Integrating novel therapy in advanced renal cell carcinoma

Transcription

1 Integrating novel therapy in advanced renal cell carcinoma Tian Zhang, MD Assistant Professor of Medicine GU Oncology Duke Cancer Institute March 11, 2017

2 Disclosures Research Funding Janssen Pfizer Consultant Acerta G1 Therapeutics

3 Outline Approved systemic therapies in RCC Immunotherapies in RCC Checkpoint inhibitors in RCC Cabozantinib in RCC METEOR, CABOSUN trials Integrating novel systemic therapies

4 FDA Approval Timeline: mrcc Therapy (Post Cytokine Era) Tyrosine Kinase Inhibitors Sorafenib 1 (12/05) Sunitinib 2 (1/06) Pazopanib 3 (10/09) Axitinib 4 (1/12) Cabozantinib Lenvatinib (4/16) (6/16) mtor Inhibitors Oral Intravenous Temsirolimus 5 (5/07) Everolimus 6 (3/09) Anti-VEGF Antibody Everolimus 6 (6/16) Bevacizumab + IFN-α 7 (7/09) Immunotherapy HD IL Nivolumab 8 (11/15) 1. NEXAVAR (sorafenib) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; SUTENT (sunitinib malate) [prescribing information]. New York, NY: Pfizer Labs; VOTRIENT (pazopanib) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; INLYTA (axitinib) [prescribing information]. New York, NY: Pfizer Labs; TORISEL (temsirolimus) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; AFINITOR (everolimus) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; AVASTIN (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.

5 First Line: Summary of Efficacy Data Drug Control N (Drug vs Control) ORR, % PFS, Months OS, Months Sunitinib 1,2 IFN-α 375 vs vs 12 (P<0.001) 11 vs 5 (P<0.001) 26.4 vs 21.8 (P=0.049) VEGF Inhibitors Pazopanib 3,4 Placebo 290 vs 145 Pazopanib 5,6 Sunitinib 557 vs 553 Bevacizumab + IFN-α 7,8 Placebo + IFN-α 369 vs vs 3 (P<0.001) 31 vs 25 (P=0.03) 26 vs 13 (P<0.0001) 9.2 vs 4.2 (P<0.0001) 8.4 vs 9.5 (HR=1.05) 8.5 vs 5.2 (P<0.0001) 22.9 vs 20.5 (P=0.224 [1-sided]) 28.3 vs 29.1 (P=0.24) 18.3 vs 17.4 (P=0.069) Bevacizumab + Placebo + IFN-α 9 IFN-α 327 vs vs 13 (P<0.001) 10.2 vs 5.4 (P<0.001) 23.3 vs 21.3 (P=0.1291) mtori Temsirolimus 10,11, IFN-α 209 vs 207 (n=210, Tem/IFN) 8.6 vs vs 3.1 (P=0.0001) 10.9 vs 7.3 (P=0.008) *Stratified HR. For poor-risk patients. 1. Motzer RJ, et al. N Engl J Med. 2007;356: Motzer R, et al. J Clin Oncol. 2009;27: Sternberg C, et al. J Clin Oncol. 2010;28: Sternberg C, et al. Eur J Cancer. 2013;49: Motzer RJ, et al. N Engl J Med. 2013;369: Motzer RJ, et al. N Engl J Med. 2014;370: Rini B, et al. J Clin Oncol. 2008;26: Rini B, et al. J Clin Oncol. 2010;28: Escudier B, et al. J Clin Oncol. 2010;28: Torisel [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals; Hudes G, et al. N Engl J Med. 2007;356:

