Inmunoterapia en cáncer renal metastásico: redefiniendo el tratamiento de segunda línea

Inmunoterapia en cáncer renal metastásico: redefiniendo el tratamiento de segunda línea Daniel Castellano Oncología Médica. Unidad de Tumores Genito-Urinarios Hospital Universitario 12 de Octubre I + 12 Research Institute

Biological pathways and the resulting therapeutic targets in renal cell carcinoma 1. Herbert T. Cohen, M.D., and Francis J. McGovern, M.D. Renal cell Lancet Oncol carcinoman Engl J Med 2005;353:2477-90.

Recommended targeted agents for first-line treatment: Results from pivotal trials Agent n Median PFS (months) Median OS (months) ORR (%) Sunitinib vs IFN-α 1 750 11 vs 5 p<0.001 Bevacizumab + IFN-α vs IFN-α 2,3 649 10.2 vs 5.4 p<0.0001 Bevacizumab + IFN-α vs IFN-α 4,5 732 8.5 vs 5.2 p<0.0001 Pazopanib vs placebo 6,7 435 11.1 vs 2.8 p<0.0001 Poor-risk patients Temsirolimus vs IFN-α 8 626 5.5 vs 3.1 p<0.001 26.4 vs 21.8 p=0.051 23.3 vs 21.3 p=0.1291 18.3 vs 17.4 p=0.069 22.9 vs 20.5* p=0.224 10.9 vs 7.3 p=0.008 47 vs 12 p<0.001 31 vs 13 p=0.0001 26 vs 13 p<0.0001 30 vs 3* p<0.001 8.6 vs 4.8 NS *Includes cytokine refractory and treatment-naïve patients; Poor-risk patients (modified MSKCC criteria) NS, not studied 1. Motzer RJ, et al. J Clin Oncol 2009;27:3584 90; 2. Escudier B, et al. Lancet 2007;370:2103 11; 3. Escudier B, et al. J Clin Oncol 2010;28:2144 50; 4. Rini BI, et al. J Clin Oncol 2008;26:5422 8; 5. Rini BI, et al. J Clin Oncol 2010;28:2137 43; 6. Sternberg C, et al. J Clin Oncol 2010;28:1061 8; 7. Sternberg C, et al. Eur J Cancer 2013;49:1287 96; 8. Hudes G, et al. New Engl J Med 2007;356:2271 81

Recommended targeted agents for secondline treatment: Results from pivotal trials Trial Experimental Arm Control Arm Study Eligibility N ORR, % mpfs, mo mos, mo TARGET[1] Sorafenib Placebo 2L, after systemic tx 903 PR: 10% vs 2%* 5.5 vs 2.8* 19.3 vs 15.9 INTORSECT[2] Temsirolimus Sorafenib 2L, after sunitinib 512 8% vs 8% 4.3 vs 3.9 12.3 vs 16.6* RECORD-1[3] Everolimus Placebo 2L, after systemic tx 416 PR: 1.8% vs 0% 4.9 vs 1.9* 14.8 vs 14.4 VEG105192[4,5] Pazopanib Placebo 1L/2L 435 30% vs 3%* 9.2 vs 4.2* 22.9 vs 20.5 AXIS[6,7] Axitinib Sorafenib 2L, after systemic tx 723 PR: 19% vs 9%* 6.8 vs 4.7* 20.1 vs 19.2 Despite significant mpfs improvements, mos changes were generally not significant[1-6] 1. 2. 3. 4. 5. 6. 7. Escudier B et al. N Engl J Med. 2007;356(2):125-134. Hutson TE et al. J Clin Oncol. 2014;32(8):760-767. Motzer RJ et al. Cancer. 2010;116(18):4256-4265. Sternberg CN et al. Eur J Cancer. 2013;49(6):1287-1296. Sternberg CN et al. J Clin Oncol. 2010;28(6):1061-1068. Motzer RJ et al. Lancet Oncol. 2013;14(6):552-562. INLYTA. Summary of product characteristics.

