low incidence of AE despite numerous co-morbidities 16

17 17 Was the accelerated approval too early?

18 IMvigor211: A Phase III Randomized Study Examining Atezolizumab vs. Chemotherapy for Platinum-Treated Advanced Urothelial Carcinoma Thomas Powles, 1 Yohann Loriot, 2 Ignacio Durán, 3 Alain Ravaud, 4 Margitta M. Retz, 5 Nicholas J. Vogelzang, 6 Sanjeev Mariathasan, 7 Na Cui, 7 Christina L. Derleth, 7 Michiel S. van der Heijden 8 1 Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, UK; 2 Département de Médecine Oncologique, Université Paris-Saclay and Gustave Roussy, Villejuif, France; 3 Department of Medical Oncology, Hospital Universitario Virgen del Rocío and Institute of Biomedicine of Seville, Seville, Spain; 4 Hôpital Saint-André CHU and Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; 5 Department of Urology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; 6 US Oncology Research, Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA; 7 Genentech, Inc., South San Francisco, CA, USA; 8 Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands Powles T, et al. EAS 2017, IMvigor

19 19 IMvigor211 Study Design Key Eligibility Criteria 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) Stratification Factors No. of risk factors a (0 vs. 1/2/3) Liver metastases (yes vs. no) PD-L1 status (0/1 vs. 2/3) Chemotherapy (vinflunine vs. taxanes) R 1:1 Atezolizumab 1200 mg q3w Chemotherapy (investigator s choice) Vinflunine q3w Docetaxel q3w Paclitaxel q3w Loss of clinical benefit No crossover permitted per protocol RECIST v1.1 progression Survival follow-up Primary endpoint Additional endpoints OS, tested hierarchically in pre-specified populations Efficacy: RECIST v1.1 ORR, PFS and DOR Safety PROs: EORTC QLQ-C30 a Defined by time from prior chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dl. 19

20 Overall Survival OS Analysis: IC2/3 Population Events/ Patients Median OS (95% CI) 12-mo OS Rate (95% CI) Atezolizumab 72/ mo (8.6, 15.5) 46% (37, 56) Chemotherapy 88/ mo (8.4, 12.2) 41% (32, 50) HR = 0.87 (95% CI: 0.63, 1.21) P = Months No. at Risk Atezolizumab Chemotherapy

21 Overall Survival OS Analysis: ITT Population Events/ Patients Median OS (95% CI) 12-mo OS Rate (95% CI) Atezolizumab 324/ mo (7.8, 9.6) 39% (35, 44) Chemotherapy 350/ mo (7.2, 8.6) 32% (28, 37) HR = 0.85 (95% CI: 0.73, 0.99) P = Months No. at Risk Atezolizumab Chemotherapy

22 OS in Clinical and Treatment Subgroups Subgroup PD-L1 status Tobacco use history IC2/3 IC1/2/3 ITT Current Previous Never Atezolizumab mos Chemotherapy mos 11.1 mo 10.6 mo 8.9 mo 8.2 mo 8.6 mo 8.0 mo 9.2 mo 6.7 mo 8.4 mo 8.2 mo 10.4 mo 8.1 mo ECOG PS mo 10.1 mo 6.1 mo 6.4 mo Primary tumor site Liver metastases Lymph node only metastases Chemotherapy stratification Bladder Urethra Renal pelvis Ureter Yes No Yes No Taxane Vinflunine 8.9 mo 7.7 mo NE 12.5 mo 5.9 mo 8.5 mo 8.9 mo 8.1 mo 4.0 mo 5.2 mo 10.1 mo 9.7 mo 17.4 mo 12.2 mo 8.1 mo 7.2 mo 8.3 mo 7.5 mo 9.2 mo 8.3 mo 1.0 Atezolizumab better Chemotherapy better NE, not estimable. Unstratified hazard ratios are plotted. Dashed line refers to HR for ITT population. 22

