The role of mtor inhibitors in renal cancer. Tom Powles Professor of Urology Cancer at Barts Cancer Institute Director of Cancer Barts Cancer Centre

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1 The role of mtor inhibitors in renal cancer. Tom Powles Professor of Urology Cancer at Barts Cancer Institute Director of Cancer Barts Cancer Centre

2 disclosures Novartis Pfizer Merck BMS Roche AZ

3 PI3K pathway in renal cancer AZ2014 Temsirolimus AZ2014

4 RECORD-1 everolimus v.s. placebo in VEFG refractory disease. Eligibility Criteria VEGF refractory disease ECOG PS nd line (20%) 3 rd line (42%) 4 th line (25%) 5 th line (22%) R A N D O M I S A T I O N 1:1 N=723 everolimus 10 mg PO BD(n=277) Crossover Placebo Primary end point: PFS Secondary end points: OS, ORR, Cross over This presentation is for scientific discussion only Please do not distribute following this meeting 4

5 Probability, % RECORD-1: PFS Everolimus (Median PFS, 4.90 months) Placebo (Median PFS, 1.87 months) HR, 0.33 (95% CI, ) Log-rank P < Time, months No. of Patients at Risk Everolimus Placebo Motzer RJ et al. Cancer. 2010;116:

6 A randomised phase II study of AZ2014 v.s. everolimus in VEGF refractory Key Eligibility Criteria VEGF refractory Metastatic disease clear cell metastatic clear cell RCC All MSKCC group No previous mtor R AZ mg PO BD Everolimus 10mg PO OD Endpoints Primary: Progression Free Survival Secondary: Overall survival and adverse events. Stratification: MSKCC score + duration of previous TKI Powles et al Eur Urol 2015

7 Progression free Survival at the date of trial suspension Number at risk Everolimus AZD2014 Stratified log-rank P = Time (months) HR 2.8 (95%CI: ) P=0.01 Median PFS Everolimus 4.6 months (95%CI: ) AZD months (95%CI: ) Everolimus AZD2014

8 Overall survival at final analysis Number at risk Everolimus AZD2014 Stratified log-rank P = Time (months) HR 2.3 (95%CI: ) P=0.02 Median OS Everolimus 16.7 months (95% CI 6.0-NA) AZD months (95%CI ) Everolimus AZD2014

9 A randomised phase II study of GDC0980 v.s. everolimus in VEGF refractory metastatic clear cell RCC Key Eligibility Criteria VEGF refractory Metastatic disease clear cell All MSKCC group No previous mtor R GDC0980 Everolimus 10mg PO OD Endpoints Primary: Progression Free Survival Secondary: Overall survival and adverse events. Stratification: MSKCC score + duration of previous TKI Powles et al JCO 2015

10 Progression Free Survival.

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12 INTORSECT* Study Design Patients with mrcc and PD on 1st-line sunitinib (N=512) Stratification factors: Duration of sunitinib therapy ( or >6 mo) MSKCC risk group Histology (clear cell or non clear cell) Nephrectomy status R A N D O M I Z E 1:1 Temsirolimus 25 mg IV weekly (n=259) Sorafenib 400 mg oral BID (n=253) N= sites in 20 countries PFS 2 nd Endpoints Response rate Overall Survival Toxicity

13 Overall Survival (probability) Overall Survival Patients at risk, n Sorafenib Temsirolimus Temsirolimus Sorafenib Time (months) Median OS, months % CI 10.13, , P=0.014 (log-rank) Stratified HR: 1.31 (95% CI: 1.05, 1.63) No PFS advantage CI, confidence interval; HR, hazard ratio; OS, overall survival. 13

14 Randomize 1:1 Checkmate 25 Previously treated mrcc Stratification factors Region MSKCC risk group Number of prior antiangiogenic therapies Nivolumab 3 mg/kg intravenously every two weeks Everolimus 10 mg orally once daily Patients were treated until progression or intolerable toxicity occurred Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted MSKCC, Memorial Sloan-Kettering Cancer Center. 14

15 Overall Survival (Probability) Overall survival 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. 15

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17 Rini et al JCO 2013

18 The role of everolmus in VEFG resistant disease. First line therapy Therapy for VEGF resistant disease 1 Pazopanib or Sunitinib Temisolimus for MSKCC poor risk Recommended with survival advantage Recommended without survival advantage Cabozantinib or Nivolumab Axitinib or Everolimus 2 or Sorafenib 3 Axitinib or Cabozantinib 4 or Everolimus or Nivolumab 4 or Sorafenib Everolimus or Sorafenib Personalized therapy

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21 Motzer et al JCO 2014

22 Conclusions Everolimus has activity and a role, but that has diminished over the last year. Nivolumab and cabozantinib should be used preferably. The role of temsirolimus is more uncertain. Areas ive not talked about Non-clear cell First line everolmus