ESMO Guidelines 2015

2nd-line 1st-line Current treatment landscape: anti-vegf agents and mtor inhibitors Pazopanib vs. sunitinib Motzer et al. NEJM 2013 Median OS HR 0.91 Sunitinib vs. IFN-α Motzer et al. JCO 2009 Bev + IFN-α vs. IFN-α + placebo Escudier et al. JCO 2010 Pazopanib vs. placebo Sternberg et al. EJC 2013 Temsirolimus vs. IFN-α Hudes et al. NEJM 2007 Axitinib vs. sorafenib Motzer et al. Lancet Oncol 2013 Sorafenib vs. placebo Escudier et al. JCO 2009 Everolimus vs. placebo Motzer et al. Cancer 2010 Temsirolimus vs. sorafenib Hutson et al. JCO 2014 HR 0.82; P = 0.051 HR 0.86; P = 0.129 HR 0.91; P = 0.221 HR 0.73; P = 0.008 HR 0.97; P = 0.374 HR 0.88; P = 0.146 HR 0.87; P = 0.162 HR 1.31; P = 0.010 Comparator Agent under investigation Months

Targeted Immunotherapy

Tumors use complex, overlapping mechanisms to evade and suppress the immune system APC 1 Inhibition of tumor antigen presentation e.g. down regulation of MHC I 4 Recruitment of immunosuppressive cell types e.g. T-reg Tumor cell 2 Secretion of immunosuppressive factors e.g. TGF-ß Regulator y T cell APC = antigen-presenting cell; MHC = major histocompatibility complex; TGF-ß = tumor growth factor-ß. Drake CG, et al. Adv Immunol. 2006;90:51 81; Vesely MD, et al. Annu Rev Immunol. 2011;29:235 271. 3 Inhibition of attack by immune cells e.g. disruption of T-cell checkpoint pathways Inactive T cell

Regulating the T-cell immune response Activating receptors CD28 OX40 Inhibitory receptors CTLA-4 PD-1 TIM-3 T-cell responses are regulated through a complex balance of inhibitory ( checkpoint ) and activating signals Tumors can dysregulate checkpoint and activating pathways, and consequently the immune response CD137 Agonistic antibodies T-cell stimulation LAG-3 Antagonistic (blocking) antibodies Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response The image shows only a selection of the receptors/pathways involved. CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 = lymphocyte-activation gene-3; PD-1 = programmed cell death-1; TIM-3 = T-cell immunoglobulin domain and mucin domain-3. Adapted from Mellman I, et al. Nature. 2011;480:481 489; Pardoll DM. Nat Rev Cancer. 2012;12:252 264.

PD-1/PD-L1 Inhibitors Currently in Clinical Development Target Agent Nivolumab (MDX1106, BMS936558) Class IgG4 fully human Ab KD 3 nm PD-1 Pembrolizumab (MK-3475) IgG4 engineered humanized Ab 29 pm Pidilizumab (CT-011) IgG1 humanized Ab - AMP-224 Fc-PD-L2 fusion protein - BMS935559 (MDX-1105) IgG4 fully human Ab - PD-L1 MPDL3280A MEDI4736 IgG1 engineered fully human Ab IgG1 engineered fully human Ab - - MSB0010718C NA -

PD-1/PD-L1 Therapy: Select Pivotal Trials Tumor Type Melanoma RCC NSCLC HNSCC Phase III (unless otherwise indicated) Pembro (2 doses) vs ipi [NCT01866319] Nivo vs ipi vs ipi/nivo [NCT01844505] Nivo vs chemo (ipi progression) [NCT01721772,NCT01721746] Pembro vs chemo (ipi progression; phase II) [NCT01704287] Nivo vs everolimus (TKI progression) [NCT01668784] Nivo/ipi vs sunitinib MPDL + bev vs MPDL vs sunitinib (phase II) [NCT01984242] Pembro (2 doses) vs doc [NCT01905657] Nivo vs doc (squamous or nonsquamous) [NCT01642004, NCT01673867] Nivo vs chemo choice [NCT02041533] Nivo vs investigator s choice [NCT02105636] Patients with known or suspected autoimmune disease are generally excluded from these trials.