6 Second Line: Summary of Efficacy Data VEGF Inhibitors Drug Control N (Drug vs Control) ORR, % PFS, Months OS, Months Sorafenib 1,2 Placebo 451 vs vs 0 Axitinib 3,4 Sorafenib 361 vs vs 12 (P=0.0001) 5.5 vs 2.8 (HR=0.44) (P< ) 17.8 vs 15.2 (P=0.146) 17.8 vs 14.3 (P=0.029]) 6.7 vs vs 19.2 (P<0.0001) (P=0.374) mtori Everolimus 5,6 Placebo 272 vs vs 0.0 Temsirolimus 7 Sorafenib 259 vs vs vs vs vs 14.4 (P<0.001) (P=0.162) (P=0.19) 12.3 vs 16.6 (P=0.014) VEGF/MET/ AXL Inhibitor Cabozantinib 8 Everolimus 330 vs vs 5 (P=0.001) 7.4 vs 3.9 (HR=0.52) (P<0.001) First interim data: NR (HR=0.67), (P=0.005) Immunotherapy Nivolumab 9 Everolimus 410 vs vs 5 (P<0.0001) 4.6 vs 4.4 (HR=0.88) (P=0.11) 25 vs 19.6 (HR=0.73) (P=0.002) Independent review. Investigator. Post-crossover placebo-censored OS data. 1. Escudier B, et al. N Engl J Med. 2007;356: Escudier B, et al. J Clin Oncol. 2009;27: Rini B, et al. Lancet. 2011;378: Motzer R, et al. Lancet. 2013;14: Motzer R, et al. Lancet. 2008;372: Motzer R, et al. Cancer. 2010;116: Hutson TE, et al. J Clin Oncol. 2014;32: Choueiri TK, et al. N Engl J Med. 2015;373: Motzer RJ, et al. N Engl J Med. 2015;373:

7 NCCN Guidelines: mrcc Treatment Relapse or stage IV and surgically unresectable Predominant clear cell histology Non-clear cell histology Chemotherapy Systemic therapy First-line Therapy* Clinical trial or Sunitinib (category 1) or Temsirolimus (category 1 for poorprognosis patients, category 2B for selected patients of other risk groups) or Bevacizumab + IFN (category 1) or Pazopanib (category 1) or High dose IL-2 for selected patients or Axitinib or Sorafenib for selected patients and Best supportive care Follow-up *Category 1 recommendations are listed in order of FDA approval; Poor-prognosis patients, defined as those with 3 predictors of short survival; Patients with excellent performance status and normal organ function; Best supportive care can include palliative RT, metastasectomy, bisphosphonates, or RANK ligand inhibitors for bony metastases; In clear cell and non-clear cell RCC with predominant sarcomatoid features, gemcitabine + doxorubicin (category 2B) and gemcitabine + sunitinib (category 2B) have shown benefit; Currently available tyrosine kinase inhibitors used in first-line therapy include: axitinib, pazopanib, sorafenib, or sunitinib; # Based on the results of phase III trials, eligible patients should preferentially receive this agent over everolimus. Adapted from the NCCN clinical practice guidelines in oncology (NCCN Guidelines ): kidney cancer. National Comprehensive Cancer Network website. V Accessed 12/14/15. Subsequent Therapy Clinical trial or Targeted therapy: After tyrosine inhibitor therapy Axitinib (category 1) Cabozantinib (category 1) # Nivolumab (category 1) # Everolimus (category 1) Sorafenib Sunitinib Pazopanib Temsirolimus (category 2B) Bevacizumab (category 2B) After cytokine therapy Axitinib (category 1) Sorafenib (category 1) Sunitinib (category 1) Pazopanib (category 1) Temsirolimus Bevacizumab or Cytokine therapy: High-dose IL-2 for selected patients (category 2B) and Best supportive care

8 Nivolumab and Atezolizumab trials in RCC 8

9 CheckMate 025: Study Design Previously treated mrcc* Stratification factors: Region MSKCC risk group Number of prior antiangiogenic therapies *Inclusion/Exclusion: 1-2 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 No prior CNS metastasis 10 mg/day prednisone equivalent OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; Nivolumab 3 mg/kg intravenously every 2 weeks (n=410) Randomization 1:1 No crossover allowed Everolimus 10 mg qd orally (n=411) Primary endpoint: OS Tumor assessment by RECIST 1.1 every 8 weeks Patients were treated until progression or intolerable toxicity occurred Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted Secondary endpoints: Confirmed ORR

