Integrating novel therapy in advanced renal cell carcinoma Tian Zhang, MD Assistant Professor of Medicine GU Oncology Duke Cancer Institute March 11, 2017
Disclosures Research Funding Janssen Pfizer Consultant Acerta G1 Therapeutics
Outline Approved systemic therapies in RCC Immunotherapies in RCC Checkpoint inhibitors in RCC Cabozantinib in RCC METEOR, CABOSUN trials Integrating novel systemic therapies
FDA Approval Timeline: mrcc Therapy (Post Cytokine Era) 1992 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 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-2 1992 Nivolumab 8 (11/15) 1. NEXAVAR (sorafenib) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2015. 2. SUTENT (sunitinib malate) [prescribing information]. New York, NY: Pfizer Labs; 2015. 3. VOTRIENT (pazopanib) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2015. 4. INLYTA (axitinib) [prescribing information]. New York, NY: Pfizer Labs; 2014. 5. TORISEL (temsirolimus) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2015. 6. AFINITOR (everolimus) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. 7. AVASTIN (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2015. 8. OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
First Line: Summary of Efficacy Data Drug Control N (Drug vs Control) ORR, % PFS, Months OS, Months Sunitinib 1,2 IFN-α 375 vs 360 47 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 363 30 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 322 31 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 4.8 5.5 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;356:115-124. 2. Motzer R, et al. J Clin Oncol. 2009;27:3584-3590. 3. Sternberg C, et al. J Clin Oncol. 2010;28:1061-1068. 4. Sternberg C, et al. Eur J Cancer. 2013;49:1287-1296. 5. Motzer RJ, et al. N Engl J Med. 2013;369:722-731. 6. Motzer RJ, et al. N Engl J Med. 2014;370:1769-1770. 7. Rini B, et al. J Clin Oncol. 2008;26:5422-5428. 8. Rini B, et al. J Clin Oncol. 2010;28:2137-2143. 9. Escudier B, et al. J Clin Oncol. 2010;28:2144-2150. 10. Torisel [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals; 2010. 11. Hudes G, et al. N Engl J Med. 2007;356:2271-2281.
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 452 2 vs 0 Axitinib 3,4 Sorafenib 361 vs 362 23 vs 12 (P=0.0001) 5.5 vs 2.8 (HR=0.44) (P<0.000001) 17.8 vs 15.2 (P=0.146) 17.8 vs 14.3 (P=0.029]) 6.7 vs 4.7 20.1 vs 19.2 (P<0.0001) (P=0.374) mtori Everolimus 5,6 Placebo 272 vs 138 1.0 vs 0.0 Temsirolimus 7 Sorafenib 259 vs 253 8.0 vs 8.0 4.3 vs 3.9 4.9 vs 1.9 14.8 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 328 21 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 411 25 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;356:125-134. 2. Escudier B, et al. J Clin Oncol. 2009;27:3312-3318. 3. Rini B, et al. Lancet. 2011;378:1931-1939. 4. Motzer R, et al. Lancet. 2013;14:552-562. 5. Motzer R, et al. Lancet. 2008;372:449-456. 6. Motzer R, et al. Cancer. 2010;116:4256-4265. 7. Hutson TE, et al. J Clin Oncol. 2014;32:760-767. 8. Choueiri TK, et al. N Engl J Med. 2015;373:1814-1823. 9. Motzer RJ, et al. N Engl J Med. 2015;373:1803-1813.
