Therapeutic Algorithm for Renal Cancer Walter M. Stadler MD, FACP

Disclosures Consultant: Speakers Bureau: Bayer, Caremark/CVS, Genentech, Johnson & Johnson, MedPacto, Merck Millenium, NCI/SAIC-Frederick, Sotio Speakers Bureau: CME providers (sponsorship unknown): Imedex, CME Innovations, CME Network, Dava Oncology, Research-to-Practice, Medical Communications Media, Grant/Research Support (to institution): Active Biotech, Bayer, Bristol-Myers-Squibb, Boerhinger-Ingelheim, Dendreon Exilixis, Novartis, Genentech (Roche), Glaxo-Smith-Kline, Merck, Medivation, Millenium (Astellas), Pfizer, NIH, Alliance Stockholder: None Expert Witness Miscellaneous/Editorial: Cancer (ACS), BCAN, Demos Medical Publishing, KCA, Up-To-Date, Wolters-Kluwer

Pathology Clear cell (conventional) Papillary Chromophobe Fuhrman grading 1-4 Papillary Type 1 & 2 Mucinous-tubular and spindle? Clear-cell papillary Chromophobe Genetically related to benign oncocytoma Collecting duct Genetically related to urothelial Medullary (only in sickle cell trait or disease) TFE-3 translocation tumor Same translocation as alveolar-soft part sarcoma More than one translocation Renal Cancer|

Therapy: What we know Disease natural history is highly variable Metastatic site ablative therapy has a role Primary tumor resection has a role in low volume metastatic disease Immunotherapy has activity HD IL2 leads to dramatic and durable tumor responses in a very small minority of clear cell renal cancer patients Immune checkpoint inhibitors are rapidly emerging as effective VEGF pathway inhibitors slow disease progression in majority of clear cell renal cancer patients Likely improve survival mTOR inhibitors have modest anti-tumor activity Survival improved in untreated poor prognosis patients

International prognostic model β SE Square root of days from diagnosis to study entry −0.0192 0.002 ECOG performance status 0 −1.524 0.11 ECOG performance status 1 −0.838 Number of metastatic sites 0.324 0.032 Protocol immunotherapy −0.574 0.094 Natural log of hemoglobin −2.47 0.20 Natural log of LDH 0.611 0.062 Square root of white blood count 0.623 0.071 1/Square root of alkaline phosphatase −6.665 1.39 Serum calcium 0.105 0.033 Overall survival by risk category for the original data set (solid line) and validation data set (dashed line). Manola J et al. Clin Cancer Res 2011;17:5443-5450

Take Home Point 1 For asymptomatic metastatic patients with minimal burden of disease consider Ablative therapy to render NED Active surveillance

Treatment: HD IL2 Cytokine Working Group trial HD IL2 vs sc IL2/IFNA HD IL2: 600,000 IU/kg q8o x 14 doses sc IL2/IFNA: 5 x 106 IU/m2 4d/wk IL2; 5 x106 IU/m2 2d/wk Selection criteria Non-clear cell have minimal to no benefit Suggestion that post-VEGFR TKI treatment has higher toxicity and lower efficacy sc IL2/IFNA HD IL2 Pt number 91 95 Deaths 1 CR 3 8 (p= 0.21) PR 6 14 Resp. Duration 15 mo 24 mo (p=0.18) Med. Surv. 13 mo 17 mo (p = 0.21) Durable 3 yr CR 7 (p=0.01)

Duration of Response (mo) Nivolumab (anti-PD1) in renal caner Population Dose (mg/kg) Patients (n) ORR n (%) Duration of Response (mo) SD 24 wk PFSR at 24 wk (%) ALL RCC 1, 10 33 9 (27) 5.6+ to 22.3+ 56 RCC 1 17 4 (24) 5.6+ to17.5+ 47 10 16 5 (31)* 8.4 to 22.3+ 5 (31) 67 *One CR. Phase 3 vs everolimus completed accrual

RECIST 1.1 Response Rate (ORR) MPDL3280A Phase 1a (anti-PDL1) RECIST 1.1 Response Rate (ORR) SD of 24 Weeks or Longer 24-Week PFS Overall population (N = 140) 21% 16% 45% RCC* (n = 47) 13% 32% 53% Clear cell (n = 40) 35% 57% Non-clear cell (n = 6) 17% 20% * 1 patient with unknown histology. Includes sarcomatoid and papillary RCC. All patients first dosed prior to August 1, 2012; data cutoff February 1, 2013. ORR includes unconfirmed PR/CR and confirmed PR/CR. Cho, et al, ASCO 2013

Nivolumab + Ipilimumab Hammers, et al, ASCO 2014 Renal Cancer|

Take home point 2 Consider HD IL2 first in patients with clear cell, good PS, and good cardiopulmonary reserve Should be performed at center with experience Utility in comparison to PD1 checkpoint inhibitors? Investigational immunotherapy approaches are reasonable Large number of phase 2 and phase 3 trials in process Anti- PD1 pathway agents likely to enter armamentarium

Kinase interaction map Sorafenib Sunitinib Karaman, et al Nature Biotech. 26:127, 2008

First line: Sunitinib vs IFNA Total Death Sunitinib 190 IFN-a 200 13

Motzer RJ et al. N Engl J Med 2013;369:722-731. Kaplan–Meier Estimates of Progression-free Survival According to Independent Review. First line:Sunitinib vs Pazopanib Motzer RJ et al. N Engl J Med 2013;369:722-731.

