ESMO E-Learning Next Generation Drugs in Kidney Cancer

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NEXT GENERATION DRUGS IN KIDNEY CANCER

Dr Aine O’Reilly Karolinska Institutet Stockholm, Sweden KIDNEY CANCER SUBTYPES

Medullary Collecting Papillary duct Type 1 and 2

Chromophobe Translocation

Clear cell

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 CABOZANTINIB

VEGFR

MET

AXL

RET

FLT3

Kit A PHASE I STUDY OF CABOZANTINIB (XL184) In patients with renal cell cancer: ORR

Choueiri TK, et al., Ann Oncol 2014;25(8):1603–8. By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO). 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):1603–8. By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO). 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):917–27. CABOZANTINIB VERSUS EVEROLIMUS In advanced renal cell carcinoma: METEOR

CABOMETYX™ 60 mg once daily§ (N=330) Randomised Randomisation 1:1 658 patients†‡ No crossover allowed Everolimus 10 mg once daily§ (N=328)

Inclusion Criteria: Primary Endpoint: PFS

 Clear cell histology Secondary Endpoints: OS, ORR,

 Progressive disease post at least safety and tolerability 1 line VEGF targeted therapy

† 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, 917-927, Copyright 2016, with permission from Elsevier. 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, 917-927, Copyright 2016, with permission from Elsevier. CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR: PFS

Cabozantinib Everolimus N=330 N=328 IRC Investigator IRC Investigator Objective response rate 17 (13–22) 24 (19–29) 3 (2–6) 4 (2–7) (95% CI) Best overall response, n (%) Confirmed complete response 0 0 0 0 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):917–27. CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR: OS

MSKCC risk group

Tumour MET status

Bone metastases

Visceral and bone metastases Number of previous VEGFR TKIs Duration of first VEGFR TKIs

BONE METASTASES BONE and VISCERAL METASTASES NO BONE METASTASES

CABOZANTINIB EVEOLIMUS CABOZANTINIB EVEOLIMUS CABOZANTINIB EVEOLIMUS N=77 N=65 N=60 N=52 N=253 N=263

ORR 17 (9–27) 0 20 (11–32) 0 17 (13–23) 4 (2–7) % (95% CI)

PFS 7.4 (5.5–10.4) 2.7 (1.9–3.8) 5.6 (4.5–9.4) 1.9 (1.8–2.9) 7.4 (6.5–9.2) 4.2 (3.8–5.5) MONTHS (95% CI)

OS 20.1 12.1 20.1 10.7 NE 17.5 MONTHS (95% CI) (14.9–NE) (9.6-16.4) (12.4-NE) (7.5-12.5) (18.4–NE) (15.7–19.6) SRE 18 (23) 19 (29) - - 31 (12) 7 (10) No. (%)

TIME TO SRE 3.7 (0.4–14.5) 2.5 (0.3–7.3) - - 5.6 (0.5–18.4) 4.3 (0.7–13.4) MONTHS (range)

NE, not estimable; SRE, skeletal related event

Escudier B, et al., J Clin Oncol 2018;36(8):765–72. CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR: Toxicity

Cabozantinib (N=331) Everolimus (N=322) n (%) 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) 0 130 (40) 24 (7%) 0 Nausea 158 (48) 15 (5) 0 92 (29) 1 (<1) 0 Decreased appetite 146 (44) 10 (3) 0 111 (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) 0 0 30 (9) 0 0 Hypothyroidism 76 (23) 0 0 1 (<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) 0 107 (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 42 (13) 19 (6) 0 73 (23) 53 (17) 0 Hypertriglyceridaemia 17 (5) 4 (1) 0 31 (10) 7 (2) 3 (1) Hyperglycaemia 15 (5) 2 (1) 1 (<1) 46 (14) 16 (5) 0 Proteinuria 37 (11) 8 (2) 0 28 (9) 2 (1) 0

Choueiri TK, et al., Lancet Oncol 2016;17(7):917–27. CABOZANTINIB VERSUS EVEROLIMUS In advanced RCC: METEOR – Tolerability