23 IMvigor211 Conclusion The primary endpoint of OS was not met in the IC2/3 population Due to delayed separation of the Kaplan-Meier curves, the differences in mos and HR do not fully reflect the clinical activity achieved with atezolizumab The safety data showed no new safety signals and demonstrated a more favorable safety profile for atezolizumab than for chemotherapy 23

24 24 Nivolumab in mbc

25 Overall Survival At a median follow-up of 7 00 months (IQR ), median OS was 8 74 months (95% CI 6 05 to not reached) in the overall population, Median OS months (8 74 to not reached) in the subgroup of patients with PD- L1 expression of > 1% Median OS 5 95 months ( ) in the subgroup with PD-L1 expression of < 1% 25

26 26 Pembrolizumab K-045

27 KEYNOTE-045: Study Design Key Eligibility Criteria Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra Transitional cell predominant PD after platinum-based chemo for advanced disease or recurrence within 12 mo of perioperative platinum-based therapy for localized muscle-invasive disease ECOG PS 0-2 Provision of tumor sample for biomarker assessment Stratification Factors ECOG PS (0/2 vs 2) Hemoglobin level (<10 vs 10 g/dl) Liver metastases (yes vs no) Time from last chemotherapy dose (<3 vs 3 mo) R (1:1) N=542 n=270 n=272 Pembrolizumab 200 mg IV Q3W For 2 years Paclitaxel 175 g/m 2 Q3W (n=84) OR Docetaxel 75 mg/m 2 Q3W (n=84) OR Vinflunine 320 mg/m 2 Q3W (n=87) Key End Points Primary: OS and PFS in total and PD-L1 CPS 10% populations Secondary: OR and DOR in total and PD-L1 CPS 10% populations; safety in total population CPS = combined positive score; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; IV = intravenous; OS = overall survival; PD = progressive disease; PD-L1 = programmed death ligand 1; PFS = progression-free survival; PS = performance status; Q3W every 3 weeks; R = randomization. 27

28 KEYNOTE-045: Baseline Characteristics ECOG PS scores range from 0 to 5, with 0 indicating no symptoms and higher scores indicating greater disability. PD-L1 CPS: the percentage of tumor and infiltrating immune cells with PD-L1 expression out of the total number of tumor cells. Risk factors include the Bellmunt risk factors: ECOG PS score >0; hemoglobin concentration <10 g/dl; presence of liver metastases, 2 plus time since the completion/discontinuation of previous therapy <3 mo. 3 CPS = combined positive score; ECOG = Eastern Cooperative Oncology Group; PD-L1 = programmed death ligand 1; PS = performance status. 1. Bellmunt J, et al. N Engl J Med. 2017; February 17 [Epub ahead of print]; 2. Bellmunt J, et al. J Clin Oncol. 2010;28: ; 3. Sonpavde G, et al. Eur Urol. 2013;63:

29 KEYNOTE-045: Overall Survival Total Population CPS 10% Population The median OS was 10.3 months (95% CI, 8.0 to 11.8) in the pembrolizumab group vs 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group In patients who had a tumor PD-L1 CPS of 10% or more, the median OS was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group vs 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group CI = confidence interval; CPS = combined positive score 29

30 30 KEYNOTE-045: Overall Survival in Key Subgroups

31 KEYNOTE-045: Conclusion Pembrolizumab significantly improved OS over chemotherapy in patients with advanced urothelial carcinoma following first-line platinum-based therapy: OS benefit observed in all PD-L1 populations No significant difference in PFS between pembrolizumab and chemotherapy ORR significantly higher and responses more durable with pembrolizumab Lower incidence of treatment-related AEs of any grade (60.9% vs 90.2%) and grade 3-5 severity (15.0% vs 49.4%) with pembrolizumab Updated results after 22.5 mths follow-up remained consistent a Responses ongoing at data cutoff: All patients: 57.9% in the pembrolizumab arm; 20.0% in the chemotherapy arm CPS 10: 73.3% in the pembrolizumab arm; 33.3% in the chemotherapy arm a R de Wit, et al. ESMO Poster Presentation