Nivolumab monotherapy: Phase 2 study in mrcc CA209-010 study mrcc 1 prior antiangiogenic therapy (n = 168) R* Arm 1 0.3 mg/kg nivolumab IV Q3W Arm 2 2 mg/kg nivolumab IV Q3W Treat until progressio n or intolerable toxicity Arm 3 10 mg/kg nivolumab IV Q3W Primary objective: To assess whether a dose-response relationship exists in the 0.3, 2, and 10 mg/kg arms as measured by PFS Stratified by MSKCC prognostic score (0 vs. 1 vs. 2/3) and number of prior lines of therapy in the metastatic setting (1 vs. >1) *Treatment arms blinded. MSKCC = Memorial Sloan-Kettering Cancer Center. Motzer R, et al. Poster presented at ASCO 2014 (abstr. 5009); National Institutes of Health. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed September 2014.

OS (%) Activity of nivolumab monotherapy in mrcc 100 90 80 70 60 50 Nivolumab 0.3 mg/kg 2 mg/kg 10 mg/kg (n = 60) (n = 54) (n = 54) mpfs, months (80% CI) a 2.7 (1.9, 3.0) 4.0 (2.8, 4.2) 4.2 (2.8, 5.5) ORR (%) b 20 22 20 Median OS, months (80% CI) 18.2 (16.2, 24.0) 25.5 (19.8, 28.8) 24.7 (15.3, 26.0) 40 30 20 10 0 0.3 mg/kg (events: 36/60) 2 mg/kg (events: 29/54) 10 mg/kg (events: 32/54) Patients at risk 0 3 6 9 12 15 18 21 24 27 30 33 Months 0.3 mg/kg 60 56 50 41 37 35 31 27 24 13 0 0 2 mg/kg 54 52 45 42 38 35 32 28 26 12 0 0 10 mg/kg 54 50 47 45 38 32 29 29 26 8 1 0 a stratified trend test P value: 0.9; b ORR defined by RECIST v1.1; data cut-off March 5, 2014. Motzer R, et al. Poster presented at ASCO 2014 (abstr. 5009).

OS (%) OS of nivolumab monotherapy in mrcc: MSKCC risk group and number of prior treatments 100 90 80 70 60 50 40 30 20 10 0 Risk group Favourable (events: 25/56) Intermediate (events: 40/70) Poor (events: 32/42) 0 3 6 9 12 15 18 21 24 27 30 Months mos, months (95% CI) Favourable NR (24.9, NR) Intermediat 20.3 (13.4, NR) e Poor 12.5 (8.1, 18.6) NR = not reached; Symbols represent censored observations. Motzer R, et al. Poster presented at ASCO 2014 (abstr. 5009). 100 90 80 70 60 50 40 30 20 10 0 33 Number of prior treatments 1 prior treatment (events: 22/46) 2 prior treatments (events: 75/122) 0 3 6 9 12 15 18 21 24 27 30 33 Months mos, months (95% CI) 1 NR (19.8, NR) 2 18.7 (13.4, 26.0)

Randomize 1:1 Study design Previously treated mrcc Stratification factors Region MSKCC risk group Number of prior antiangiogenic therapies Nivolumab 3 mg/kg intravenously every two weeks Everolimus 10 mg orally once daily Patients were treated until progression or intolerable toxicity occurred Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted MSKCC, Memorial Sloan-Kettering Cancer Center. 17

Metastatic renal cell carcinoma Case Study Details (1) Age Gender Initial symptoms 75 years Male Gross hematuria.

Case Study Details (2) Prior treatment history Nov 2011: Nephrectomy. Lung metastases. Retroperitoneal lymph node involvement. Tumour description Size Histology Other details Furhman grade 3. 10 cm greatest axis. pt3b Lymphovascular infiltration. Anemia and > MSKCC - Intermediate risk

Case Study Details (3) First-line therapy. Sunitinib Dosage used Duration of treatment Treatment outcomes 50mg 26 months Partial response Reason for treatment discontinuation Progressive disease (lung and mediastinal para-aortic lymph node.

