Alternativas de Futuro en Cáncer Renal Enrique Grande

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1 Alternativas de Futuro en Cáncer Renal Enrique Grande Hospital Ramón y Cajal de Madrid

2 The ncreasingly Challenging Field of mrcc Sorafenib (US 2005, EU 2006) 3,4 Sunitinib (US & EU 2006) 3,4 Early 1940s: experiments with cytotoxic chemotherapy 1 High-dose L-2 approved in the US (1995). High treatment-related toxicity; small number of durable responses 2 Temsirolimus and Bevacizumab plus F (US & EU 2007) 3,4 Everolimus (US & EU 2009) 3,4 Axitinib (US & EU 2012) Early 1980s: F-α and high-dose L-2 used for RCC treatment Pazopanib (US 2009, EU 2010) 3,4 Abeloff MD, et al. Clinical ncology 4th ed. Philadelphia, PA; 2. Coppin C, et al. Cochrane Database Syst Rev 2005;1:CD001425; 3. U.S. Food and Drug Administration ( 4. European Medicines Agency (

3 The PFS-plateau with VEGFR Multi-Kinaseinhibitors in 1st Line mrcc Motzer RJ, et al. Engl J Med 2007;356(2): Sternberg C, et al. J Clin ncol. 2010;28(6): Escudier B, et al. J Clin ncol 2010;28(13): Motzer RJ, et al. J Clin ncol 2013;31(30): Hutson TH, et al. J Clin ncol 31, 2013 (suppl 6; abstr LBA348) Eisen T, et al. J Clin ncol 31, 2013 (suppl; abstr 4506)

4 verall Survival in Sequential Randomized Trials TK-TK vs TK-mTR Historical F Suntinib Pivotal Trial RECRD-3 SU_EVE arm SWTCH SU-SR arm Motzer RJ, et al. Engl J Med 2007;356(2): Motzer RJ, et al. J Clin ncol 2014 Michel MS, ral Presentation at ASC GU 2014

5 What can we expect in a short term in the field of mrcc SURTME PRTECT CARMEA EVEREST SRCE S-TRAC ATLAS CheckMate 214 (ipi + nivo vs sun) ASSURE ADAPT ALLACE A (cabo vs sun) MPRT RAPD MPDL3280 +/- bevacizumab METER (cabo vs evero) CheckMate 25 (nivo vs evero) ephrectomy Y/ Adjuvancy Vaccines Targeted agents mmune Checkpoint

6 What can we expect in a short term in the field of mrcc SURTME PRTECT CARMEA EVEREST SRCE S-TRAC ATLAS CheckMate 214 (ipi + nivo vs sun) ASSURE ADAPT ALLACE A (cabo vs sun) MPRT RAPD MPDL3280 +/- bevacizumab METER (cabo vs evero) CheckMate 25 (nivo vs evero) ephrectomy Y/ Adjuvancy Vaccines Targeted agents mmune Checkpoint

7 The decision for ephrectomy is not difficult at the extremes in primary metastatic RCC C yes C no

8 CARMEA: Phase study of sunitinib versus nephrectomy + sunitinib Metastatic clear-cell RCC =576 R A D M Z A T ephrectomy Sunitinib 50 mg/day (Schedule 4/2) Sunitinib 50 mg/day (Schedule 4/2) Primary objective: s sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of overall survival? P: Arnaud Mejean (CCAFU, HEGP, Paris, France) (CT )

9 SURTME: Phase study investigating immediate versus deferred nephrectomy Eligibility criteria Synchronous mrcc and primary tumour in situ =458 R A D M Z A T ephrectomy Sunitinib 50 mg/day (Schedule 4/2) Sunitinib 50 mg/day (Schedule 4/2) ephrectomy Primary endpoint: PFS Secondary endpoints: S, association with prognostic gene and protein expression profiles P: Axel Bex (C, Amsterdam, etherlands) (CT )