32 32 Pembrolizumab K-052

33 33 KEYNOTE-052: Study Design

34 34 KEYNOTE-052: Baseline Characteristics

35 KEYNOTE-052: Objective Responses Median time to response was 2 months 35

36 KEYNOTE-052: PFS Median PFS was 2 months (95% CI 2 3); 6 month PFS of 30% (25 35) 6 month OS was 67% (95% CI 62 73) 36

37 KEYNOTE-052: Conclusion First-line pembrolizumab demonstrated clinically meaningful antitumor activity in cisplatin-ineligible patients with advanced urothelial cancer No new safety signals were identified 37

38 38 Avelumab

39 39 Durvalumab

40 Summary of IO (2 nd line) trials Chism D. J Natl Compr Canc Netw 2017;15(10):

41 Summary of cisplatin-ineligible first line trials Chism D. J Natl Compr Canc Netw 2017;15(10):

42 Comparing Toxicities between PD-1 and PD-L1 inhibitors Pillai RN. Cancer 2017 Sep 28. doi: /cncr

43 Summary Chemotherapy still has an important role in the management of mbc We have 5 IO drugs with some data for use in muc but only one with phase III trial data to support its use (Pembrolizumab) Biomarker studies seem to show a relationship but not clear Accelerated approval does not guarantee phase 3 trial success More IO drugs and combination trials are ongoing Cost will play a big role in its usage and access in non reimbursable markets 43

44 Outline Current standards Immunotherapy in mbc Immunotherapy in mrcc Summary 44

45 Rationale for Immunotherapy in RCC Spontaneous remissions attributed to the immune system of advanced RCC have been observed 1 RCC exhibits immune cell infiltrates, and several immune escape mechanisms have been reported in RCC 2,3 Historically, the mainstay of treatment for patients with mrcc was immunotherapy with interleukin-2 or interferon-α 1 Immuno-Oncology (I-O) is an evolving treatment modality encompassing agents designed to directly harness the patient s own immune system to fight cancer 7,8 Studies have documented alterations in various immune cell types in RCC, including 3-6 : Tregs CD45+ Memory T Cells CD8+ T Cells CD4+ T Cells levels: Poor prognosis levels: Fair/Poor prognosis levels: Fair/Poor prognosis/no association levels: Fair/Poor prognosis RCC=renal cell carcinoma; mrcc=metastatic renal cell carcinoma; Treg=regulatory T cell. 1. Escudier B. Ann Oncol. 2012;23(Suppl 8):viii35-viii40 2. Noessner E et al. OncoImmunology. 2012;1(8): Bockorny B et al. Expert Opin Biol Ther. 2013;13(6): Hotta K, et al. Br J Cancer. 2011;105(8): Nakano O et al. Cancer Res. 2001;61(13): Igarashi T et al. Urol Int. 2002;69(1): Ascierto PA et al. J Trans Med. 2014;12:141. doi: / Eggermont A et al. OncoImmunol. 2014;3(1):e27560.

46 46 NCCN 2017

47 Phase III, randomized, open-label trial of nivolumab vs everolimus in subjects with advanced or metastatic clear cell RCC who have received prior anti-angiogenic therapy N=821 Key Inclusion Criteria Advanced/metastatic clear cell RCC No more than 3 total prior regimens in advanced/metastatic setting 1 or 2 prior anti-angiogenic therapy regimens in advanced/metastatic setting Karnofsky PS 70%; No CNS metastases No prior therapy with mtor inhibitor No glucocorticoid use (equivalent to >10 mg of prednisone daily) R 1:1 Nivolumab 3 mg/kg IV q2w Until progression*, unacceptable toxicity, withdrawal of consent, or end of trial Everolimus 10 mg PO qd Primary Outcome Measure: OS Secondary Outcome Measures: PFS, ORR, DOR etc 1. Motzer RJ et al. N Engl J Med doi: /nejmoa * Patients may continue treatment beyond progression (RECIST 1.1) if investigator-assessed clinical benefit is achieved and treatment is well tolerated. Safety and Efficacy of Nivolumab for Metastatic Renal Cell Carcinoma: Real-World Data From an Italian Expanded Access Program N=389 Key Inclusion Criteria 18 years with advanced or metastatic RCC 1 prior systemic treatment in the advanced or metastatic setting Patients with untreated CNS metastases or active autoimmune disease were excluded Nivolumab 3 mg/kg IV q2w Until progression*, unacceptable toxicity, withdrawal of consent This analysis included all patients who received 1 dose of nivolumab AEs monitored and graded using the National Cancer Institute CTCAETerminology Criteria for Adverse Events v4.0 ORR, PFS), and OS were evaluated 47

