NEXT GENERATION DRUGS IN KIDNEY CANCER. Dr Aine O Reilly Karolinska Institutet Stockholm, Sweden

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1 NEXT GENERATION DRUGS IN KIDNEY CANCER Dr Aine O Reilly Karolinska Institutet Stockholm, Sweden

2 KIDNEY CANCER SUBTYPES Papillary Type 1 and 2 Medullary Collecting duct Chromophobe Translocation Clear cell Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.

3 VEGF & MTOR PATHWAYS IN RCC Reprinted from The Lancet, 373(9669), Rini BI, et al., Renal cell carcinoma, Copyright 2009, with permission from Elsevier.

4 EVOLUTION OF SYSTEMIC THERAPIES IN KIDNEY CANCER Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.

5 OVERALL SURVIVAL IN KIDNEY CANCER Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.

6 NEXT GENERATION DRUGS IN KIDNEY CANCER Part 1: Recently approved agents Cabozantinib Nivolumab Lenvatinib + everolimus Part 2: Future directions Combination targeted therapy and immune checkpoint inhibitor Combination of immune checkpoint inhibitor

7 CABOZANTINIB VEGFR MET AXL RET FLT3 Kit

8 A PHASE I STUDY OF CABOZANTINIB (XL184) In patients with renal cell cancer: ORR Choueiri TK, et al., Ann Oncol 2014;25(8): By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO).

9 A PHASE I STUDY OF CABOZANTINIB (XL184) In patients with renal cell cancer: PFS and OS Choueiri TK, et al., Ann Oncol 2014;25(8): By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO).

10 CABOZANTINIB VERSUS EVEROLIMUS In advanced renal cell carcinoma: METEOR Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial Choueiri TK, et al., The Lancet Oncology 2016;17(7):

11 CABOZANTINIB VERSUS EVEROLIMUS In advanced renal cell carcinoma: METEOR CABOMETYX 60 mg once daily (N=330) Randomised 658 patients Randomisation 1:1 No crossover allowed Everolimus 10 mg once daily (N=328) Inclusion Criteria: Clear cell histology Progressive disease post at least 1 line VEGF targeted therapy Primary Endpoint: PFS Secondary Endpoints: OS, ORR, safety and tolerability Dose reductions were allowed in both arms. The primary progression-free survival (PFS) analysis was conducted in the first 375 subjects randomized to treatment. The intent-to-treat (ITT) population included all 658 patients. Patients received treatment until disease progression or experiencing unacceptable toxicity. Patients in both arms who had disease progression could continue treatment at the discretion of the investigator. Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial, , Copyright 2016, with permission from Elsevier.

12 CABOZANTINIB VERSUS EVEROLIMUS In advanced renal cell carcinoma: METEOR: Demographics Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial, , Copyright 2016, with permission from Elsevier.

13 CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR: PFS Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial, , Copyright 2016, with permission from Elsevier.

14 CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR: ORR Objective response rate (95% CI) Best overall response, n (%) Cabozantinib N=330 Everolimus N=328 IRC Investigator IRC Investigator 17 (13 22) 24 (19 29) 3 (2 6) 4 (2 7) Confirmed complete response Confirmed partial response 57 (17) 78 (24) 11 (3) 14 (4) Stable disease 216 (65) 209 (63) 203 (62) 205 (63) Progressive disease 41 (12) 29 (9) 88 (27) 87 (27) Not evaluable or missing 16 (5) 14 (4) 26 (8) 22 (7) Choueiri TK, et al., Lancet Oncol 2016;17(7):

15 CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR: OS Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial, , Copyright 2016, with permission from Elsevier.

16 OS AND PFS IN SUBGROUPS OS PFS MSKCC risk group Tumour MET status Bone metastases Visceral and bone metastases Number of previous VEGFR TKIs Duration of first VEGFR TKIs Reprinted from The Lancet Oncology, 17(7), Choueiri TK, et al., Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial, , Copyright 2016, with permission from Elsevier.

