Emerging Role of Nivolumab in Advanced Renal Cell Carcinoma Yu-Chieh Tsai, MD, PhD (蔡育傑) Medical oncologist Department of Oncology National Taiwan University Hospital

Disclosure Honorarium (Speaker): AstraZeneca, Astellas, BMS/Ono, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi　

Kidney Cancer : Global Overview Globally ~338,000 new cases of kidney cancers were diagnosed in 2012 with ~143,000 deaths. Unmet need: Traditionally, renal cell carcinoma (the most common type of kidney cancer) is chemo-resistant and not responsive to systemic therapy. World Cancer Reports. 2014 (WHO)

Renal Cancer in Taiwan New case Renal Cell Ca. Histology Mortality 2003 628 545 459 2004 646 589 427 2005 733 657 488 2006 743 665 478 2007 798 720 522 2008 887 814 526 2009 937 847 468 2010 1,028 938 490 2011 1,044 954 2012 1,222 1,125 496 2013 1,228 1,144 2014 1,382 1,290 Cancer Registry Annual Report (Taiwan)

US FDA Approved Drugs for mRCC Targeted therapy Pazopanib Sunitinib Bevacizumab Axitinib Lenvatinib 1992~2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Temsirolimus Sorafenib Cabozantinib Everolimus High dose interleukin-2 IFN- Nivolumab Immunotherapy

Cytokine Era (1992-2005) Inspired by rare report of spontaneous regression of metastatic tumors 14% response rate (CR 5% + PR 9%) with durable responses in a small percentage of patients Systemic toxicities High dose interleukin-2 Motzer criteria Fyfe et al J Clin Oncol. 1995 Motzer et al. J Clin Oncol. 1999

Targeted Therapy Era (2005-2012 ) Included 5 VEGF/VEGFR & 2 mTOR inhibitors Most of them showed PFS benefit (except temsirolimus) Overall response rates - 1st line : 26~47% - 2nd line (after TKI) : 2~19% Median overall survival may reach 32.0 months in RECORD-3 randomized trial Most patients ultimately develop resistance and few have durable disease control Modified from Brugarolas J. N Engl J Med 2007

Most Targeted Therapy Trials Showed Benefit in PFS but not in OS Drug Control Study Design PFS, Mos OS, Mos VEGF Inhibitors Sorafenib[1] Placebo Pts previously treated with IL-2 or IFN-α 5.5 vs 2.8 (HR: 0.44; P < .000001) 17.8 vs 15.2 (HR: 0.88; P = .146) Axitinib[2] Sorafenib Pts previously treated with sunitinib, bevacizumab with IFN-α, temsirolimus, or cytokines 8.3 vs 5.7 (HR: 0.66; P < .0001) 20.1 vs 19.2 (HR: 0.97; P = .374) mTOR inhibitors Everolimus[3] Pts previously treated with VEGFR TKI 4.9 vs 1.9 (HR: 0.33; P < .001) 14.8 vs 14.4 (HR: 0.87; P = .162) Temsirolimus[4] Pts previously treated with sunitinib 4.3 vs 3.9 (HR: 0.87; P = .19) 12.3 vs 16.6 (HR: 1.31; P = .01) 1. Escudier B, et al. J Clin Oncol. 2009;27:3312-3318. 2. Motzer RJ, et al. Lancet Oncol. 2013;14:552-562. 3. Motzer R, et al. Cancer. 2010;116:4256-4265. 4. Hutson TE, et al. J Clin Oncol. 2014;32:760-767

New Era (2015- ) Included 2 VEGFR TKI & 1 PD-1 inhibitor 2nd line trials. control: everolimus Nivolumab & cabozantinib showed OS benefit - mOS: 21.4~25 months Lenvatinib + everolimus (phII) showed amazing PFS - mPFS: 14.6 months Overall response rates - Cabozantinib : 21 % - Lev+Eve : 43 % Choueiri et al. N Engl J Med. 2017