10 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

11 Checkmate 025: Overall survival Overall Survival (Probability) Median OS, months (95% CI) Nivolumab 25.0 (21.8 NE) Everolimus 19.6 ( ) HR (98.5% CI): 0.73 ( ) P = Everolimus Nivolumab No. of patients at risk Months Nivolumab Everolimus Minimum follow-up was 14 months. NE, not estimable. Motzer RJ et al, NEJM, 2015

12 Overall survival by PD-L1 expression 1.0 PD-L1 1% (n = 24%) Median OS, months (95% CI) Nivolumab 21.8 ( ) Everolimus 18.8 ( ) PD-L1 <1% (n = 76%) Median OS, months (95% CI) Nivolumab 27.4 (21.4 NE) Everolimus 21.2 ( ) HR (95% CI): 0.79 ( ) HR (95% CI): 0.77 ( ) Overall Survival (Probability) Everolimus Nivolumab Everolimus Nivolumab No. of patients at risk Months Nivolumab Everolimus Months

13 CheckMate 025: OS Subgroup Analysis Events (Patients) Subgroup Nivolumab Everolimus HR (95% CI) Number of sites of metastases 1 2 Bone metastases Yes No Liver metastases Yes No Prior therapy Sunitinib Pazopanib Months on 1L therapy <6 6 Prior anti-angiogenic therapies 1 2 MSKCC risk score Favorable Intermediate Poor IMDC risk score Favorable Intermediate Poor 14 (68) 168 (341) 42 (76) 141 (334) 54 (100) 129 (310) 123 (257) 53 (126) 61 (110) 122 (300) 144 (317) 37 (90) 38 (137) 95 (193) 50 (79) 13 (55) 102 (242) 61 (96) 21 (71) 194 (338) 45 (70) 170 (341) 52 (87) 163 (324) 138 (261) 79 (136) 81 (130) 134 (281) 162 (312) 53 (99) 50 (145) 104 (192) 61 (74) 21 (70) 123 (241) 61 (83) Nivolumab Better Everolimus Better 0.68 ( ) 0.74 ( ) 0.72 ( ) ( ) ( ) 0.60 ( ) 0.76 ( ) 0.78 ( ) 0.79 ( ) ( ) 0.81 ( ) 0.48 ( )

14 Checkmate 025: Progression-free survival Progression-Free Survival (Probability) Everolimus Median PFS, months (95% CI) Nivolumab 4.6 ( ) Everolimus 4.4 ( ) HR (95% CI): 0.88 ( ) P = Nivolumab No. of patients at risk Months Nivolumab Everolimus 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 ( ))

15 CheckMate 025: Tumor Response and Overall Survival Confirmed objective response rate (95% CI), % Median duration of response (95% CI), months Median time to onset of confirmed response, months (min, max) Nivolumab (n=410) Everolimus (n=411) 21.5 (17.6, 25.8) 3.9 (2.2, 6.2) 23.0 (12.0, NE) 13.7 (8.3, 21.9) 3.0 (1.4, 13.0) 3.7 (1.5, 11.2) Overall survival, events (%) 183 (45) 215 (52) Median survival (95% CI), months 25.0 (21.7, NE) 19.6 (17.6, 23.1) HR (95% CI) 0.73* (0.60, 0.89) P value *HR is obtained from a Cox proportional hazards model stratified by MSKCC risk group, number of prior anti-angiogenic therapies, and region with treatment as the sole covariate. P value is obtained from a two-sided log-rank test stratified by MSKCC risk group, number of prior anti-angiogenic therapies, and region. The corresponding O Brien-Fleming efficacy boundary significance level is OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.