17 BONE METASTASES BONE METASTASES BONE and VISCERAL METASTASES NO BONE METASTASES CABOZANTINIB N=77 EVEOLIMUS N=65 CABOZANTINIB N=60 EVEOLIMUS N=52 CABOZANTINIB N=253 EVEOLIMUS N=263 ORR % (95% CI) PFS MONTHS (95% CI) 17 (9 27) 0 20 (11 32) 0 17 (13 23) 4 (2 7) 7.4 ( ) 2.7 ( ) 5.6 ( ) 1.9 ( ) 7.4 ( ) 4.2 ( ) OS MONTHS (95% CI) 20.1 (14.9 NE) 12.1 ( ) 20.1 (12.4-NE) 10.7 ( ) NE (18.4 NE) 17.5 ( ) SRE No. (%) TIME TO SRE MONTHS (range) 18 (23) 19 (29) (12) 7 (10) 3.7 ( ) 2.5 ( ) ( ) 4.3 ( ) NE, not estimable; SRE, skeletal related event Escudier B, et al., J Clin Oncol 2018;36(8):

18 CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR: Toxicity n (%) Cabozantinib (N=331) Everolimus (N=322) Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4 Any adverse event 70 (21) 210 (63) 25 (8) 103 (32) 167 (52) 26 (8) Diarrhoea 206 (62) 43 (13) 0 85 (26) 7 (2) 0 Fatigue 159 (48) 36 (11) (40) 24 (7%) 0 Nausea 158 (48) 15 (5) 0 92 (29) 1 (<1) 0 Decreased appetite 146 (44) 10 (3) (35) 3 (1) 0 Palmar-plantar erythrodysaesthesia syndrome 115 (35) 27 (8) 0 16 (5) 3 (1) 0 Vomiting 106 (32) 7 (2) 0 44 (14) 3 (1) 0 Weight decreased 105 (32) 9 (3) 0 42 (13) 0 0 Constipation 89 (27) 1 (<1) 0 64 (20) 1 (<1) 0 Dysgeusia 80 (24) (9) 0 0 Hypothyroidism 76 (23) (<1) 1 (<1) 0 Hypertension 73 (22) 49 (15) 0 14 (4) 12 (4) 0 Dysphonia 68 (21) 2 (1) 0 16 (5) 0 0 Cough 67 (20) 1 (<1) (33) 3 (1) 0 Stomatitis 65 (20) 8 (2) 0 71 (22) 7 (2) 0 Mucosal inflammation 60 (18) 5 (2) 0 64 (20) 10 (3) 1 (<1) Dyspnoea 56 (17) 10 (3) 0 82 (26) 11 (3) 3 (1) Anaemia Hypertriglyceridaemia 42 (13) 17 (5) 19 (6) 4 (1) Hyperglycaemia 15 (5) 2 (1) 1 (<1) 46 (14) 16 (5) 0 Proteinuria 37 (11) 8 (2) 0 28 (9) 2 (1) (23) 31 (10) 53 (17) 7 (2) 0 3 (1) Choueiri TK, et al., Lancet Oncol 2016;17(7):

19 CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR Tolerability Cabozantinib n=331 Everolimus n=322 Median duration exposure, months (IQR) 8.3 ( ) 4.4 ( ) Median daily dose, mg (IQR) 43 (36 56) 9 (7 11) Dose reductions, n (%) 206 (62) 80 (25) Drug discontinuation*, n (%) 40 (12) 34 (11) Data at December 2015 cut off *Discontinuation for adverse event not related to progression IQR interquartile range Choueiri TK, et al., Lancet Oncol 2016;17(7):

20 CABOZANTINIB VS. SUNITINIB AS INITIAL TARGETED THERAPY For patients with metastatic RCC of poor or intermediate risk: CABOSUN Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A CABOSUN Trial Choueiri TK, et al., J Clin Oncol 2017;35(6):591 7.

21 CABOZANTINIB VS. SUNITINIB AS INITIAL TARGETED THERAPY For patients with metastatic RCC of poor or intermediate risk: CABOSUN N=150 Locally advanced or metastatic RCC No prior systemic treatment Cabozantinib PO QD for 6 weeks Sunitinib PO QD for 4 weeks Choueiri TK, et al., J Clin Oncol 2017;35(6):591 7.

22 CABOSUN: PFS Cabozantinib Median PFS 8.2 months Sunitinib Median PFS 5.6 months HR 0.66; 95% CI, ; p=0.012 Choueiri TK, et al., J Clin Oncol 35(6), 2017: Reprinted with permission. 2017, American Society of Clinical Oncology. All rights reserved.

23 CABOSUN: RESPONSE Choueiri TK, et al., J Clin Oncol 35(6), 2017: Reprinted with permission. 2017, American Society of Clinical Oncology. All rights reserved.