Cancer Immunoediting Schreiber et al. Science. 2011

Activation of T Cells Requires Two Signals Sharma et al. Science. 2015

Mechanism of Immune checkpoint Inhibitors Ribas A. N Engl J Med. 2012

mRCC : anti-CTLA-4 Therapy (ipilimumab) (3mg/kg) (Gr.3~5) (3mg/kg -> 1mg/kg) Yang et al. J Immunother. 2007

mRCC : anti-PD-L1 Therapy (atezolizumab) (20.6 months) (29.1 months) Status of prior VEGF TKI Phase Ia Study For ccRCC p’t (n = 63) - mOS: 28.9 months - mPFS: 5.6 months - ORR: 15% For patients with Fuhrman grade4 and/or sarcomatoid histology ORR was 22% (n=18) McDermott et al. J Clin Oncol. 2016

Restoring Active T-cell Response by PD-1 Inhibition 1. Normal Immune Response 2. Tumor Immune Evasion 3. Immune Response Restored T-cell activation and tumor attack. T-cell inactivation through the PD-1 immune checkpoint. T-cell reactivation and decreased tumor growth* through PD-1 immune checkpoint inhibition. While having an effect on the tumor, this could also affect normal cells. Opdivo＠ is a fully human IgG4 anti-PD-1 monoclonal antibody

mRCC: anti-PD-1 Therapy (nivolumab): CheckMate-025 Eligibility Criteria aRCC with clear-cell component KPS  70% 1-2 prior anti-angiogenic therapies Progression within 6 months prior to enrollment Nivolumab* 3 mg/kg IV every 2 weeks Primary Endpoint: OS Secondary Endpoints: PFS ORR Duration of response Safety Survival by PD-L1 expression N = 821 R ANDOM I S E 1:1 Everolimus* 10 mg/d orally Stratification factors Region MSKCC risk group No. of prior anti-angiogenic Tx Patients were treated until progression or intolerable toxicity occurred Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted

Demographic and Clinical Characteristics Nivolumab Group (N=410) Everolimus Group (N=411) Median age (range) - yr 62 (23-88) 62 (18-86) Sex - no. (%) Male 315 (77) 304 (74) Female 95 (23) 107 (26) MSKCC risk group - No. (%) Favorable 145 (35) 148 (36) Intermediate 201 (49) 203 (49) Poor 64 (16) 60 (15) Site of metastasis - No. (%) Lung 278 (68) 273 (66) Liver 100 (24) 87 (21) Bone 76 (19) 70(17) Motzer et al. N Engl J Med. 2015

Previous Treatment Characteristic Nivolumab Group (N=410) Everolimus Group (N=411) Previous nephrectomy - no. (%) Yes 364 (89) 359 (87) No 46 (11) 52 (13) Median time from initial diagnosis to randomization (range) – mo 31 (1-392) 31 (2-372) Previous antiangiogenic regimens - No. (%) 1 294 (72) 297 (72) 2 116 (28) 114 (28) Previous systemic cancer therapy - No. (%) Sunitinib 246 (60) 242 (59) Pazopanib 119 (29) 131 (32) Axitinib 51 (12) 50 (12) Motzer et al. N Engl J Med. 2015

Nivolumab Achieved an Unprecedented Median OS of More Than 2 years Escudier et al. Eur Urol. 2017 Median OS, months (95% CI) Nivolumab 26.0 (22.2–29.6) Everolimus 19.7 (17.6–22.3) HR (95% CI) 0.73 (0.61–0.88) P = 0.0006 Overall Survival (Probability) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 6 12 18 Months 24 30 36 42 76% 67% 52% Nivolumab 42% Everolimus 3 9 15 21 27 33 39 No. at risk Nivolumab Everolimus 410 359 305 251 204 129 38 411 325 268 214 162 103 32 390 337 276 225 171 80 5 367 289 247 183 130 61 Motzer et al. N Engl J Med. 2015; Plimack et al. 15th International Kidney Cancer Symposium 2016

Overall Survival by MSKCC Risk Group Escudier et al. Eur Urol. 2017

Nivolumab Demonstrated Long-term OS Benefit Atkins et al. Ann Oncol. 2017 McDermott et al. ASCO 2016 Abstract #4507

Progression-Free Survival: No significant Difference Motzer et al. N Engl J Med. 2015

Objective Response Rate Escudier et al. Eur Urol. 2017 Nivolumab Group (N=410) Everolimus Group (N=411) Objective response rate, % 103 (25%) 22 (5%) Odds ratio; p value 5.98; p<0.001 Best overall response 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, months (range) 3.5(1.4-24.8) 3.7(1.5-11.2) Median duration of response, months (range) 12.0 (0-27.6) 12.0 (0-22.2) Motzer et al. N Engl J Med. 2015