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.2.2016. http://www.nccn.org. 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
Nivolumab and Atezolizumab trials in RCC 8
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; 2015. 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
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 23 77 35 49 16 72 28 42 34 23 26 74 36 49 15 72 28 42 34 24
Checkmate 025: Overall survival Overall Survival (Probability) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 Median OS, months (95% CI) Nivolumab 25.0 (21.8 NE) Everolimus 19.6 (17.6 23.1) HR (98.5% CI): 0.73 (0.57 0.93) P = 0.0018 Everolimus Nivolumab 18 21 24 27 30 33 No. of patients at risk Months Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0 Everolimus 411 366 324 287 265 241 187 115 61 20 2 0 Minimum follow-up was 14 months. NE, not estimable. Motzer RJ et al, NEJM, 2015
Overall survival by PD-L1 expression 1.0 PD-L1 1% (n = 24%) Median OS, months (95% CI) Nivolumab 21.8 (16.5 28.1) Everolimus 18.8 (11.9 19.9) PD-L1 <1% (n = 76%) Median OS, months (95% CI) Nivolumab 27.4 (21.4 NE) Everolimus 21.2 (17.7 26.2) HR (95% CI): 0.79 (0.53 1.17) HR (95% CI): 0.77 (0.60 0.97) 1.0 0.9 0.9 Overall Survival (Probability) 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Everolimus Nivolumab 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Everolimus Nivolumab 0.1 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 No. of patients at risk Months Nivolumab 94 86 79 73 66 58 45 31 18 4 1 0 Everolimus 87 77 68 59 52 47 40 19 9 4 1 0 0.0 0 3 6 9 12 15 Months 18 21 24 27 30 33 276 265 245 233 210 189 145 94 48 22 2 0 299 267 238 214 200 182 137 92 51 16 1 0
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) 0 1 2 Nivolumab Better Everolimus Better 0.68 (0.34-1.35) 0.74 (0.60-0.91) 0.72 (0.47-1.09) - 0.81 (0.55-1.18) - 0.81 (0.64-1.04) 0.60 (0.42-0.84) 0.76 (0.55-1.06) 0.78 (0.61-0.99) 0.79 (0.63-0.99) - 0.80 (0.52-1.21) 0.81 (0.61-1.06) 0.48 (0.32-0.70)
Checkmate 025: Progression-free survival Progression-Free Survival (Probability) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Everolimus Median PFS, months (95% CI) Nivolumab 4.6 (3.7 5.4) Everolimus 4.4 (3.7 5.5) HR (95% CI): 0.88 (0.75 1.03) P = 0.1135 Nivolumab 0 3 6 9 12 15 18 21 24 27 30 No. of patients at risk Months Nivolumab 410 230 145 116 81 66 48 29 11 4 0 Everolimus 411 227 129 97 61 47 25 16 3 0 0 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 (0.47 0.88))
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 0.0018 *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 0.0148. OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
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, % 79 18 1 88 33 4 Fatigue 33 2 0 34 3 0 Nausea 14 <1 0 17 1 0 Pruritus 14 0 0 10 0 0 Diarrhea 12 1 0 21 1 0 Decreased appetite 12 <1 0 21 1 0 Rash 10 <1 0 20 1 0 Cough 9 0 0 19 0 0 Anemia 8 2 0 24 8 <1 Dyspnea 7 1 0 13 <1 0 Edema peripheral 4 0 0 14 <1 0 Pneumonitis 4 1 <1 15 3 0 Mucosal inflammation 3 0 0 19 3 0 Dysgeusia 3 0 0 13 0 0 Hyperglycemia 2 1 <1 12 3 <1 Stomatitis 2 0 0 29 4 0 Hypertriglyceridemia 1 0 0 16 4 1 Epistaxis 1 0 0 10 0 0 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).
Safety Summary Nivolumab N = 406 Everolimus N = 397 Any Grade Grade 3-4 Any Grade Grade 3-4 Treatment-related AEs, % 79 19 88 37 Treatment-related AEs leading to discontinuation, % 8 5 13 7 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).
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 4 2 0-2 -4-6 Worse Better Nivolumab Everolimus 0 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 W eek No. of patients at risk Nivolumab 362 334 302 267 236 208 186 164 159 144 132 119 112 97 90 89 81 72 63 59 53 44 43 31 30 26 20 Everolimus 344 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9 Questionnaire completion rate: 80% during the first year of follow-up.