10 What can we expect in a short term in the field of mrcc SURTME PRTECT CARMEA EVEREST SRCE S-TRAC ATLAS CheckMate 214 (ipi + nivo vs sun) ASSURE ADAPT ALLACE A (cabo vs sun) MPRT RAPD MPDL3280 +/- bevacizumab METER (cabo vs evero) CheckMate 25 (nivo vs evero) ephrectomy Y/ Adjuvancy Vaccines Targeted agents mmune Checkpoint

11 ASSURE: Adjuvant sorafenib or sunitinib for unfavorable RCC (Phase ) Eligibility Patients with high- and intermediate-risk resected and non-metastatic RCC Clear-cell or non-clear cell RCC =1923 R A D M S A T Sunitinib once daily (4 weeks on/2 weeks off) for 1 year Sorafenib bid for 1 year Placebo for 1 years Primary endpoint: disease-free survival Secondary endpoints: S, decreases in left ventricular EF, frequency of clinically significant CHF (grade 3 or higher), QoL Haas et al. ASC GU 2015, abstract 403

12 ASSURE: Disease characteristics Sunitinib Sorafenib Placebo Total Histology Clear Cell 513 (79%) 519 (80%) 509 (79%) 1541 (79%) Papillary 39 (6%) 52 (8%) 59 (9%) 150 (8%) Chromophobe 40 (6%) 43 (7%) 28 (4%) 111 (6%) Mixed 31 (5%) 21 (3%) 31 (5%) 83 (4%) Unclassified 23 (4%) 14 (2%) 19 (3%) 56 (3%) Sarcomatoid Features 51 (8%) 58 (9%) 61 (10%) 170 (9%) Risk (as Stratified) ntermediate High 323 (50%) 324 (50%) 326 (50%) 973 (50%) Very High 324 (50%) 325 (50%) 321 (50%) 970 (50%) AJCC Stage 57 (9%) 61 (9%) 64 (10%) 182 (9%) 158 (25%) 167 (26%) 154 (24%) 479 (25%) 422 (65%) 409 (63%) 424 (66%) 1255 (65%) V 9 (1%) 12 (2%) 4 (1%) 25 (1%) Haas et al. ASC GU 2015, abstract 403

13 Proportion Alive and Disease-Free ASSURE: Disease-Free Survival Sunitinib Sorafenib Placebo Median 5.8 yrs Median 5.8 yrs Median 6.0 yrs Time (Months) Events Patients 5-yr DFS 97.5% C HR 97.5% C Sunitinib % % Sorafenib % % Placebo % % Haas et al. ASC GU 2015, abstract 403

14 Proportion Alive and Disease-Free ASSURE: DFS for Clear Cell Population Sunitinib Sorafenib Placebo Median 5.6 yrs Median 5.1 yrs Median 5.7 yrs Time (Months) Events Patients 5-yr DFS 97.5% C HR 97.5% C Sunitinib % % Sorafenib % % Placebo % % Haas et al. ASC GU 2015, abstract 403

15 ASSURE: Disease-Free Survival for Clear Cell Population During Treatment 84% vs 92% 50% improvement in DFS Haas et al. ASC GU 2015, abstract 403

16 Phase adjuvant studies in mrcc Study Arms Duration Primary endpoint ASSURE S-TRAC ATLAS SRCE PRTECT EVEREST Sunitinib Sorafenib Placebo Sunitinib Placebo Axitinib Placebo Sorafenib Sorafenib Placebo Pazopanib Placebo Everolimus Placebo 1 year 1923 Disease-free survival 1 year 720* Disease-free survival 3 years 690 Disease-free survival 3 years 1 year 3 years 1656 Disease-free survival 1 year 1500 Disease-free survival 54 weeks 1218 Recurrence-free survival