16 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, % Fatigue Nausea 14 < Pruritus Diarrhea Decreased appetite 12 < Rash 10 < Cough Anemia <1 Dyspnea <1 0 Edema peripheral <1 0 Pneumonitis 4 1 < Mucosal inflammation Dysgeusia Hyperglycemia 2 1 < <1 Stomatitis Hypertriglyceridemia Epistaxis 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).

17 Safety Summary Nivolumab N = 406 Everolimus N = 397 Any Grade Grade 3-4 Any Grade Grade 3-4 Treatment-related AEs, % Treatment-related AEs leading to discontinuation, % 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).

18 Change from baseline in quality of life scores on FKSI-DRS 6 Mean change from baseline in the nivolumab group increased over time and differed significantly from the everolimus group at each assessment through week 76 (P<0.05) Mean Change From Baseline Worse Better Nivolumab Everolimus W eek No. of patients at risk Nivolumab Everolimus Questionnaire completion rate: 80% during the first year of follow-up.

19 Atezolizumab in RCC Phase 1 Atezolizumab in mrcc expansion cohort of phase 1 70 patients -56 regardless of PD-L1 status -14 in PD-L1+ enriched -63 with clear cell -7 with non-clear cell -64% with previous VEGF therapy MTD not reached Median treatment duration 8 mos Median PFS 5.6 mos Median OS 28.9 mos McDermott DF et al, J Clin Oncol, 2016, 34(8):

20 Atezolizumab in RCC Phase 1 OS based on presence (IC1/2/3) or absence (IC 0) of tumor-infiltrating lymphocytes OS based on previous VEGF TKI therapies McDermott DF et al, J Clin Oncol, 2016, 34(8):

21 Atezolizumab in RCC Phase 1 McDermott DF et al, J Clin Oncol, 2016, 34(8):

22 Biomarkers for immunotherapy Atezolizumab phase 1 study OS based on presence (IC1/2/3) or absence (IC 0) of tumor-infiltrating lymphocytes OS based on previous VEGF TKI therapies McDermott DF et al, J Clin Oncol, 2016, 34(8):

23 Biomarkers for immunotherapy Atezolizumab phase 1 study Identifying markers of tumor response No difference in tumor infiltrating CD8 cells Effector T cell gene signatures seem to differ somewhat Effector T-cell: regulatory T-cell ratio seems to be more significant More biomarker work on immune cell profiling is necessary McDermott DF et al, J Clin Oncol, 2016, 34(8):

24 Checkpoint therapies in RCC Nivolumab FDA-approved in November 2016 for treatment of VEGF-refractory metastatic RCC Improved median OS by 6 months (25 vs. 19.6) compared to everolimus No improvement in PFS Atezolizumab showed similar PFS 5.6 months and median OS of 28.9 months Pembrolizumab studies ongoing Need better biomarkers to predict response

25 Cabozantinib in RCC

26 Cabozantinib MOA in RCC (METEOR) Cabozantinib inhibits RTKs, including MET, AXL, and VEGF receptors MET, AXL, and VEGF are upregulated in clear cell RCC All are controlled by HIFα, which is activated due to VHL loss or hypoxia VEGF and MET drive tumor angiogenesis MET and AXL drive motility, invasion, and metastasis of tumor cells o High expression of either is associated with poor survival in RCC o Both are associated with resistance to VEGFR inhibitors in preclinical models of RCC MET AXL HGF GAS6 Motility, invasion, and metastasis Resistance to VEGFR TKIs Angiogenesis HIFα Cabozantinib Tumor Cell VEGF Angiogenesis Gibney, et al. Ann Oncol. 2013;24:343. Rankin, et al. Proc Natl Acad Sci U S A. 2014;111: Ciamporcero, et al. Mol Cancer Ther. 2015;14:101. Zhou, et al. Oncogene [Epub ahead of print].