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): 833-42
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): 833-42
Atezolizumab in RCC Phase 1 McDermott DF et al, J Clin Oncol, 2016, 34(8): 833-42
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): 833-42
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): 833-42
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
Cabozantinib in RCC
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;111:13373. Ciamporcero, et al. Mol Cancer Ther. 2015;14:101. Zhou, et al. Oncogene. 2015 [Epub ahead of print].
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;373:1814-1823. 2. Choueiri TK, et al. ESMO. 2015 (abstr 4LBA). 3. Motzer R, et al. J Clin Oncol. 2004;22:454-463.
Baseline Characteristics Characteristic* Cabozantinib (N=330) Everolimus (N=328) Median age, years (range) 63 (32 86) 62 (31 84) Male, % 77 73 Enrollment Region, % Europe / North America 51 / 36 47 / 37 Asia-Pacific & Latin America 14 16 ECOG Performance Status, % 0 68 66 1 32 34 MSKCC risk group 1, % Favorable 45 46 Intermediate 42 41 Poor 12 13 Metastatic sites per IRC, % Lung 58 61 Liver 25 30 Bone 23 19 * 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
Prior Therapies Characteristic* Cabozantinib (N=330) Everolimus (N=328) Number of VEGFR TKIs, % 1 71 70 2 or more 29 30 VEGFR-TKI, % Sunitinib 64 62 Pazopanib 44 41 Axitinib 16 17 Sorafenib 6 9 Other systemic therapy, % Cytokines 12 16 Nivolumab 5 4 Bevacizumab 2 3 Radiotherapy, % 33 33 Nephrectomy, % 85 85 * Prior therapies were consistent with the PFS population Presented at the European Cancer Congress, Vienna, 26 September 2015
METEOR PFS Choueiri, TK et al, NEJM, 2015
METEOR Overall Survival Cabozantinib Median OS 21.4 mo (18.7-NE) Everolimus Median OS 16.5 mo (14.7-18.8) Choueiri TK et al, Lancet Oncol, 2016
METEOR subset analysis Choueiri TK et al, Lancet Oncol, 2016
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 74 11 27 2 Fatigue 56 9 46 7 Nausea 50 4 28 <1 Decreased appetite 46 2 34 <1 PPE syndrome 42 8 6 <1 Hypertension 37 15 7 3 Vomiting 32 2 14 <1 Weight decreased 31 2 12 0 Constipation 25 <1 19 <1 Dysgeusia 24 0 9 0 Stomatitis 22 2 24 2 Hypothyroidism 20 0 <1 0 Dysphonia 20 <1 4 0 Mucosal inflammation 19 <1 23 3 Asthenia 19 4 16 2 Dyspnea 19 3 28 4 Cough 18 <1 33 <1 Back pain 17 2 15 2 Abdominal pain 16 4 10 1 Rash 15 <1 28 <1 Peripheral Edema 9 0 22 2 Pyrexia 8 <1 16 <1 Pruritus 8 0 15 <1 * AEs >15% cut off (Bold = >30% in either arm) Choueiri TK, et al. N Engl J Med. 2015;373:1814-1823.
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 (0.3-20.5) 4.4 (0.21-18.9) Median daily dose, mg 45 9.2 Any dose reduction due to AE, % 59.8 24.2 Discontinued due to AE, % 9 10 Median time to first dose modification,* days 55 60 Median time to second dose modification,* days 93 93 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;373:1814-1823. Choueiri TK, et al. ESMO. 2015 (abstr 4LBA). Data on file. Exelixis, Inc.; 2015.