24 CABOSUN: OS Cabozantinib Median OS 30.3 months Sunitinib Median OS 21.8 months HR, 0.80; 95% CI, 0.50 to 1.26 Choueiri TK, et al., J Clin Oncol 35(6), 2017: Reprinted with permission. 2017, American Society of Clinical Oncology. All rights reserved.

25 CABOSUN: TOXICITY Adverse events Choueiri TK, et al., J Clin Oncol 35(6), 2017: Reprinted with permission. 2017, American Society of Clinical Oncology. All rights reserved.

26 LENVATINIB VEGF receptor 1, 2,3 FGF receptor 1, 2, 3, 4 PDGFR kinase

27 A PHASE 1B CLINICAL TRIAL OF LENVATINIB + EVEROLIMUS For treatment of mrcc Molina AM, et al., Cancer Chemother Pharmacol. 2014;73(1): Licensed under CC BY 4.0

28 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc 153 patients a LENVIMA 18 mg + everolimus 5 mg (n=51) LENVIMA 24 mg (n=52) Randomised 1:1:1 Major: Progression-free survival b Other: Objective response rate Everolimus 10 mg (n=50) Other: Overall survival Motzer RJ, et al., Lancet Oncol 2015;16(15):

29 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc: Baseline demographics Lenvatinib plus everolimus (n=51) Motzer RJ, et al., Lancet Oncol 2015;16(15): Singleagent lenvatinib (n=52) Singleagent everolimus (n=50) Age (years) 61 (44-79) 64 (41-79) 59 (37-77) Sex, n (%) Men women ECOG performance status, n (%) 0 1 MSKCC risk group, n (%) Favourable Intermediate Poor Heng risk group,* n (%) Favourable Intermediate Poor Haemoglobin, n (%) 130 g/l (men) or 115 g/l (women) >130 g/l (men) or >115 g/l (women) Corrected serum calcium, n (%) 2.5 mmol/l <2.5 mmol/l Number of metastases, n (%) (69) 16 (31) 27 (53) 24 (47) 12 (24) 19 (37) 20 (39) 8 (16) 32 (64) 10 (20) 33 (65) 18 (35) 6 (12) 44 (88) 18 (35) 15 (29) 18 (35) 39 (75) 13 (25) 29 (56) 23 (44) 11 (21) 18 (35) 23 (44) 7 (14) 33 (64) 12 (23) 36 (69) 16 (31) 8 (15) 44 (85) 9 (17) 15 (29) 28 (54) 38 (76) 12 (24) 28 (56) 22 (44) 12 (24) 19 (38) 19 (38) 9 (18) 29 (58) 12 (24) 31 (62) 19 (38) 8 (16) 42 (84) 5 (10) 15 (30) 30 (60) Site of metastasis, n (%) Bone Liver Lung Lymph nodes Lenvatinib plus everolimus (n=51) 12 (24) 10 (20) 27 (53) 25 (49) Singleagent lenvatinib (n=52) 13 (25) 14 (27) 35 (67) 31 (60) Singleagent everolimus (n=50) 16 (32) 13 (26) 35 (70) 33 (66) Previous nephrectomy, n (%) 44 (86) 43 (83) 48 (96) Previous VEGF-targeted therapy, n (%) Axitinib Bevacizumab Pazopanib Sorafenib Sunitinib Tivozanib Other Duration of previous VEGFtargeted therapy (months) Best response for previous VEGFtargeted therapy, n (%) Complete response Partial response Stable disease Progressive disease Not evaluated or unknown Previous checkpoint inhibitor therapy 1 (2) 0 9 (18) 1 (2) 36 (71 3 (6) 1 (2) 0.8 ( ) 1 (2) 14 (28) 20 (39) 7 (14) 9 (18) 2 (4) 1 (2) 13 (25) 0 35 (67) 1 (2) ( ) 0 10 (19) 28 (54) 10 (19) 4 (8) 0 4 (8) 13 (26) 2 (4) 28 (56) 2 (4) 1 (2) 8.9 ( ) 0 10 (20) 21 (42) 15 (30) 4 (8) 1 (2) 2 (4) 2 (4) Previous interferon therapy 4 (8) 3 (6) 7 (14) Previous radiotherapy 6 (12) 11 (21) 11 (22)

30 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc: PFS Lenvatinib plus everolimus (n=51) Progression-free survival Events 26 (51%) Singleagent lenvatinib (n=52) 38 (73%) Singleagent everolimus (n=50) 37 (74%) Median (95% CI) progressionfree survival (months) 14.6 ( ) 7.4 ( ) 5.5 ( ) Progression-free survival (95% CI) At 6 months 64% (48-76) 63% (48-75) 39% (24-53) At 12 months 51% (35-65) 34% (21-48) 21% (10-36) Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial, , Copyright 2015, with permission from Elsevier.