27 METEOR: Study Design 1,2 Advanced RCC (N=650) Clear cell histology Measurable disease Progression on prior VEGFR TKI within 6 months of enrollment No limit to the number of prior therapies Antibodies targeting PD-1/PD-L1 allowed Brain metastases allowed if treated Cabozantinib 60 mg qd orally Randomization 1:1 No crossover allowed Everolimus 10 mg qd orally Tumor assessment by RECIST 1.1 every 8 weeks Treatment until loss of clinical benefit or intolerable toxicity Primary endpoint: PFS Secondary endpoints: OS, ORR Stratification: MSKCC 3 risk groups: favorable, intermediate, poor Number prior VEGFR TKIs: 1, 2 or more ORR=objective response rate; OS=overall survival; PFS=progression-free survival. 1. Choueiri TK, et al. N Engl J Med. 2015;373: Choueiri TK, et al. ESMO (abstr 4LBA). 3. Motzer R, et al. J Clin Oncol. 2004;22:

28 Baseline Characteristics Characteristic* Cabozantinib (N=330) Everolimus (N=328) Median age, years (range) 63 (32 86) 62 (31 84) Male, % Enrollment Region, % Europe / North America 51 / / 37 Asia-Pacific & Latin America ECOG Performance Status, % MSKCC risk group 1, % Favorable Intermediate Poor Metastatic sites per IRC, % Lung Liver Bone * Characteristics were consistent with the PFS population 1 Motzer R. et al., J Clin Oncol, 2004 Presented at the European Cancer Congress, Vienna, 26 September 2015

29 Prior Therapies Characteristic* Cabozantinib (N=330) Everolimus (N=328) Number of VEGFR TKIs, % or more VEGFR-TKI, % Sunitinib Pazopanib Axitinib Sorafenib 6 9 Other systemic therapy, % Cytokines Nivolumab 5 4 Bevacizumab 2 3 Radiotherapy, % Nephrectomy, % * Prior therapies were consistent with the PFS population Presented at the European Cancer Congress, Vienna, 26 September 2015

30 METEOR PFS Choueiri, TK et al, NEJM, 2015

31 METEOR Overall Survival Cabozantinib Median OS 21.4 mo (18.7-NE) Everolimus Median OS 16.5 mo ( ) Choueiri TK et al, Lancet Oncol, 2016

32 METEOR subset analysis Choueiri TK et al, Lancet Oncol, 2016

33 METEOR : Overview of All Grade and Grade 3-4 Adverse Events* Preferred Term, Cabozantinib, % (N=331) Everolimus, % (N=322) All Grades Grade 3-4 All Grades Grade 3-4 Diarrhea Fatigue Nausea <1 Decreased appetite <1 PPE syndrome <1 Hypertension Vomiting <1 Weight decreased Constipation 25 <1 19 <1 Dysgeusia Stomatitis Hypothyroidism 20 0 <1 0 Dysphonia 20 <1 4 0 Mucosal inflammation 19 < Asthenia Dyspnea Cough 18 <1 33 <1 Back pain Abdominal pain Rash 15 <1 28 <1 Peripheral Edema Pyrexia 8 <1 16 <1 Pruritus <1 * AEs >15% cut off (Bold = >30% in either arm) Choueiri TK, et al. N Engl J Med. 2015;373:

34 METEOR: Exposure and Dose Reductions of Cabozantinib Cabozantinib (n=331) Everolimus (n=322) Starting dose 60 mg qd 10 mg qd Dose reduction allowed for management of AEs 40 mg qd then 20 mg qd 5 mg qd then 2.5 mg qd Median duration of exposure (range), months 7.6 ( ) 4.4 ( ) Median daily dose, mg Any dose reduction due to AE, % Discontinued due to AE, % 9 10 Median time to first dose modification,* days Median time to second dose modification,* days Duration of treatment with cabozantinib was nearly twice that of everolimus Although the overall incidence of AEs was similar due to class-specific mechanisms of action the safety profile differed between treatment arms Dose reductions were used to adjust to the individual patient s tolerability *Dose modification includes dose reductions and dose interruptions. Choueiri TK, et al. N Engl J Med. 2015;373: Choueiri TK, et al. ESMO (abstr 4LBA). Data on file. Exelixis, Inc.; 2015.