Safety Data and irAEs CheckMate 025 McDermott et al. ASCO 2016 Abstract #4507

Safety and Adverse Events Nivolumab Group (n = 406) Everolimus Group (n =397) Any Grade Grade 3 or 4 All events 319 (79) 76 (19) 349 (88) 145 (37) Fatigue 134 (33) 10 (2) 134 (34) 11 (3) Nausea 57 (14) 1 (<1) 66 (17) 3 (1) Diarrhea 50 (12) 5 (1) 84 (21) Decreased appetite 48 (12) 2 (<1) 82 (21) 4 (1) Rash 41 (10) 79 (20) Cough 36 (9) 77 (19) Anemia 32 (8) 7 (2) 94 (24) 31 (8) Dyspnea 30 (7) 51 (13) 2 (1) Peripheral edema 17 (4) 56 (14) Pneuomnitis 16 (4) 6 (1) 58 (15) Mucosal Inflammation 75 (19) 12 (3) Dysgeusia Hyperglycemia 9 (2) 46 (12) 15 (4) Stomatitis 8 (2) 117 (29) Hypertriglyceridemia 64 (16) 20 (5) Epistaxis Motzer et al. N Engl J Med. 2015

Time to Onset and Resolution of Treatment-related Select AEs with Nivolumab aTime to resolution is based on the time of onset of the AE (not at the start of treatment). + indicates a censored value GI = gastrointestinal; NR = not reached Plimack et al. 15th International Kidney Cancer Symposium 2016

Health Related Quality of Life (FKSI-DRS) 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 Time (week) -6 -4 -2 2 6 Numner at risk Nivolumab group EveArolimus group 361 343 334 316 302 270 267 219 236 191 208 157 186 143 164 122 159 102 144 97 132 87 119 74 112 73 63 90 58 89 49 81 35 30 59 53 21 43 15 31 26 9 Average amount of change from baseline (31.0 for both arm) Everolimus group The questionnaire consists of 9 symptom-specific questions that address lack of energy, pain, weight loss, bone pain, fatigue, dyspnea, cough, fevers, and hematuria. Scoring range is form 0 to 36 (36 means no symptom) FKSI-DRS：Functional Assessment of Cancer Therapy Kidney Symptom index – Disease-Related Cella et al. Lancet Oncol. 2016

Other Considerations of CheckMate-025 1. Asian population 2 Other Considerations of CheckMate-025 1. Asian population 2. Treatment beyond progression 3. Predictive biomarkers

CheckMate 025 in Japanese Patients: Antitumor activity Tomita et al. Jpn J Clin Oncol. 2017

Treatment-related AEs Occurring in >15% of Japanese Patients Tomita et al. Jpn J Clin Oncol. 2017

Treatment Beyond Progression in CheckMate 025 Escudier et al. ASCO 2016 Abstract #4509; Eur Urol. 2017

Treated Beyond Progression with Nivolumab: Benefit in Overall Survival Escudier et al. ASCO 2016 Abstract #4509

Tumor Burden Change Post Progression A total of 142 of 153 p’t treated with nivolumab beyond progression had tumor measurements Of these 142 p’t, 14% (n=20) had  30% tumor burden reduction post-progression A total of 52 of 56 p’t treated with everolimus beyond progression had tumor measurements None of these 52 p’t had  30% tumor burden reduction post-progression Escudier et al. ASCO 2016 Abstract #4509; Eur Urol. 2017

Robert S. Kerbel TJCC 2017

Overall Survival by Tumor PD-L1 Expression Patients with qualifiable PD-L1 expression No. (%) Nivolumab Group (370/410, 90%) Everolimus Group (386/411, 94%)  1% 94 (25) 87 (23) <1% 276 (75) 299 (77) 5% 44 (12) 41 (11) <5% 326 (88) 345 (89) N Engl J Med. 2015; 373:1803-13

Estimate of the Neoantigen Repertoire Nat Rev Cancer. 2017; 17:209-222 Science. 2015; 348:69-74

Presented By Toni Choueiri at 2015 ASCO Annual Meeting Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): Biomarker correlations with clinical outcomes Presented By Toni Choueiri at 2015 ASCO Annual Meeting