48 CheckMate 025 Baseline Patient Characteristics Characteristic Nivolumab (N=410) Everolimus (N=411) Total ( N=821) Male, n (%) 315 (77) 304 (74) 619 (75) Median age, years (range) 62 (23 88) 62 (38 86) 62 (34 85) Karnofsky performance status no (%) < Disease sites that could be evaluated - no (%) 1 2 Metastasis site, n (%) Lung Liver Bone Number of prior systemic therapies, n (%) Sunitinib Pazopanib Axitinib Previous nephrectomy - no. (%) Yes No 2(<1) 22 (5) 110 (27) 150 (17) 126 (31) 68 (17) 341 (83) 278 (68) 100 (24) 76 (19) 246 (60) 119 (29) 51 (12) 364 (89) 46 (11) 1 (<1) 30 (7) 116 (28) 130 (32) 134(33) 71 (17) 338 (82) 273 (66) 87 (21) 70 (17) 242 (59) 131 (32) 50 (12) 359 (87) 52 (13) NA = not available, percentages may not add to 100% due to rounding 3 (<1) 52 (6) 24 (6) 15 (4) 260 (12) 139 (17) 679 (83) 551 (67) 187 (23) 146 (18) 488 (59) 250 (30) 101 (12) 723 (88) 98 (12) Characteristic Nivolumab (N = 389) Male, n (%) 291 (75) Median age, years (range) 75, n (%) ECOG PS, n (%) NA Histology, n (%) Clear cell Non-clear cell NA Metastasis site, n (%) Bone Liver CNS Number of prior systemic therapies, n (%) Real-World Data 65 (34 85) 70 (18) 176 (45) 174 (45) 24 (6) 15 (4) 356 (92) 26 (7) 7 (2) 193 (50) 128 (33) 32 (8) 80 (21) 137 (35) 170 (44) NA = not available, percentages may not add to 100% due to rounding

49 Overall Survival CheckMate 025 Real-World Data Median OS at 2 years follow-up, months (95% CI) Nivolumab 26.0 ( ) Everolimus 19.7 ( ) HR (95% CI): 0.73 ( ); P= Median follow-up of 9.2 months Median OS was not reached With a (range: 1 17). 6-month and 9-month OS rates were 80% and 73%, respectively. Median follow-up was 33.6 months 1. Motzer RJ et al. N Engl J Med doi: /nejmoa

50 Progression-Free Survival (Probability) CheckMate 025 Progression-Free Survival Real-World Data Median PFS, months (95% CI) Nivolumab 4.6 ( ) Everolimus 4.4 ( ) HR=0.88 (95% CI, ) P=0.11 Median PFS was 4.6 months (95% CI: 3.6, 5.7;) 6-month and 9-month PFS rates were 44% and 35%, respectively Everolimus Months Nivolumab No. of patients at risk Nivolumab Everolimus In an ad hoc sensitivity analysis of patients who had not progressed or died at 6 months, median PFS was 15.6 months for Nivolumab versus 11.7 months for Everolimus (HR=0.64; 95% CI, ) 1 1. Motzer RJ et al. N Engl J Med doi: /NEJMoa