35 METEOR conclusions Cabozantinib superior to everolimus in second line setting Median PFS 7.4mo vs 3.8mo Median OS 21.4mo vs 16.5mo Cabozantinib has significant toxicities Median dose 44mg Monitor nausea/vomiting, diarrhea, hypertension, dyspepsia, fatigue Cabozantinib may have better effect in patients with bone metastases

36 CABOSUN Study Design Advanced RCC (N=150) Clear cell component Measurable disease No prior systemic therapy ECOG PS 0-2 IMDC intermediate or poor risk groups Stratification: IMDC risk group 1 : intermediate, poor Bone metastases: yes, no Cabozantinib 60 mg qd orally (6 week cycles) Randomization 1:1 No cross-over allowed Sunitinib 50 mg qd orally (4 weeks on/2 weeks off) Primary endpoint: PFS Secondary endpoints: OS, ORR, Safety Tumor assessment by RECIST 1.1 every other cycle Treatment until disease progression or intolerable toxicity 1 Heng D et al., J Clin Oncol, 2009

37 CABOSUN Patients Screened N=157 Randomized (1:1) N=157 Cabozantinib n=79 Sunitinib n=78 Received cabozantinib n= 78 Continuing treatment n= 13 Received sunitinib n= 72 Continuing treatment n= 2 Efficacy analysis n= 79 Safety analysis n= 78 Efficacy analysis n= 78 Safety analysis n= 72 Data cut-off for primary endpoint: April 15, 2016

38 Baseline Characteristics Characteristic Cabozantinib (N=79) Sunitinib (N=78) Median age, years (range) 63 (40-82) 64 (31-87) Male, % ECOG performance status, % IMDC risk group 1, % Intermediate Poor Prior nephrectomy, % Bone metastases, % Adverse risk factors 1 : Intermediate risk group Poor-risk group hemoglobin<lln, cca>uln, KPS<80%, neutrophils>uln time from diagnosis to therapy <1 year, platelets>uln 1-2 risk factors 3 or more risk factors Choueiri TK et al, J Clin Oncol, 2016

39 CABOSUN PFS Progression-Free Survival (probability) Cabozantinib Sunitinib Arm PFS Events Median PFS (95% CI), mo HR (95% CI)* Cabozantinib Sunitinib * Adjusted for bone metastases and IMDC risk group Time since randomization (months) No. at Risk Cabozantinib Sunitinib (6.2, 9.0) 5.6 (3.4, 8.1) 0.66 ( ) p-value (one-sided) = Choueiri TK et al, J Clin Oncol, 2016

40 PFS Subgroup Analysis N Median PFS (mo) HR (95%CI) Cabozantinib Sunitinib All Patients ( ) IMDC Risk Group Intermediate ( ) Poor ( ) Bone Metastases No ( ) Yes ( ) Favors Cabozantinib Favors Sunitinib Choueiri TK et al, J Clin Oncol, 2016

41 Tumor Responses Cabozantinib (N=79) Sunitinib (N=78) Objective response rate, n (%) 36 (46%) 14 (18%) 95% CI (%) 34%-57% 10%-28% Best overall response, n Complete response 1 1 Partial response Stable disease Progressive disease Not evaluable or missing* 3 16 *No post-baseline imaging performed for the following reasons: Cabozantinib: clinical progression (1), withdrew consent (1), initiation of alternative therapy (1) Sunitinib: clinical progression (2), withdrew consent (7), adverse event (4), death (2), initiation of alternative therapy (1) 13 Choueiri TK et al, J Clin Oncol, 2016