Context of Definitive Trial(s) VEGF Pathway inhibitors in renal cancer Agent(s) Context of Definitive Trial(s) Comparator No Prior Therapy Prior IL2 or IFNA Prior VEGF Pathway Outcome Bevacizumab/IFNA IFNA X PFS (bev) Sunitinib OS (sun) Sorafenib Placebo PFS (sor) Pazopanib PFS (Paz) Axitinib PFS (Ax) None Tivozanib OS (sor) Dovitinib X (and 1 prior mTOR)

VEGF pathway inhibitor toxicities Cardiac (~73%) Hypertension Reversible Posterior Leukoencephalopathy MI CVA CHF Integument Hand/Foot Mucositis Diarrhea Systemic Fatigue Dysgeusia Metabolic Liver toxicity Hypothyroidism The degree that patients experience these toxicities varies a little bit from one agent to the other but they're present in almost all of them. Discuss when therapy might need to be discontinued. Hall, et al. J Am Coll Cardiol HF, 2013

Take home point 3 There is no definitive data as to which VEGF pathway inhibitor to use first Best evidence suggests pazopanib Dose intensity probably matters VEGF pathway inhibitors can be used sequentially Is there an advantage to intermittent therapy? Every drug company has at least one VEGFR inhibitor (The Lemming Principal) There are pharmacologic, but minimal clinical differences between the agents

mTOR Inhibitors (The Lemming Principal Revisited) Sirolimus (Rapamycin) Temsirolimus Everolimus (RAD001)

First line: Temsirolimus vs IFNA Renal Cancer|

Second line: Everolimus vs Placebo Renal Cancer|

Cross-over upon progression Comparative and sequential data Primary PFS-1st line Secondary Combined PFS ORR-1st line OS Safety Study endpoints 1 : 1 R A N D O M I Z E** Everolimus 10 mg/day SCREEN Sunitinib 50 mg/day*** 1st Line Everolimus 10 mg/day Sunitinib 50 mg/day*** 2nd Line Cross-over upon progression N = 471 *NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off. Motzer, et al; ASCO 2013 21

Sunitinib versus everolimus sequential Renal Cancer|

mTOR toxicities Metabolic Integument Systemic Infectious risks Hyperglycemia Hyperlipidemia Increased creatinine Integument Diarrhea Mucositis Pruritic rash Systemic Fatigue Edema Pneumonitis Infectious risks Hematologic Thrombocytopenia Discuss how to handle side effects. In particular, TP w and w/o symptoms Issues in discontinuation

Context of Definitive Trial mTOR inhibitors Agent Context of Definitive Trial Comparator No Prior Therapy Prior VEGF Pathway Outcome Temsirolimus* IFNA X OS (tem) Everolimus Placebo PFS (ev) Temsirolimus Sorafenib OS (sor) Sunitinib OS (sun) *Poor prognosis only, included non-clear cell

Take home point 4 It’s not clear where and when mTOR inhibitors should be used with best data as first line therapy in poor prognosis pts

Adjuvant therapy Large randomized placebo controlled phase 3 trials Sorafenib, Sunitinib (ECOG ASSURE) pT1b G3-4 N0 (or pNX where clinically N0) M0 pT2 G (any) N0 (or pNX where clinically N0) M0 pT3 G (any) N0 (or pNX where clinically N0) M0 pT4 G (any) N0 (or pNX where clinically N0) M0 or T(any) G (any) N+(fully resected) M0 Pazopanib Everolimus (in progress) Renal Cancer|

ASSURE: Disease-Free Survival Median 5.8 yrs Median 6.0 yrs Events Patients 5-yr DFS 97.5% CI HR Sunitinib 265 647 53.8% 49.0 – 59.1% 1.01 0.83 – 1.23 Sorafenib 272 649 52.8% 48.0 – 58.0% 0.98 0.81 – 1.19 Placebo 270 55.8% 51.2 – 60.9% The DFS for sunitinib, sorafenib and placebo demonstrated very tightly overlapping kaplan meier curves with little separation. Median DFS for sunitinib is 70 months (5.83 years), for sorafenib is 69.7 months (5.81 years), for placebo is 72.4 months (6.03 years). Presented by: Naomi B. Haas, MD

RCC Conclusions VEGF pathway directed agents are active in clear cell RCC Sunitinib, Pazopanib, Sorafenib, Axitinib and Bevacizumab/IFNA improve PFS Pazopanib is first line reference standard Sequential VEGF pathway directed therapy probably improves survival mTOR inhibitors are active in RCC Temsirolimus improves survival of poor prognosis RCC over IFNA Everolimus improves PFS of RCC patients previously treated with a VEGFR inhibitor Role of mTOR inhibitors is decreasing Immunotherapy is active HD-IL2 leads to long term complete responses, but only in ~5% of highly selected patients PD1 pathway inhibitors likely to play a role