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
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
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
Baseline Characteristics Characteristic Cabozantinib (N=79) Sunitinib (N=78) Median age, years (range) 63 (40-82) 64 (31-87) Male, % 84 73 ECOG performance status, % 0 46 46 1 42 41 2 13 13 IMDC risk group 1, % Intermediate 81 81 Poor 19 19 Prior nephrectomy, % 72 77 Bone metastases, % 37 36 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
CABOSUN PFS Progression-Free Survival (probability) 1.0 0.8 0.6 0.4 0.2 Cabozantinib Sunitinib Arm PFS Events Median PFS (95% CI), mo HR (95% CI)* Cabozantinib Sunitinib 0.0 64 61 * Adjusted for bone metastases and IMDC risk group 0 6 12 18 24 30 Time since randomization (months) No. at Risk Cabozantinib 79 50 26 15 3 1 Sunitinib 78 32 17 7 1 0 8.2 (6.2, 9.0) 5.6 (3.4, 8.1) 0.66 (0.46-0.95) p-value (one-sided) = 0.012 Choueiri TK et al, J Clin Oncol, 2016
PFS Subgroup Analysis N Median PFS (mo) HR (95%CI) Cabozantinib Sunitinib All Patients 157 8.2 5.6 0.69 (0.48-0.99) IMDC Risk Group Intermediate 127 8.4 6.2 0.68 (0.45-1.01) Poor 30 6.3 2.8 0.75 (0.34-1.66) Bone Metastases No 100 8.7 7.6 0.80 (0.51-1.26) Yes 57 6.3 3.4 0.51 (0.29-0.90) Favors Cabozantinib Favors Sunitinib Choueiri TK et al, J Clin Oncol, 2016
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 35 13 Stable disease 26 28 Progressive disease 14 20 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
CABOSUN Overall Survival As of September 15, 2016 Updated OS expected ASCO 2017 Choueiri TK et al, J Clin Oncol, 2016
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* 99 65 99 68 Fatigue 86 6 82 15 Hypertension 81 28 68 22 Diarrhea 73 10 54 11 AST increased 62 3 32 3 ALT increased 55 5 28 0 Anorexia 47 5 32 0 PPE 42 8 33 4 Dysgeusia 41 0 29 0 Thrombocytopenia 40 1 63 11 Oral mucositis 36 5 29 6 Anemia 33 1 46 1 Nausea 32 3 39 4 Weight loss 32 4 17 0 Neutropenia 15 0 35 4 Leukopenia 12 0 35 3 * Events reported in at least 30% of patients in either study group; PPE, palmar-plantar erythrodysesthesia 17
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* 99 65 99 68 Fatigue 86 6 82 15 Hypertension 81 28 68 22 Diarrhea 73 10 54 11 AST increased 62 3 32 3 ALT increased 55 5 28 0 Anorexia 47 5 32 0 PPE 42 8 33 4 Dysgeusia 41 0 29 0 Thrombocytopenia 40 1 11 Oral mucositis 36 5 29 6 Anemia 33 1 46 1 Nausea 32 3 39 4 Weight loss 32 4 17 0 Neutropenia 15 0 35 4 Leukopenia 12 0 35 3 * Events reported in at least 30% of patients in either study group; PPE, palmar-plantar erythrodysesthesia 17
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* 99 65 99 68 Fatigue 86 6 82 15 Hypertension 81 28 68 22 Diarrhea 73 10 54 11 AST increased 62 3 32 3 ALT increased 55 5 28 0 Anorexia 47 5 32 0 PPE 42 8 33 4 Dysgeusia 41 0 29 0 Thrombocytopenia 40 1 63 11 Oral mucositis 36 5 29 6 Anemia 33 1 46 1 Nausea 32 3 39 4 Weight loss 32 4 17 0 Neutropenia 15 0 35 4 Leukopenia 12 0 35 3 * Events reported in at least 30% of patients in either study group; PPE, palmar-plantar erythrodysesthesia 17
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
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
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
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
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
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
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
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
PDIGREE Building on cabo-sun trial, an Alliance proposal: PDIGREE Metastatic RCC Key Inclusion: 1. Metastatic RCC (clear cell) 2. ECOG 0-1 3. 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 -- 12-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
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
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: 634 56
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
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