51 Objective Response Rate Nivolumab was associated with a greater number of objective responses 1 Nivolumab n=410 Everolimus n=411 Objective response rate, % Odds ratio (95% CI) 6.13( ) P< Best overall response, % Complete response Partial response Stable disease Progressive disease Not evaluated Median time to response, months (range) Median duration of response, months (range)* CheckMate < ( ) 3.7 ( ) 12.0 (0 36.8) 12.0 (0 33.0) Ongoing response, n/n (%) 30/105 (29) 3/22 (14) Best response N = 389 ORR, n (%) 95% CI (%) Best objective response, n (%) CR PR SD PD Real-World Data Not determined 86/389 (22) 18, 26 2 (<1) 84 (22) 120 (31) 144 (37) 39 (10) CR = complete response; PD = progressive disease 1. Motzer RJ et al. N Engl J Med doi: /nejmoa

52 Checkmate 025: Overall Survival by Number and Sites of Metastasis Subgroup No. of sites of metastasis Nivolumab Events/patients, n Everolimus Events/patients, n 1 14/68 21/ / /338 Bone metastases Yes 42/76 45/70 No 141/ /341 Liver metastases Yes 54/100 52/87 No 129/ /324 Motzer RJ et al. Oral presentation at ASCO GU Nivolumab Favors Everolimus 52

53 Checkmate 025: Treatment-Related AEs in 15% of Patients Nivolumab n=406 Everolimus n=397 Any grade Grade 3 Grade 4 * Any grade Grade 3 Grade 4 Treatment-related AEs 1, % Fatigue Nausea 15 < Pruritus Diarrhea Decreased appetite 12 < Rash 10 < Cough Anemia Dyspnea <1 0 Peripheral edema <1 0 Pneumonitis 4 1 < Mucosal inflammation Dysgeusia Hyperglycemia 2 1 < <1 Stomatitis Hypertriglyceridemia Epistaxis * Grade 4 AEs not listed in table: increased blood creatinine (1), acute kidney injury (1), anaphylactic reaction (1). Grade 4 AEs not listed in table: increased blood triglycerides (2), acute kidney injury (1), sepsis (1), chronic obstructive pulmonary disorder (1), increased blood cholesterol (1), neutropenia (1), pneumonia (1). 1. Motzer RJ et al. N Engl J Med doi: /NEJMoa

54 Real world data: Treatment-related AEs in 1% of patients Treatment-related AE Any grade (N = 389) Grade 3 4 (N = 389) Total, n (%) 124 (32) 27 (7) General, n (%) Fatigue/asthenia Pyrexia Lack of appetite/anorexia 60 (15) 49 (13) 12 (3) 5 (1) 9 (2) 9 (2) 0 1 (<1) Skin and mucosal, n (%) Rash 38 (10) 34 (9) 2 (<1) 2 (<1) Gastrointestinal, n (%) Diarrhea Nausea/vomiting 33 (8) 18 (5) 8 (2) 5 (1) 3 (1) 2 (<1) Pain, n (%) 7 (2) 0 Endocrine, n (%) Hypothyroidism Hyperthyroidism Autoimmune hypophysitis 12 (3) 6 (2) 6 (2) 1 (<1) 1 (<1) (<1) Respiratory/pulmonary, n (%) Pneumonitis 7 (2) 3 (1) 3 (1) 1 (<1) Hematologic, n (%) Anemia 11 (3) 9 (2) 3 (1) 3 (1) Hepatic/pancreatic, n (%) Increased transaminase 9 (2) 5 (1) Treatment-related grade 3 4 AEs occurred in 27 (7%) patients AEs were generally manageable with treatment according to protocol-specified guidelines No treatment-related deaths were reported 0 0

55 Checkmate Conclusions Nivolumab significantly improved efficacy compared to everolimus in previously treated pts with advanced metastatic RCC. Median OS: 26 months (Nivolumab) vs 19.7 months (Everolimus) (hazard ratio, 0.73; P = 0.002). ORR 25% (nivolumab) vs 5% (Everolimus) (OR: 1.72; P =.0246) All-grade and grade 3/4 toxicity were lower with nivolumab compared to everolimus. The survival improvement and favorable safety profile demonstrated provides evidence for nivolumab as a potential new treatment option for previously treated patients with mrcc.