42 CABOSUN Overall Survival As of September 15, 2016 Updated OS expected ASCO 2017 Choueiri TK et al, J Clin Oncol, 2016

43 All-Causality Adverse Events Cabozantinib (N=78) Sunitinib (N=72) Preferred Term, % All Grades Grade 3/4 All Grades Grade 3/4 Any adverse event* Fatigue Hypertension Diarrhea AST increased ALT increased Anorexia PPE Dysgeusia Thrombocytopenia Oral mucositis Anemia Nausea Weight loss Neutropenia Leukopenia * Events reported in at least 30% of patients in either study group; PPE, palmar-plantar erythrodysesthesia 17

44 All-Causality Adverse Events Cabozantinib (N=78) Sunitinib (N=72) Preferred Term, % All Grades Grade 3/4 All Grades Grade 3/4 Any adverse event* Fatigue Hypertension Diarrhea AST increased ALT increased Anorexia PPE Dysgeusia Thrombocytopenia Oral mucositis Anemia Nausea Weight loss Neutropenia Leukopenia * Events reported in at least 30% of patients in either study group; PPE, palmar-plantar erythrodysesthesia 17

45 All-Causality Adverse Events Cabozantinib (N=78) Sunitinib (N=72) Preferred Term, % All Grades Grade 3/4 All Grades Grade 3/4 Any adverse event* Fatigue Hypertension Diarrhea AST increased ALT increased Anorexia PPE Dysgeusia Thrombocytopenia Oral mucositis Anemia Nausea Weight loss Neutropenia Leukopenia * Events reported in at least 30% of patients in either study group; PPE, palmar-plantar erythrodysesthesia 17

46 CABOSUN Conclusions Cabozantinib significantly improves PFS compared to sunitinib in previously-untreated RCC patients of intermediate- and poor-risk IMDC categories: 8.2 vs. 5.6 months (HR=0.69, one-sided p=0.012) Benefit from cabozantinib was seen across subgroups Cabozantinib improves ORR over sunitinib ORR: 46% vs 18% Emerging trend towards improved OS with cabozantinib (HR=0.80, ns) Cabozantinib's safety profile was similar to sunitinib Cabozantinib represents a potential new treatment option for untreated RCC patients 19

47 Integrating novel therapies: First line Consider HD IL-2 PS 0-1 Good risk Consider clinical trials Single agent sunitinib or pazopanib PS 1-2, intermed-poor risk, bone mets Single agent cabozantinib PS 3, Poor risk Single agent temsirolimus

48 Integrating novel therapies: Second line Nivolumab No previous PD-1 therapy Good PS Axitinib Consider clinical trials No prior cabozantinib, Bone mets Single agent cabozantinib Consider clinical trials

49 Integrating novel therapies: Second line Nivolumab No previous PD-1 therapy Good PS Axitinib Consider clinical trials?? Lenvatinib+ Everolimus No prior cabozantinib, Bone mets Single agent cabozantinib Consider clinical trials

50 Conclusions Checkpoint inhibitor therapy is now proven treatment in RCC Approval of nivolumab Pending further development of atezolizumab and pembrolizumab Cabozantinib superior to everolimus in second-line setting, superior to sunitinib for intermediate-poor risk patients in firstline setting Sequencing and combination therapy trials needed and ongoing Treatment selection depends on patient appearance, clinical risk factors Need better biomarkers for treatment prediction

51 Acknowledgments GU Oncology team Urology team Dan George - Brant Inman Andy Armstrong - Ed Rampersaud Mike Harrison - Mike Ferrandino Megan McNamara - Judd Moul - Tom Polascik Tumor immunology Kent Weinhold