Key eligibility criteria Advanced or metastatic clear-cell RCC One or two prior anti-angiogenic therapies Measurable disease (RECIST v1.1) Karnofsky performance status (KPS) 70% Progression on or after most recent therapy and within 6 months of enrollment 21

Study endpoints Primary endpoint Overall survival (OS) Secondary endpoints included Objective response rate (ORR) Progression-free survival (PFS) Adverse events Quality of life (QoL) OS by PD-L1 expression 22

Case Study Details (4) Second-line therapy Nivolumab CA 209-025 Dosage used Duration of treatment Treatment outcomes 3mg/Kg every 2 wks 11 months Partial response (almost complete response) in lung and lymph nodes. Reason for treatment discontinuation Progressive disease (liver and lung)

CT scans Baseline (05/2013)

CT scans (07/2013) (12/2013) (10/2013)

CT scans (02/2014)

Demographics and baseline characteristics Characteristic Nivolumab N = 410 Everolimus N = 411 Median age (range), years 62 (23 88) 62 (18 86) Sex, % Female Male MSKCC risk group, % Favorable Intermediate Poor Number of prior anti-angiogenic regimens in advanced setting, % 1 2 Region, % US/Canada Western Europe Rest of the world 23 77 35 49 16 72 28 42 34 23 26 74 36 49 15 72 28 42 34 24 27

Overall Survival (Probability) Overall survival 1.0 0.9 0.8 0.7 0.6 0.5 Median OS, months (95% CI) Nivolumab 25.0 (21.8 NE) Everolimus 19.6 (17.6 23.1) HR (98.5% CI): 0.73 (0.57 0.93) P = 0.0018 Nivolumab 0.4 0.3 Everolimus 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 No. of patients at risk Months Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0 Everolimus 411 366 324 287 265 241 187 115 61 20 2 0 Minimum follow-up was 14 months. NE, not estimable. 28

Overall survival by subgroup analyses Subgroup MSKCC risk group Nivolumab n/n Everolimus n/n Favorable 45/145 52/148 Intermediate 101/201 116/203 Poor 37/64 47/60 Prior anti-angiogenic regimens 1 128/294 158/297 2 55/116 57/114 Region US/Canada 66/174 87/172 Western Europe 78/140 84/141 Rest of the world 39/96 44/98 Age, years Sex <65 111/257 118/240 65 to <75 53/119 77/131 75 19/34 20/40 Female 48/95 56/107 Male 135/315 159/304 Analyses based on interactive voice response system data. 0.25 0.5 0.75 1 1.5 2.25 Favors Nivolumab Everolimus 30

Subgroup OS: Prior therapy Nivolumab Events/patients Everolimus Events/patients Hazard ratio (95% CI) Prior therapy Sunitinib Pazopanib 123/257 53/126 138/261 79/136 Months on first-line therapy <6 6 61/110 122/300 81/130 134/281 Prior antiangiogenic therapies 1 2 144/317 37/90 162/312 53/99 0 1 2 Favors Nivolumab Everolimus

Overall Survival (Probability) Overall survival by PD-L1 expression 1.0 0.9 0.8 PD-L1 1% (n = 24%) Median OS, months (95% CI) Nivolumab 21.8 (16.5 28.1) Everolimus 18.8 (11.9 19.9) PD-L1 <1% (n = 76%) Median OS, months (95% CI) Nivolumab 27.4 (21.4 NE) Everolimus 21.2 (17.7 26.2) HR (95% CI): 0.79 (0.53 1.17) HR (95% CI): 0.77 (0.60 0.97) 1.0 0.9 0.8 0.7 0.7 0.6 Nivolumab 0.6 Nivolumab 0.5 0.5 0.4 Everolimus 0.4 Everolimus 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 No. of patients at risk Months Nivolumab 94 86 79 73 66 58 45 31 18 4 1 0 Everolimus 87 77 68 59 52 47 40 19 9 4 1 0 0.0 0 3 6 9 12 15 Months 18 21 24 27 30 33 276 265 245 233 210 189 145 94 48 22 2 0 299 267 238 214 200 182 137 92 51 16 1 0 32