Summary and conclusions Presented By Toni Choueiri at 2015 ASCO Annual Meeting

Therapeutic Evolution of mRCC Therapy Hsieh et al. Nat Rev Dis Primers. 2017

First-Line Challengers: Ongoing Trials (1) (IO+IO versus sunitinib) IO: immuno-oncology Laurence Albiges EAU 2017

Hypothetical Effect on OS of Blocking Two T-cell Checkpoint Pathways The preliminary data of combining CTLA-4 and PD-1 blockade in mRCC were presented in ASCO 2014 (abstract #4504) & ASCO 2015 (abstract #4516) Antonia et al. Clin Cancer Res. 2014

First-Line Challengers: Ongoing Trials (2) (IO+TT versus sunitinib) IO: immuno-oncology TT: targeted therapy Laurence Albiges EAU 2017

Robert S. Kerbel TJCC 2017

IMmotion 150 Phase II Study RANDOMIZATION Atezolizumab 1200 mg + Bevacizumab 15mg/kg q3w Locally advanced or metastatic RCC with clear cell and/or sarcomatoid component Previously untreated with any systemic therapy Crossover Tx permitted Atezolizumab+Bevacizumab Atezolizumab 1200mg q3w PD Sunitinib 50mg (4wk on, 2wk off) Atezolizumab+Bevacizumab N=305 1:1:1 Primary Endpoint : PFS Secondary Endpoint : ORR, duration of response, OS, ..

Baseline Demographics Thomas Powles ASCO GU 2017

Primary Endpoint: Progression-free Survival (ITT) Thomas Powles ASCO GU 2017

IMmotion 150 Biomarkers: Angiogenesis David McDermott AACR 2017

IMmotion 150 Biomarkers: Immune David McDermott AACR 2017

IMmotion 150 Biomarkers: Myeloid Inflammation David McDermott AACR 2017

First-Line Challengers: Ongoing Trials (3) (IO+TT versus TT+TT versus sunitinib) IO: immuno-oncology TT: targeted therapy Laurence Albiges EAU 2017

Lenvatinib and/or Everolimus in mRCC 2nd Line (VEGFR / FGFR inhibitor) 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 T LENVATINIB 18 mg PO qd + EVEROLIMUS 5 mg PO qd Primary objective PFS (LEN ± EVE vs EVE) Secondary objectives PFS (LEN + EVE vs LEV) ORR (RECIST v1.1) OS Safety and tolerability (CTCAE v4.0) LENVATINIB 24 mg PO qd EVEROLIMUS 10 mg PO qd Median PFS Lenvatinib + everolimus: 14.6 months Lenvatinib : 7.4 months Everolimus: 5.5 months Combo vs. Everolimus -> HR 0·40; p=0·0005 Lancet Oncol. 2015; 16:1473-82

Take Home Message In CheckMate 025 phase III study, Opdivo＠ (nivolumab) showed (compared with everolimus in mRCC 2nd line) - Longer overall survival - Better objective response rate - Better health-related QoL - Less treatment-related AE Opdivo＠ (nivolumab) is well tolerated in Asian patients with mRCC. Opdivo＠ (nivolumab) is approved in Taiwan to treat patients with mRCC whose disease progressed on an antiangiogenic therapy.

Case Presentation

Brief History A 77 y/o male patient, no major systemic disease Left renal cancer, cT3bN0M1 with left renal vein and IVC thrombi, lung metastasis (+) s/p CT-guided biopsy on 2014.7.23. pathology reported clear cell RCC

Pazopanib / Sunitinb Pazopanib 800mg daily was used on 2014.8.14~2014.12.1 Intermittent hematuria, not sure if drug-related Sunitinib 50mg daily (2 weeks on /1 week off) since 2014.12.2 -> shifted gradually to 37.5mg daily (9 days on /5 day off) for better QoL Hypertension, Gr.3, controlled with multiple drugs

Sunitinib

Nivolumab Ataxia in 2016.10 Nivolumab 3mg/kg every 2 weeks x 3 months - Well tolerated, no treatment-related AE 1 month after Cyberknife

T-cell receptor sequencing Presented By Toni Choueiri at 2015 ASCO Annual Meeting