31 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc: Independent assessment of PFS Lenvatinib + everolimus vs. everolimus HR 0.45 [95% CI ]; p= Lenvatinib vs. everolimus HR 0.62 [95% CI ]; p=0.12 Reprinted from The Lancet Oncology, 17(1), Motzer R, et al., Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma, e4 e5, Copyright 2016, with permission from Elsevier.

32 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc: ORR Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial, , Copyright 2015, with permission from Elsevier.

33 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc: OS Lenvatinib + everolimus versus everolimus HR 0.55, 95% CI ; p=0.062 Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial, , Copyright 2015, with permission from Elsevier.

34 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc: OS Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial, , Copyright 2015, with permission from Elsevier.

35 LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mrcc: Lenvatinib + everolimus vs. lenvatinib PFS Lenvatinib + everolimus vs. lenvatinib HR 0.66, 95% CI ; p=0.12 Reprinted from The Lancet Oncology, 17(1), Motzer R, et al., Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma, e4 e5, Copyright 2016, with permission from Elsevier.

36 LENVATINIB, EVEROLIMUS & THE COMBINATION In patients with mrcc: Lenvatinib + everolimus vs. lenvatinib OS Lenvatinib + everolimus vs. lenvatinib HR 0.75, ; p=0.32 Reprinted from The Lancet Oncology, 16(15), Motzer R, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial, , Copyright 2015, with permission from Elsevier.

37 LENVATINIB, EVEROLIMUS & THE COMBINATION In patients with mrcc: Toxicity n (%) Lenvatinib plus everolimus (n=51) Lenvatinib (n=52) Everolimus (n=50) Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4 Any TEAE 14 (28) 29 (57) 7 (14) 8 (15) 38 (73) 3 (6) 23 (46) 21 (42) 4 (8) Diarrhoea 33 (65) 10 (20) 0 31 (60) 6 (12) 0 16 (32) 1 (2) 0 Decreased appetite 23 (45) 3 (6) 0 28 (54) 2 (4) 0 9 (18) 0 0 Fatigue or asthenia 23 (45) 7 (14) 0 22 (42) 4 (8) 0 18 (36) 0 1 (2) Vomiting 19 (37) 3 (8) 0 18 (35) 2 (4) 0 5 (10) 0 0 Nausea 18 (35) 3 (6) 0 28 (54) 4 (8) 0 8 (16) 0 0 Cough 19 (37) (15) 1 (2) 0 15 (30) 0 0 Hypercholesterolaemia 16 (31) 1 (2) 0 5 (10) 0 1 (2) 8 (16) 0 0 Decreased weight 15 (29) 1 (2) 0 22 (42) 3 (6) 0 4 (8) 0 0 Stomatitis 15 (29) (23) 1 (2) 0 20 (40) 1 (2) 0 Hypertriglyceridaemia 14 (27) 4 (8) 0 5 (10) 2 (4) 0 8 (16) 4 (8) 0 Hypertension 14 (27) 7 (14) 0 16 (31) 9 (17) 0 4 (8) 1 (2) 0 Proteinuria 9 (18) 2 (4) 0 6 (12) 10 (19) 0 6 (12) 1 (2) 0 Rash 9 (18) (17) (22) 0 0 Hyperglycaemia 8 (16) (6) (12) 4 (8) 1 (2) Back pain 8 (16) 2 (4) 0 11 (21) (14) 0 0 Mouth-ulceration 5 (10) (8) 1 (2) 0 Palmar-plantar erythrodysaesthesia syndrome 4 (8) (15) (4) 0 0 Anaemia 4 (8) 4 (8) 0 3 (6) 1 (2) 0 7 (14) 6 (12) 0 Motzer RJ, et al., Lancet Oncol 2015;16(15):

38 NIVOLUMAB Atkins MB, et al., Ann Oncol 2017;28(7): By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO)

39 CHECKMATE 010 Endpoint 0.3 mg/kg (n=60) 2 mg/kg (n=54) 10 mg/kg (n=54) Overall response 12 (20%) 12 (22%) 11 (20%) Median progression-free survival 2.7 months 4.0 months 4.2 months Median overall survival 18.2 months 25.5 months 24.7 months 1-year overall survival 63% 72% 70% Treatment related serious adverse events 2 (3.4%) 6 (11%) 4 (7.4%) Motzer RJ, et al., Lancet Oncol 2015;16(15):

40 LONG-TERM OS WITH NIVOLUMAB In previously treated patients with advancer RCC from Phase I and II studies In Phase I and II studies, minimum follow-up was 50.5 months and 49.2 months, respectively NE, not estimable McDermott DF, et al., J Clin Oncol 2016;34(15_suppl):abstr Reproduced with permission from Dr McDemott.