Cabozantinib Everolimus n=331 n=322

Median duration exposure, months (IQR) 8.3 (4.2–14.6) 4.4 (1.9–8.6)

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):917–27. 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 A031203 CABOSUN Trial

Choueiri TK, et al., J Clin Oncol 2017;35(6):591–7. CABOZANTINIB VS. SUNITINIB AS INITIAL TARGETED THERAPY For patients with metastatic RCC of poor or intermediate risk: CABOSUN

Cabozantinib PO QD for 6 weeks N=150

 Locally advanced or metastatic RCC

 No prior systemic treatment Sunitinib PO QD for 4 weeks

Choueiri TK, et al., J Clin Oncol 2017;35(6):591–7. CABOSUN: PFS

Cabozantinib Median PFS 8.2 months Sunitinib Median PFS 5.6 months HR 0.66; 95% CI, 0.46–0.95; p=0.012

Cabozantinib Median OS 30.3 months Sunitinib Median OS 21.8 months HR, 0.80; 95% CI, 0.50 to 1.26

Adverse events

 VEGF receptor 1, 2 ,3

 FGF receptor 1, 2, 3, 4

 PDGFR kinase A PHASE 1B CLINICAL TRIAL OF LENVATINIB + EVEROLIMUS For treatment of mRCC

Molina AM, et al., Cancer Chemother Pharmacol. 2014;73(1):181–9. Licensed under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mRCC

153 patientsa LENVIMA 18 mg + Major: Progression-free survivalb everolimus 5 mg (n=51) Randomised LENVIMA 24 mg (n=52) Other: Objective response rate 1:1:1

Everolimus 10 mg (n=50) Other: Overall survival

Motzer RJ, et al., Lancet Oncol 2015;16(15):1473–82. LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mRCC: Baseline demographics

Lenvatinib Single- Single- Lenvatinib Single- Single- plus agent agent plus agent agent everolimus lenvatinib everolimus everolimus lenvatinib everolimus (n=51) (n=52) (n=50) (n=51) (n=52) (n=50) Age (years) 61 (44-79) 64 (41-79) 59 (37-77) Site of metastasis, n (%) Sex, n (%) Bone 12 (24) 13 (25) 16 (32) Men 35 (69) 39 (75) 38 (76) Liver 10 (20) 14 (27) 13 (26) women 16 (31) 13 (25) 12 (24) Lung 27 (53) 35 (67) 35 (70) Lymph nodes 25 (49) 31 (60) 33 (66) ECOG performance status, n (%) † 0 27 (53) 29 (56) 28 (56) Previous nephrectomy, n (%) 44 (86) 43 (83) 48 (96) 1 24 (47) 23 (44) 22 (44) Previous VEGF-targeted therapy,‡ n (%) MSKCC risk group, n (%) 1 (2) 2 (4) 0 Axitinib Favourable 12 (24) 11 (21) 12 (24) 0 1 (2) 4 (8) Bevacizumab Intermediate 19 (37) 18 (35) 19 (38) 9 (18) 13 (25) 13 (26) Pazopanib Poor 20 (39) 23 (44) 19 (38) 1 (2) 0 2 (4) Sorafenib 36 (71 35 (67) 28 (56) Heng risk group,* n (%) Sunitinib 3 (6) 1 (2) 2 (4) Favourable 8 (16) 7 (14) 9 (18) Tivozanib 1 (2) 0 1 (2) Intermediate 32 (64) 33 (64) 29 (58) Other Poor 10 (20) 12 (23) 12 (24) Duration of previous VEGF- 0.8 14.5 8.9 Haemoglobin, n (%) targeted therapy (months) (2.0-66.2) (0.7-81.8) (1.6-57.8) ≤130 g/L (men) or ≤115 g/L 33 (65) 36 (69) 31 (62) (women) Best response for previous VEGF- >130 g/L (men) or >115 g/L targeted therapy, n (%) 18 (35) 16 (31) 19 (38) (women) Complete response 1 (2) 0 0 Partial response 14 (28) 10 (19) 10 (20) Corrected serum calcium, n (%) Stable disease 20 (39) 28 (54) 21 (42) ≥2.5 mmol/L 6 (12) 8 (15) 8 (16) Progressive disease 7 (14) 10 (19) 15 (30) <2.5 mmol/L 44 (88) 44 (85) 42 (84) Not evaluated or unknown 9 (18) 4 (8) 4 (8) Number of metastases, n (%) Previous checkpoint inhibitor 1 (2) 2 (4) 2 (4) 1 18 (35) 9 (17) 5 (10) therapy 2 15 (29) 15 (29) 15 (30) ≥3 18 (35) 28 (54) 30 (60) Previous interferon therapy 4 (8) 3 (6) 7 (14) Previous radiotherapy 6 (12) 11 (21) 11 (22) Motzer RJ, et al., Lancet Oncol 2015;16(15):1473–82. LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mRCC: PFS