56 Real world data - Conclusions The EAP population included some subgroups that were poorly represented or not represented at all in the pivotal CheckMate 025 study 3 Despite these differences, comparison of the survival curves suggests that the 9- month OS rate (73%) in the EAP approached that observed in the nivolumab arm of the CheckMate 025 trial 3 As in CheckMate 025, 4 some patients treated beyond progression derived further benefit with improved tumor response The safety profile of nivolumab appeared consistent with that reported in the CheckMate 025 trial 3 Noting the limitations of this study type, preliminary data from this EAP appear to confirm data from the pivotal trial and suggest that nivolumab is effective for the treatment of metastatic RCC in routine clinical practice 3. Motzer RJ et al. N Engl J Med. 2015;373: Escudier B et al. Eur Urol doi: /j.eururo Escudier B et al. Eur Urol doi: /j.eururo

57 Checkmate 214: 1L Nivolumab + Ipilimumab Phase III, randomized, open-label trial of nivolumab combined with ipilimumab vs sunitinib monotherapy in treatment-naïve patients with advanced or metastatic clear cell RCC 1 N=1070 Key Inclusion Criteria Advanced/metastatic clear cell RCC No prior systemic therapy for RCC Prior adjuvant/neoadjuvant therapy allowed if the agent did not target the VEGF pathway, and recurrence occurred 6 months after last dose Karnofsky PS 70% Available FFPE archival or recent tumor tissue sample No prior treatment with VEGF pathway agents or agents targeting T-cell costimulation or checkpoint pathways No current or history of CNS metastases R 1:1 Nivolumab 3 mg/kg IV q3w for 4 doses, then q2w Ipilimumab 1 mg/kg IV q3w for 4 doses Sunitinib 50 mg PO qd for 4 weeks ( 6 week cycles) Until progression*, unacceptable toxicity, withdrawal of consent, or end of trial (up to 5 years) Start Date: October 2014 Estimated Trial Completion Date: September 2019 Estimated Primary Completion Date: June 2019 Status: Ongoing, not recruiting Study Director: Bristol-Myers Squibb Primary Outcome Measures: PFS and OS Key Secondary Outcome Measures: ORR, safety Select Exploratory Outcome Measure: HRQoL, HRU, predictive biomarkers * Patients may continue treatment beyond progression (RECIST 1.1) if investigator-assessed clinical benefit is achieved and treatment is well-tolerated Clinicaltrials.gov. NCT Accessed November 9, Hammers H et al. Poster presentation at ASCO TPS4578. See 57speaker notes for abbreviations. 57

58 58 Results of Checkmate-214

59 1 st line Phase III trials of combination IO based therapies in mrcc 59 Therapeutic target Control Experimental arm(s) arm PD-1 and CTLA-4 Sunitinib Nivolumab + Ipilimumab x 4 Nivolumab PD1 and IDO-1 Sunitinib Pembrolizumab + Epacadostat or Pazopanib PD-1 and VEGF Sunitinib Bevacizumab + Atezolizumab PD-L1 and VEGF Sunitinib Axitinib + Avelumab PD-L1 and VEGF Sunitinib Axitinib + Pembrolizumab VEGF/FGF and (PD1 or mtor) Vaccine (DC+autologous tumor) Sunitinib Sunitinib Lenvatinib + Pembrolizumab OR Lenvatinib + Everolimus Sunitinib + AGS-003 (rocapuldencel-t) Modified from G. Sonpavde

60 Outline Current standards Immunotherapy in mbc Immunotherapy in mrcc Summary 60

61 Summary IO has an established role in the treatment of mrcc ( Nivolumab) New standard established with recent IO data in first line mrcc ( int/ poor risk) A number of ongoing studies in the first line setting with IO combination studies show promise Cost and access present a major challenge which needs to be overcome 61

62 62 Thank you