41 CHECKMATE 025 Nivolumab vs. everolimus in advanced RCC Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma Motzer RJ, et al., N Engl J Med 2015;373(19):

42 CHECKMATE 025 Nivolumab vs. everolimus in advanced RCC Patients with ADVANCED RCC previously treated with a prior anti-angiogenic systemic therapy* Randomised 1:1 OPDIVO (nivolumab) monotherapy 3 mg/kg IV every 2 weeks (n=410) Everolimus 10 mg qd po (n=411) Primary endpoint Overall survival Treatment continued until disease progression or unacceptable toxicity *One or two previous regimens; no more than three total previous regimens, including cytokines and cytotoxic chemotherapy drugs. 1-hour infusion; dose modifications were not permitted. Motzer RJ, et al., N Engl J Med 2015;373(19):

43 CHECKMATE 025: BASELINE DEMOGRAPHICS Nivolumab vs. everolimus in advanced RCC From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19): Copyright 2015, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

44 CHECKMATE 025: OS Nivolumab vs. everolimus in advanced RCC From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19): Copyright 2015, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

45 CHECKMATE 025: ORR Nivolumab vs. everolimus in advanced RCC Nivolumab (n=410) Everolimus (n=411) Objective response rate, n (%) 103 (25) 22 (5) Odds ratio (95% CI) 5.98 ( ) Best overall response, n (%) Complete response Partial response Stable disease Progressive disease Not evaluated 4 (1) 99 (24) 141 (34) 143 (35) 23 (6) 2 (1) 20 (5) 227 (55) 114 (28) 48 (12) Median time to response, months (range) Median duration of response, months (range)* 3.5 ( ) 3.7 ( ) 12.0 (0 27.6) 12.0 (0 22.2) *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. Motzer RJ, et al.. N Engl J Med 2015;373(19):

46 CHECKMATE 025: PFS Nivolumab vs. everolimus in advanced RCC From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19): Copyright 2015, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

47 CHECKMATE 025: TOXICITY Nivolumab vs. everolimus in advanced RCC No Grade 5 toxicity associated with nivolumab Discontinuation for AEs: Nivolumab 8%, everolimus 13% From N Engl J Med, Motzer R, et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma, 373(19): Copyright 2015, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

48 IMMUNE RELATED ADVERSE EVENTS

49 IMMUNE RELATED RESPONSE CRITERIA Changes in tumour burden in immune-related response criteria (irrc), compared with RECIST Criteria irrcª RECIST v1.1 Progressive disease 25% vs. nadir (at any time) in two consecutive images 4 wk apart 20% in sum of target lesion diameters, and must be absolute of 5 mm vs. smallest diameter sums on study (including baseline sum, if Stable disease Partial response Complete response New, measurable lesions ( 5 x 5 mm) New, non-measurable lesions (<5 x 5 mm) Non-index lesions 50% vs. baseline cannot be established, nor can 25% vs. nadir 50% vs. baseline in two observations 4 wk apart Disappearance of all lesions in two consecutive observations 4 wk apart Combined into total tumour burden Do not define progression; preclude ircr Contribute to defining ircr; complete disappearance required that is smallest) Neither sufficient nor in target lesion sums to qualify for PD or PR compared with the smallest diameter sums on study 30% in sum of target lesion diameters vs. baseline diameter sums Disappearance of all target lesions Considered to have PD Depends on baseline measurements; can be considered to have CR-PD in certain scenarios Considered to have PD ªirRC often require confirmation by a second consecutive assessment 4 weeks later. RECIST, Response Evaluation Criteria in Solid Tumours. Maronne KA, et al., Oncology (Williston Park) 2016;30(8):

50 REGULATORY BODY STATUS FDA approval EMA approval Cabozantinib April 2016 June 2016 Nivolumab November 2015 February 2016 Lenvatinib + everolimus May 2016 June 2016