Lenvatinib Single- Single- plus agent agent everolimus lenvatinib everolimus (n=51) (n=52) (n=50) Progression-free survival 26 38 37 Events (51%) (73%) (74%) Median (95% CI) 14.6 7.4 5.5 progression- (5.9-20.1) (5.6-10.2) (3.5-7.1) free survival (months) Progression-free survival (95% CI) At 6 months 64% (48-76) 63% (48-75) 39% (24-53) At 12 51% (35-65) 34% (21-48) 21% (10-36) months

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, 1473–82, Copyright 2015, with permission from Elsevier. LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mRCC: Independent assessment of PFS

Lenvatinib + everolimus vs. everolimus HR 0.45 [95% CI 0.27–0.79]; p=0.0029

Lenvatinib vs. everolimus HR 0.62 [95% CI 0.37–1.04]; 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. LENVATINIB, EVEROLIMUS AND THE COMBINATION In patients with mRCC: ORR

Lenvatinib + everolimus versus everolimus HR 0.55, 95% CI 0.30–1.01; p=0.062

Lenvatinib + everolimus vs. lenvatinib HR 0.66, 95% CI 0.39–1.10; p=0.12

Lenvatinib + everolimus vs. lenvatinib HR 0.75, 0.43–1.30; p=0.32

Lenvatinib plus everolimus (n=51) Lenvatinib (n=52) Everolimus (n=50) n (%) 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) 0 0 8 (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) 0 0 12 (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) 0 0 9 (17) 0 0 11 (22) 0 0 Hyperglycaemia 8 (16) 0 0 3 (6) 0 0 6 (12) 4 (8) 1 (2) Back pain 8 (16) 2 (4) 0 11 (21) 0 0 7 (14) 0 0 Mouth-ulceration 5 (10) 0 0 0 0 0 4 (8) 1 (2) 0 Palmar-plantar 4 (8) 0 0 8 (15) 0 0 2 (4) 0 0 erythrodysaesthesia syndrome 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):1473–82. NIVOLUMAB

Atkins MB, et al., Ann Oncol 2017;28(7):1484–94. By permission of Oxford University Press, on behalf of the European Society for Medical Oncology (ESMO) CHECKMATE 010

0.3 mg/kg 2 mg/kg 10 mg/kg Endpoint (n=60) (n=54) (n=54) Overall response 12 (20%) 12 (22%) 11 (20%) Median progression-free 2.7 months 4.0 months 4.2 months survival Median overall survival 18.2 months 25.5 months 24.7 months 1-year overall survival 63% 72% 70% Treatment related serious 2 (3.4%) 6 (11%) 4 (7.4%) adverse events

Motzer RJ, et al., Lancet Oncol 2015;16(15):1473–82. 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. 4507. Reproduced with permission from Dr McDemott. 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):1803–13. CHECKMATE 025

Nivolumab vs. everolimus in advanced RCC

OPDIVO® (nivolumab) Treatment monotherapy 3 mg/kg Patients with continued IV every 2 weeks† Primary ADVANCED RCC until disease Randomised (n=410) endpoint previously treated with progression 1:1 Overall a prior anti-angiogenic or survival systemic therapy* Everolimus unacceptable 10 mg qd po toxicity (n=411)

*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):1803–13. CHECKMATE 025: BASELINE DEMOGRAPHICS Nivolumab vs. everolimus in advanced RCC