52 Ongoing randomized phase III trials in metastatic ccrcc Therapeutic target Line Control arm Experimental arm(s) PD-1 and CTLA-4 First Sunitinib Nivolumab + Ipilimumab x 4 Nivolumab PD-1 and VEGF First Sunitinib Bevacizumab + Atezolizumab PD-L1 and VEGF First Sunitinib Axitinib + Avelumab PD-L1 and VEGF First Sunitinib Axitinib + Pembrolizumab VEGF/FGF and (PD1 or mtor) First Sunitinib Lenvatinib + Pembrolizumab OR Lenvatinib + Everolimus VEGF Salvage Sorafenib Tivozanib As Cabo-Sun is positive, will future first-line studies need to be compared to cabozantinib? Adapted from Sonpavde G, International Kidney Cancer Symposium, Nov 2016

53 PDIGREE: Rationale Ipilimumab and nivolumab currently awaiting phase III results in first-line RCC Several TKI + PD-1 combination in phase III studies If positive Ipi-nivo becomes a preferred first line SOC Cabozantinib demonstrated superior PFS compared to sunitinib in first line intermediate/poor risk population (CaboSun) Cabo 40 mg + nivo 3mg/kg are tolerable together Hypotheses: addition of cabo to nivo following Ipi/nivo induction will: prolong PFS in non-cr patients; increase number of CRs in first line treatment

54 PDIGREE Building on cabo-sun trial, an Alliance proposal: PDIGREE Metastatic RCC Key Inclusion: 1. Metastatic RCC (clear cell) 2. ECOG Heng intermed or poor risk 4. No previous therapies for mrcc (except IL2) Ipi 1mg/kg IV q21d Nivo 3mg/kg IV q21d x4 doses PD CR Nivo 3mg/kg IV q14d R* Cabozantinib 60mg PO daily Nivo 3mg/kg IV q14d VS. Non-CR Non-PD Nivo 3mg/kg IV q14d + Cabozantinib 40mg PO daily 1 o endpoint: PFS 2 o endpoints: -- Overall survival month CR rate -- ORR -- Toxicity of caboipi-nivo Discontinue: Progression of disease OR Unacceptable toxicity If CR: Discontinue after 1 year * Prospective stratification: Heng criteria: intermediate, poor IL-6: biomarker performed in real-time

55 PDIGREE Trial design Phase 3 prospective intergroup study Induction ipilimumab-nivolumab for 4 doses (3 months) Non-CR/non-PD: Randomization 1:1 to nivolumab versus nivolumab-cabozantinib PD: Treated with cabozantinib monotherapy CRs at 1 year: Discontinue therapy +/- consolidative focal treatment follow for time to relapse

56 PDIGREE sample size Primary endpoint PFS Nivolumab PFS 6 months versus nivolumabcabozantinib PFS 8.57 months HR 0.70, 90% power, 2-sided type I error rate 345 events out of 400 patients Accounting for 10% drop out rate, n=444 Accounting for 10% CR and 20% PD, n=634 Final sample size:

57 Sequencing first second line therapy in current era: From RECORD3 to SUAVE METASTATIC ccrcc (untreated) Stratification Prognostic risk group: Hb, PLT, Neutrophilia, KPS<80, <1 year from diagnosis to therapy and hypercalcemia SUNITINIB AVELUMAB P D AVELUMAB SUNITINIB Archival tumor (PD-L1) Blood (Nanostring gene expression) Blood (Nanostring gene expression) Blood (Nanostring gene expression) Primary endpoint: Overall PFS with the sequence Co-PIs: Sonpavde, Rini; HCRN trial Adapted from Sonpavde G, International Kidney Cancer Symposium, Nov 2016

58 Future potential strategy for optimal therapy sequencing in mrcc PS 2-3, comorbidities PS 0-1 Molecular profiling Combination therapy HD IL-2 Single agent sunitinib Single agent Nivolumab PS 0-1 PS 2-3, comorbidities Molecular profiling Combination therapy Molecular profiling Single agent X Single agent Y Single agent X Single agent Y Adapted from Sonpavde G, International Kidney Cancer Symposium, Nov 2016