51 CHOICE OF THERAPY Cabozantinib Nivolumab PD as best response 14% PD as best response 35% PFS benefit No PFS benefit Most benefit in good and intermediate risk Most benefit in poor risk Equal benefit across all age subgroups Less benefit in patients >75 High rate of toxicity Favourable toxicity profile Oral administration Intravenous administration Bone metastases -

52 NEXT GENERATION DRUGS IN KIDNEY CANCER Part 1: Recently approved agents Cabozantinib Nivolumab Lenvatinib + everolimus Part 2: Future directions Combination targeted therapy and immune checkpoint inhibitor Combination of immune checkpoint inhibitor

53 PRIMARY, ADAPTIVE, AND ACQUIRED RESISTANCE TO CANCER IMMUNOTHERAPY Reprinted from Cell, 168(4), Sharma P, et al., Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy, , Copyright 2017, with permission from Elsevier.

54 THE CANCER IMMUNOGRAM From Blank CU, et al., The cancer immunogram. Science 2016; 352(6286): Reprinted with permission from AAAS.

55 COMBINATION THERAPIES 1. Combination targeted therapy and immune checkpoint inhibitor 2. Combination of immune checkpoint inhibitors

56 Randomised Continuous nivolumab 3 mg/kg IV Q2W CHECKMATE 016: STUDY DESIGN Previously treated or treatment-naïve patients with mrcc Treatment-naïve patients with mrcc Arm N3I1: Nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg IV Q3W x4 Arm N1I3: Nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg IV Q3W x4 Arm N3I3: Nivolumab 3 mg/kg IV + ipilimumab 3 mg/kg IV Q3W x4 Primary endpoint Safety (AEs, serious AEs, laboratory tests) Secondary endpoint Efficacy (ORR, DOR, OS, PFS) For expansion cohorts N3I1 and N1I3, 1 prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC was allowed if recurrence occurred 6 months after the last dose of adjuvant or neoadjuvant therapy. Interferon alpha or interleukin-2 were allowed as prior therapy. DOR, duration of response; ORR, objective response rate; Q2W, every 2 weeks; Q3W, every 3 weeks. Hammers HJ, et al., J Clin Oncol 2017;35(34):

57 CHECKMATE 016: RESPONSES Hammers HJ, et al. J Clin Oncol 2017;35(34): Reprinted with permission American Society of Clinical Oncology. All rights reserved.

58 CHECKMATE 016: PFS Hammers HJ, et al., J Clin Oncol 2017;35(34): Reprinted with permission American Society of Clinical Oncology. All rights reserved.

59 CHECKMATE 016: OS Hammers HJ, et al., J Clin Oncol 2017;35(34): Reprinted with permission American Society of Clinical Oncology. All rights reserved.

60 CHECKMATE 214 Patients Treatment Treatmentnaïve advanced or metastatic clear-cell RCC Measurable disease KPS 70% Tumour tissue available for PD-L1 testing Randomised 1:1 Stratified by IMDC prognostic score (0 vs 1 2 vs 3 6) Region (US vs Canada/Europe vs Rest of World) Arm A Nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg IV Q3W for 4 doses, then nivolumab 3 mg/kg IV Q2W Arm B Sunitinib 50 mg orally once daily for 4 weeks (6-week cycles) Treatment until progression or unacceptable toxicity IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; QW3, every 3 weeks. Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr. LBA5.

61 CHECKMATE 214: ORR Escudier B, et al,. Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

62 CHECKMATE 214: DURATION OF RESPONSE Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

63 CHECKMATE 214: PROGRESSION FREE SURVIVAL: CO-PRIMARY ENDPOINT PFS per IRRC: IMDC intermediate/poor risk Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

64 CHECKMATE 214: OVERALL SURVIVAL: CO-PRIMARY ENDPOINT OS: IMDC intermediate/poor risk Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

65 CHECKMATE 214: PD-L1 EXPRESSION: EXPLORATORY ENDPOINT PFS by PD-L1 expression: IMDC intermediate/poor risk Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

66 EXPLORATORY ENDPOINT ORR and PFS: IMDC favourable risk a 11% of patients in both arms had tumour PD-L1 expression 1%; b IRRC-assessed by RECIST v1.1; c IRRC-assessed. Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

67 SECONDARY ENDPOINT Treatment-related adverse events: All treated patients a Two patients had grade 5 cardiac arrest. b Pneumonitis, immune mediated bronchitis, lower GI haemorrhage, hemophagocytic syndrome, sudden death, liver toxicity, lung infection. c Cardiac arrest (n=2), heart failure, multiple organ failure. Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