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 (3.68–9.72) Best overall response, n (%) Complete response 4 (1) 2 (1) Partial response 99 (24) 20 (5) Stable disease 141 (34) 227 (55) Progressive disease 143 (35) 114 (28) Not evaluated 23 (6) 48 (12)

Median time to response, 3.5 (1.4–24.8) 3.7 (1.5–11.2) months (range) Median duration of response, 12.0 (0–27.6) 12.0 (0–22.2) months (range)*

*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):1803–13. CHECKMATE 025: PFS

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):1803-13. Copyright © 2015, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. IMMUNE RELATED ADVERSE EVENTS 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 ≥20% ↑ in sum of target lesion diameters, and consecutive images ≥4 wk apart must be absolute ↑ of ≥5 mm vs. smallest diameter sums on study (including baseline sum, if that is smallest) Stable disease 50% ↓ vs. baseline cannot be established, Neither sufficient ↑ nor ↓ in target lesion sums to nor can 25% ↑ vs. nadir qualify for PD or PR compared with the smallest diameter sums on study Partial response ≥50% ↓ vs. baseline in two observations ≥30% ↓ in sum of target lesion diameters vs. ≥4 wk apart baseline diameter sums Complete response Disappearance of all lesions in two Disappearance of all target lesions consecutive observations ≥4 wk apart New, measurable lesions Combined into total tumour burden Considered to have PD (≥5 x 5 mm) New, non-measurable Do not define progression; preclude irCR Depends on baseline measurements; can be lesions (<5 x 5 mm) considered to have CR-PD in certain scenarios Non-index lesions Contribute to defining irCR; complete Considered to have PD disappearance required

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):713–21. REGULATORY BODY STATUS

FDA approval EMA approval Cabozantinib April 2016 June 2016 Nivolumab November 2015 February 2016 Lenvatinib + everolimus May 2016 June 2016 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 - 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 PRIMARY, ADAPTIVE, AND ACQUIRED RESISTANCE TO CANCER IMMUNOTHERAPY

From Blank CU, et al., The “cancer immunogram”. Science 2016; 352(6286):658–60. Reprinted with permission from AAAS. COMBINATION THERAPIES

1. Combination targeted therapy and immune checkpoint inhibitor

2. Combination of immune checkpoint inhibitors CHECKMATE 016: STUDY DESIGN

Arm N3I1: Previously treated or Nivolumab 3 mg/kg IV + Primary endpoint treatment-naïve ipilimumab 1 mg/kg IV Q3W x4 Safety patients with mRCC IV mg/kg 3 (AEs, serious AEs, Arm N1I3: laboratory tests) Nivolumab 1 mg/kg IV +

ipilimumab 3 mg/kg IV Q3W x4 Q2W Secondary endpoint nivolumab

Randomised Efficacy Treatment-naïve Arm N3I3: (ORR, DOR, patients with mRCC Nivolumab 3 mg/kg IV + OS, PFS)

ipilimumab 3 mg/kg IV Q3W x4 Continuous

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):3851–8. CHECKMATE 016: RESPONSES

Patients Treatment

 Treatment- Randomised Arm A naïve advanced 1:1 Nivolumab 3 mg/kg IV + or metastatic ipilimumab 1 mg/kg IV Q3W for Stratified by clear-cell RCC 4 doses, then nivolumab 3 mg/kg  IMDC prognostic Treatment until  Measurable IV Q2W disease score (0 vs 1–2 vs progression or 3–6)  KPS ≥70% unacceptable  Region (US vs  Tumour tissue toxicity Arm B available for Canada/Europe vs Sunitinib 50 mg orally once daily PD-L1 testing Rest of World) for 4 weeks (6-week cycles)

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. CHECKMATE 214: ORR

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

Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier. 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. 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. 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. EXPLORATORY ENDPOINT

ORR and PFS: IMDC favourable risk

a11% of patients in both arms had tumour PD-L1 expression ≥1%; bIRRC-assessed by RECIST v1.1; cIRRC-assessed.