Antitumor activity Nivolumab N = 410 Everolimus N = 411 Objective response rate, % 25 5 Odds ratio (95% CI) P value 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)* 1 24 34 35 6 5.98 (3.68 9.72) <0.0001 1 5 55 28 12 3.5 (1.4 24.8) 3.7 (1.5 11.2) 12.0 (0 27.6) 12.0 (0 22.2) Ongoing response, n/n (%) 49/103 (48) 10/22 (45) *For patients without progression or death, duration of response is defined as the time from the first response (CR/PR) date to the date of censoring. 33

Case study details (5) Third-line therapy Everolimus XL 184-308 Trial. (METEOR-Study) Dosage used Duration of treatment Treatment outcomes 10mg/day 3 months Progressive disease (lung and liver) G3 Pneumonitis Reason for treatment discontinuation Progressive disease.

Responders Response characteristics Nivolumab On treatment Everolimus Off treatment First response Ongoing response 0 16 32 48 64 80 Time (Weeks) 96 112 128 35

Progression-Free Survival (Probability) Progression-free survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Everolimus Median PFS, months (95% CI) Nivolumab 4.6 (3.7 5.4) Everolimus 4.4 (3.7 5.5) HR (95% CI): 0.88 (0.75 1.03) P = 0.1135 Nivolumab 0 3 6 9 12 15 18 21 24 27 30 No. of patients at risk Months Nivolumab 410 230 145 116 81 66 48 29 11 4 0 Everolimus 411 227 129 97 61 47 25 16 3 0 0 In a post-hoc analysis of patients who had not progressed or died at 6 months, median PFS was 15.6 months for nivolumab vs 11.7 months for everolimus (HR (95% CI): 0.64 (0.47 0.88)) 36

Safety Summary Nivolumab N = 406 Everolimus N = 397 Any Grade Grade 3-4 Any Grade Grade 3-4 Treatment-related AEs, % 79 19 88 37 Treatment-related AEs leading to discontinuation, % 8 5 13 7 Treatment-related deaths, n 0 2 a 44% of patients in the nivolumab arm and 46% of patients in the everolimus arm were treated beyond progression a Septic shock (1), bowel ischemia (1). 37

Treatment-related AEs in 10% of patients Nivolumab N = 406 Everolimus N = 397 Any grade Grade 3 Grade 4 a Any grade Grade 3 Grade 4 b Treatment-related AEs, % 79 18 1 88 33 4 Fatigue 33 2 0 34 3 0 Nausea 14 <1 0 17 1 0 Pruritus 14 0 0 10 0 0 Diarrhea 12 1 0 21 1 0 Decreased appetite 12 <1 0 21 1 0 Rash 10 <1 0 20 1 0 Cough 9 0 0 19 0 0 Anemia 8 2 0 24 8 <1 Dyspnea 7 1 0 13 <1 0 Edema peripheral 4 0 0 14 <1 0 Pneumonitis 4 1 <1 15 3 0 Mucosal inflammation 3 0 0 19 3 0 Dysgeusia 3 0 0 13 0 0 Hyperglycemia 2 1 <1 12 3 <1 Stomatitis 2 0 0 29 4 0 Hypertriglyceridemia 1 0 0 16 4 1 Epistaxis 1 0 0 10 0 0 a Grade 4 AEs not listed in table: increased blood creatinine (1), acute kidney injury (1), anaphylactic reaction (1). b 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). 38

Case Study Details (6) Adverse events CA 209-025 Nivolumab G1 asthenia. G1 autolimited Rash. Management of adverse events Local treatment.

Treatment Summary Sunitinib 26 mo. Nivolumab 11 mo. Everolimus 3 mo. Axitinib 6 mo. Tensirolimus 3 mo. Pazopanib 4+ mo. 57 + mo.