68 CHECKMATE 214: TOXICITY Immune-mediated adverse events: All treated patients 60% of patients treated with NIVO + IPI required systemic corticosteroids for an adverse event Secondary immunosuppression with infliximab (3%) and mycophenolic acid (1%) was reported Immune-mediated AE analyses included events, regardless of causality, occurring <100 days of the last dose. These analyses were limited to patients who received immune modulating medication for treatment of the event, except endocrine events that were included in the analysis regardless of treatment since these events are often managed without immunosuppression. Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier.

69 COMBINATION TARGETED THERAPY AND IMMUNE CHECKPOINT INHIBITOR Decreased vascularity, decreased permeability and Impaired lymphocyte trafficking The promotion of populations of immunosuppressive immune cells in the tumour microenvironment Functional impairment of immune cells Einstein DJ, McDermott DF, Clin Adv Hematol Oncol 2017;15(6):

70 COMBINATION CHECKPOINT INHIBITOR + TKI Javelin Renal 100 Phase 1b Axitinib + avelumab First Line NCT Phase 1 Pembrolizumab + axitinib First Line NCT Phase 1 Atezolizumab + bevacizumab First Line NCT Phase 1 Nivolumab + sunitinib or pazopanib NCT Phase 1 IMmotion 150 Randomised Phase 2 Pembrolizumab + pazopanib 600 mg or pazopanib 800 mg Atezolizumab + bevacizumab vs sunitinib 1 prior systemic therapy First Line First line

71 AVELUMAB + AXITINIB IN UNTREATED ADVANCED RCC JAVELIN Renal 100 Study design: Phase 1b JAVELIN Renal 100* Choueiri TK, et al., J Clin Oncol 2017;35(suppl):abstr Reproduced with permission from Dr Choueiri.

72 AVELUMAB + AXITINIB IN UNTREATED ADVANCED RCC JAVELIN Renal 100: ORR *According to RECIST v1.1 per investigator assessment. 1 patient died due to myocarditis prior to the first oncologic assessment, and 1 patient had a first oncologic assessment prior to the protocol-specified time window and then died due to disease progression. Choueiri TK, et al., J Clin Oncol 2017;35(suppl):abstr Reproduced with permission from Dr Choueiri.

73 AVELUMAB + AXITINIB IN UNTREATED ADVANCED RCC JAVELIN Renal 100: ORR Reprinted from Lancet Oncol, Online first 09 March 2018, Choueiri TK, et al., Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial, doi.org/ /s (18) Copyright 2018, with permission from Elsevier.

74 JAVELIN RENAL 101 Choueiri TK, et al., J Clin Oncol 35, 2017 (suppl; abstr TPS4594). Reproduced with permission from Dr Choueiri.

75 PEMBROLIZUMAB + AXITINIB IN UNTREATED ADVANCED RCC ORR=73% Median PFS 20.9 months (15.4 NE) Reprinted from Lancet Oncol, 19(3), Atkins MB, et al., Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a nonrandomised, open-label, dose-finding, and dose-expansion phase 1b trial, Copyright 2018, with permission from Elsevier.

76 Randomization 1:1 N=840 KEYNOTE 426 Patients Recurrent or Stage IV clear cell RCC Measurable disease per RECIST v1.1 No prior systemic therapy for advanced RCC Kamofsky performance status 70 Stratificatino factors IMDC risk group Geographic region Pembrolizumab 200 mg q3w + Axitinib 5 mg bid Sunitinib 50 mg qd 4 weeks on and 2 weeks off Imaging follow-up Survival follow-up BICR, blinded independent central review; BID, twice daily; IMDC, International Metastatic RCC Database Consortium; QD, once daily; Q3W, every 3 weeks; RCC, renal cell carcinoma. a Patients who discontinue treatment for reasons other than BICR-verified progressive disease should continue with imaging assessments per the protocol-defined schedule until progressive disease is BICR verified or further confirmed by investigator, initiation of a new anticancer treatment, death, withdrawal of consent, or study conclusion or early termination, whichever comes first. Rini B, et al., J Clin Oncol 35, 2017 (suppl; abstr TPS4597)

77 PHASE 1 ATEZOLIZUMAB + BEVACIZUMAB Bevacizumab 15 mg/kg every 3 weeks Starting C1D1 Atezolizumab 20 mg/kg every 3 weeks Starting C2D1 Wallin JJ, et al., Nat Commun 2016;7: Licensed under CC BY 4.0

78 PHASE 2 RANDOMISED Atezolizumab +/- bevacizumab vs. sunitinib in untreated mrcc (IMmotion 150) Courtesy of Dr McDermott. McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431)

79 IMMOTION 150: PFS Atezo. Atezolizumab; Bev, bevacizumab. *P values are for descriptive purposes only and not adjusted for multiple comparisons. McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431). Reproduced with permission from Dr Mc Dermott and Dr Thomas Powles.