Escudier B, et al., Ann Oncol 2017;28(suppl_5): abstr LBA5. Reproduced with permission from Dr Escudier. SECONDARY ENDPOINT

Treatment-related adverse events: All treated patients

aTwo patients had grade 5 cardiac arrest. bPneumonitis, immune mediated bronchitis, lower GI haemorrhage, hemophagocytic syndrome, sudden death, liver toxicity, lung infection. cCardiac 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. 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. 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):478–88. COMBINATION CHECKPOINT INHIBITOR + TKI

Javelin Renal 100 Phase 1b Axitinib + avelumab First Line NCT02133742 Phase 1 Pembrolizumab + axitinib First Line NCT01633970 Phase 1 Atezolizumab + bevacizumab First Line ≥1 prior systemic NCT01472081 Phase 1 Nivolumab + sunitinib or pazopanib therapy Pembrolizumab + pazopanib 600 mg or NCT02014636 Phase 1 First Line pazopanib 800 mg Randomised Atezolizumab + bevacizumab vs IMmotion 150 First line Phase 2 sunitinib 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 4504. Reproduced with permission from Dr Choueiri. 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 4504. Reproduced with permission from Dr Choueiri. 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/10.1016/S1470- 2045(18)30107-4. Copyright 2018, with permission from Elsevier. JAVELIN RENAL 101

Choueiri TK, et al., J Clin Oncol 35, 2017 (suppl; abstr TPS4594). Reproduced with permission from Dr Choueiri. 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 non- randomised, open-label, dose-finding, and dose-expansion phase 1b trial, 405–15. Copyright 2018, with permission from Elsevier. KEYNOTE 426

Patients Pembrolizumab • Recurrent or Stage IV 200 mg q3w + clear cell RCC Stratificatino Axitinib 5 mg bid • Measurable disease factors per RECIST v1.1 • IMDC risk Imaging Survival

• No prior systemic group N=840 follow-up follow-up therapy for advanced • Geographic Sunitinib 50 mg qd RCC region 1:1 Randomization • Kamofsky performance 4 weeks on and status ≥70 2 weeks off

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. aPatients 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) PHASE 1 ATEZOLIZUMAB + BEVACIZUMAB

Bevacizumab Atezolizumab 15 mg/kg every 3 weeks 20 mg/kg every 3 weeks Starting C1D1 Starting C2D1

Wallin JJ, et al., Nat Commun 2016;7:12624. Licensed under CC BY 4.0 http://creativecommons.org/licenses/by/4.0/ 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) 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. 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. 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, 2016. 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. PHASE 3 RANDOMISED

Atezolizumab + bevacizumab vs sunitinib in untreated mRCC (IMmotion 151) R a Atezolizumab 1200 every 3 weeks  No prior therapy in metastatic n + setting d Bevacizumab 15 mg/kg every 3 weeks

 Unresectable locally advanced o or metastatic RCC m i  Clear cell &/or sarcomatoid Sunitinib 50 mg once daily component s 4 weeks on/2 weeks off e d 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]https://clinicaltrials.gov/ct2/show/NCT02420821 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 2018. Reproduced with permission from Dr Robert J Motzer. COMBINATION IMMUNOTHERAPY AND TARGETED THERAPY

Primary End Estimated no. of Clinical Treatment Trial Point Patients Enrolled Trials.gov.No. Pembrolizumab-lenvatinib vs. PFS 735 CLEAR NCT02811861 everolimus-lenvatinib vs. sunitinib Nivolumab-ipilimumab vs. PFS and OS 1070 CheckMate 214 NCT02231749 sunitinib

Atezolizumab-bevacizumab PFS and OS in 900 IMmotion151 NCT02420821 vs. sunitinib PD-L1-detectable tumours

Avelumab-axitinib vs. PFS 583 JAVELIN Renal 101 NCT02684006 sunitinib Pembrolizumab-axitinib vs. PFS and OS 840 KEYNOTE-426 NCT02853331 sunitinib

Choueiri TK, et al., N Engl J Med 2017;376(4):354-366. 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. NON CLEAR CELL HISTOLOGY RCC: SAVOLITINIB – ORR

MET driven MET independent

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: 2993–3001. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved. EVOLUTION OF SYSTEMIC THERAPIES IN KIDNEY CANCER

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 THANK YOU!