Conclusions CheckMate 025 met its primary endpoint, demonstrating superior OS with nivolumab versus everolimus This is the only phase III trial to demonstrate a survival advantage in previously-treated patients with mrcc versus standard therapy Survival benefit with nivolumab was consistent across subgroups and irrespective of PD-L1 expression Nivolumab was associated with a greater number of objective responses The superior survival and favorable safety profile in this phase III trial provide evidence for nivolumab as a potential new treatment option for previously treated patients with mrcc 41

Study Design Lenvatinib 18 mg PO qd Key eligibility criteria: Advanced or metastatic RCC Measurable disease Progression on/after 1 prior VEGF-targeted therapy Progression within 9 mos of stopping prior treatment ECOG PS 1 R A N D O M I Z E + Everolimus 5 mg PO qd Lenvatinib 24 mg PO qd Everolimus Patients were treated until: Disease progression Unacceptable toxicity 10 mg PO qd Stratification factors: Hemoglobin (normal vs low) Corrected serum calcium ( vs < 10 mg/dl)

Progression-free Survival Primary Endpoint: Prog.-free Survival 1.0 Median, mos (95% CI) Lenvatinib/Everolimus 14.6 (5.9 20.1) Lenvatinib 7.4 (5.6 10.2) 0.8 Everolimus 5.5 (3.5 7.1) 0.6 0.4 Number at risk Lenvatinib/Everolimus 51 Lenvatinib 52 Everolimus 0.2 0.0 Lenvatinib/Everolimus vs Everolimus HR 0.40 (95% CI 0.24 0.68); P < 0.001 Lenvatinib vs Everolimus HR 0.61 (95% CI 0.38 0.98); P = 0.048 0 3 6 9 12 15 18 21 24 Time (mos) 50 41 41 29 27 29 15 23 20 11 16 11 7 10 6 3 5 4 1 1 1 0 0 0 0

Summary of Efficacy Progression-free survival Lenvatinib/Everolimus Lenvatinib (n = 51) (n = 52) Everolimus (n = 50) Median (mo) 95% CI 14.6 5.9 20.1 7.4 5.6 10.2 5.5 3.5 7.1 Benefit vs everolimus P < 0.001 P = 0.048 NA Objective response rate, % 95% CI Benefit vs everolimus Overall survival (updated) 43 29 58 P < 0.001 27 16 41 P = 0.007 6 1 17 NA Median (mo) 95% CI 25.5 16.4 NE 19.1 13.6 26.2 15.4 11.8 19.6 Benefit vs everolimus P = 0.024 P = 0.118 NA NA, not applicable; NE, not estimable.

METEOR: Phase III study of second-line treatment with cabozantinib vs everolimus in mrcc Eligibility1,2 mrcc with clear cell component Mensurable disease Progression on prior VEGFR TKI within 6 mon of enrollment No limit to the number of prior therapies PD-1/PD-L1 allowed RA ND O M I SA T I ON N=650 Cabozantinib 60 mg po daily (n~325) Everolimus 10 mg po daily (n~325) Brain metastases allowed if treated No cross-over allowed Primary endpoints: PFS Secondary endpoints: OS, ORR Exploratory endpoints: patient-reported outcomes, biomarkers, safety, PK Stratification: MSKCC risk group, number prior VEGFR TKI Escudier B, et al. ASCO GU 2016 1. www.clinicaltrials.gov (NCT01865747); 2. http://www.meteorclinicaltrial.com

Escudier B, et al. ASCO GU 2016

METEOR: PFS in Subgroups (independent radiology review committee) Escudier B, et al. ASCO GU 2016

METEOR: All cause adverse events

METEOR: Phase III study of second-line treatment with cabozantinib vs everolimus in mrcc Escudier B, et al. ASCO GU 2016