80 IMMOTION 150: PFS IN PD-L1+ PATIENTS *P-values are for descriptive purposes only and not adjusted for multiple comparisons. McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431). Reproduced with permission from Dr Mc Dermott and Dr Thomas Powles.

81 IMMOTION 150: ORR 75% of responses are ongoing across treatment arms, and the median DOR is not estimable due to an insufficient number of PFS events in responders Clinical cut-off, Oct 17, Median duration of follow-up, 2017 mo. McDermott DF, et al., J Clin Oncol 35, 2017 (suppl 6S; abstract 431). Reproduced with permission from Dr Mc Dermott and Dr Thomas Powles.

82 PHASE 3 RANDOMISED Atezolizumab + bevacizumab vs sunitinib in untreated mrcc (IMmotion 151) No prior therapy in metastatic setting Unresectable locally advanced or metastatic RCC Clear cell &/or sarcomatoid component R a n d o m i s e d Atezolizumab 1200 every 3 weeks + Bevacizumab 15 mg/kg every 3 weeks Sunitinib 50 mg once daily 4 weeks on/2 weeks off Primary endpoints: 1. PFS in patients with detectable PD-L1 expression 2. OS in all randomised patients ClinicalTrials.gov. A Study of Atezolizumab in Combination With Bevacizumab versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma [IMmotion151]

83 IMMOTION 151: PFS IN PD-L1+ PATIENTS ORR ATEZOLIZUMAB+ BEVACIZUMAB 43% SUNITINIB 35% Motzer RJ, et al., J Clin Oncol 2018;36(6_suppl):abstract 578. Presented at ASCO Reproduced with permission from Dr Robert J Motzer.

84 COMBINATION IMMUNOTHERAPY AND TARGETED THERAPY Treatment Pembrolizumab-lenvatinib vs. everolimus-lenvatinib vs. sunitinib Nivolumab-ipilimumab vs. sunitinib Primary End Point Estimated no. of Patients Enrolled Trial Clinical Trials.gov.No. PFS 735 CLEAR NCT PFS and OS 1070 CheckMate 214 NCT Atezolizumab-bevacizumab vs. sunitinib PFS and OS in PD-L1-detectable tumours 900 IMmotion151 NCT Avelumab-axitinib vs. sunitinib Pembrolizumab-axitinib vs. sunitinib PFS 583 JAVELIN Renal 101 NCT PFS and OS 840 KEYNOTE-426 NCT Choueiri TK, et al., N Engl J Med 2017;376(4):

85 NON CLEAR CELL HISTOLOGY RCC Trials of immune checkpoint inhibitors Courtesy of Moshe Ornstein, MD (Cleveland Clinic) Presented by Sumanta Pal at 2017 ASCO Annual Meeting.

86 NON CLEAR CELL HISTOLOGY RCC: SAVOLITINIB ORR MET driven MET independent Choueiri TK, et al., J Clin Oncol 35(26), 2017: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

87 NON CLEAR CELL HISTOLOGY RCC: SAVOLITINIB: PFS HR 0.33; 95% CI, 0.20 to 0.52; log-rank P < 0.001) Choueiri TK, et al., J Clin Oncol 35(26), 2017: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

88 EVOLUTION OF SYSTEMIC THERAPIES IN KIDNEY CANCER Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Disease Primers, Hsieh, JJ, et al., Nat Rev Dis Primers 2017;3:17009, copyright 2017.

89 KEY LEARNING POINTS Cabozantinib and nivolumab have regulatory approval for the treatment of advanced renal cell cancer The combination of lenvatinib and everolimus has regulatory approval for the treatment of advanced renal cell cancer The introduction of the immune checkpoint inhibitors has altered the profile of toxicity encountered in treating mrcc The next generation of clinical trials in mrcc is focused on combination therapy

90 THANK YOU!