EAU Guidelines 2016

BACKUP SLIDES

Immune checkpoint inhibitor combination therapy: Phase 1 study in mrcc CA209-016 study Advanced or metastatic RCC (previously treated or treatment-naïve patients) N = 72 Arm S Sunitinib Nivolumab 0.3, 2, or 5 mg/kg IV Q3W + Sun 50 mg/d PO D1 28 of a 42-day cycle Arm P Pazopanib Nivolumab 0.3, 2, or 5 mg/kg IV Q3W + Paz 800 mg/d PO Arm I-1 Ipilimumab Nivolumab 3 mg/kg IV Q3W + Ipi 1 mg/kg IV Q3W maintenance nivolumab 3 mg/kg Q2W IV Arm I-3 Ipilimumab Nivolumab 1 mg/kg IV Q3W + Ipi 3 mg/kg IV Q3W maintenance nivolumab 3 mg/kg Q2W IV Treat until progression, unacceptable toxicity, or withdrawal of consent Amin A, et al. Presented at ASCO 2014 (abstr. 5010); Hammers H, et al. Presented at ASCO 2014 (abstr. 4504); National Institutes of Health. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed September 2014.

Activity of nivolumab + sunitinib or nivolumab + pazopanib combination therapy Confirmed ORR, n (%) 95% CI S + N (n = 33) 17 (52) 33.5, 69.2 P + N (n = 20) 9 (45) 23.1, 68.5 Disease control rate (%) 82 80 Best overall response, n (%) Complete response Partial response Stable disease Progressive disease Unable to determine 1 (3) 16 (48) 10 (30) 1 (3) 4 (12) 0 9 (45) 7 (35) 4 (20) 0 Median duration of response, 8.5 6.9 months (range) (4.2,18.4+) (2.8, 20.7+) Ongoing responses, % (n/n) Median PFS, months (95% CI) 59 (10/17) 11.2 (9.6,15.2) 33 (3/9) 7.2 (2.8,11.1) P = pazopanib; S = sunitinib. Amin A, et al. Presented at ASCO 2014 (abstr. 5010).

Safety profile of nivolumab + sunitinib or nivolumab + pazopanib combination therapy S + N (n = 33) P + N (n = 20) Any grade Grade 3 4 Any grade Grade 3 4 Total patients with an event, n (%) 33 (100) 27 (81.8) 20 (100) 14 (70.0) Hypertension 16 (48.5) 6 (18.2) 5 (25.0) 2 (10.0) Increased ALT 13 (39.4) 6 (18.2) 5 (25.0) 4 (20.0) Hyponatraemia 6 (18.2) 5 (15.2) 0 0 Increased lymphocyte count 6 (18.2) 5 (15.2) 1 (5.0) 1 (5.0) Diarrhoea 20 (60.6) 3 (9.1) 12 (60.0) 4 (20.0) Increased AST 12 (36.4) 3 (9.1) 6 (30.0) 4 (20.0) Fatigue 27 (81.8) 3 (9.1) 12 (60.0) 3 (15.0) No grade 5 treatment-related AEs were reported Most toxicities were consistent with the known profile of TKIs 1 grade 3 4 pneumonitis in the S + N arm 36.4% and 25.0% discontinuations due to treatment-related AE in the S + N arm and P + N arm, respectively P = pazopanib; S = sunitinib. Amin A, et al. Presented at ASCO 2014 (abstr. 5010); Hammers H, et al. Presented at ASCO 2014 (abstr. 4504).

Change in baseline (%) Activity of nivolumab + ipilimumab combination therapy 120 N3 + I1 (n = 20) N1 + I3 (n = 22) 120 100 80 60 40 20 100 80 60 40 20 1st occurrence of new lesion -20-40 -60-80 -100-20 -40-60 -80-100 0 6 12 18 24 30 36 42 48 54 Time since first dose (weeks) 0 6 12 18 24 30 36 42 Time since first dose (weeks) Average ORR across the two arms: 45.5% Median duration of response: 7.2 months in N3 + I1 arm Complete responders: 1 patient in N1 + I3 arm Median PFS: 8.4 months and 8.8 months in the N3 + I1 arm and N1 + I3 arm, respectively Hammers H, et al. Presented at ASCO 2014 (abstr. 4504).