17 What can we expect in a short term in the field of mrcc SURTME PRTECT CARMEA EVEREST SRCE S-TRAC ATLAS CheckMate 214 (ipi + nivo vs sun) ASSURE ADAPT ALLACE A (cabo vs sun) MPRT RAPD MPDL3280 +/- bevacizumab METER (cabo vs evero) CheckMate 25 (nivo vs evero) ephrectomy Y/ Adjuvancy Vaccines Targeted agents mmune Checkpoint

18 Vaccines are in development in RCC Eligibility criteria: Metastatic and/or locally advanced ccrcc Favourable/intermediate risk HLA-A*02-positive o prior systemic therapy =330 R A D M S E D MA901 + GM-CSF + sunitinib Sunitinib MPRT randomised Phase trial Study completion: July 2015 Diagnosis of advanced kidney cancer Surgery Tumour sample taken =450 R A D M S E D Sunitinib + AGS-003 Sunitinib ADAPT randomised Phase trial Study completion: April 2016 AGS-003, autonomous dendritic cell product; ccrcc, clear cell renal cell carcinoma; GM-CSF, granulocyte macrophage colony-stimulating factor; MA901, consists of multiple tumour-associated peptides; SC, standard of care ADAPT study trial highlights. Available at: Accessed September 19, 2014; (CT ); (CT )

19 What can we expect in a short term in the field of mrcc SURTME PRTECT CARMEA EVEREST SRCE S-TRAC ATLAS CheckMate 214 (ipi + nivo vs sun) ASSURE ADAPT ALLACE A (cabo vs sun) MPRT RAPD MPDL3280 +/- bevacizumab METER (cabo vs evero) CheckMate 25 (nivo vs evero) ephrectomy Y/ Adjuvancy Vaccines Targeted agents mmune Checkpoint

20 PD-1 and PD-L1 antibodies in clinical development Target Agent Class PD-1 ivolumab (MDX1106, BMS ) Pembrolizumab (MK-3475) Pidilizumab (CT-011) gg4 fully human Ab gg4 engineered humanised Ab gg1 humanised Ab PD-L1 BMS (MDX-1105) MPDL3280A MED4736 Avelumab (MSB C) gg4 fully human Ab gg1 engineered fully human Ab gg1 engineered fully human Ab gg1 fully human Ab PD-1-positive T cells AMP-224 Fc of human gg-pd-l2 fusion

21 Monotherapy studies of checkpoint inhibitors in RCC: Summary of efficacy and safety Line Treatment PD-L1 Select. n RR (%) PFS (months) S (months) Adverse events (All grades) 1L+ ivolumab (0.3, 2, 10 mg/kg) 1 one A Fatigue (38 40%) ausea (8 18%) Pruritus (12 13%) Rash (4 12%) Diarrhoea (8 10%) 2L ivolumab (0.3, 2, 10 mg/kg) 2 one (5%) Fatigue (22 35%) Diarrhoea (3 15%) ausea (10 13%) Rash (7 13%) Pruritus (10 11%) 2L+ MPDL3280A 3 one A A Fatigue (22%) Decreased appetite (16%) Arthralgia (15%) Rash (15%) Diarrhoea (12%) Pruritis (12%) Pyrexia (12%) 1. Choueri et al ESM 2014; 2. Motzer et al J Clin ncol, Epub ahead of print (December 2014) 3. McDermott et al ESM 2014

22 CheckMate-025: Phase study of nivolumab vs everolimus in locally advanced/mrcc with prior anti-angiogenic therapy Eligibility: Advanced or mrcc with clear-cell component Received prior antiangiogenic therapy Progression on or after most recent therapy (within 6 months of study enrolment) Karnofsky PS 70 =822 RA D M SA T 1:1 ivolumab 3 mg/kg V every 2 weeks Everolimus 10 mg orally daily Treatment until disease progression or unacceptable toxicity Primary end point: S HR of 0.76 (32% increase in ms) required for positive study outcome Assumes a 4-month improvement in median S from 14 to 18 months Secondary end points: PFS, RR, DR, duration of S in PDL1-positive vs -negative subgroups, safety, disease-related symptom progression rate (CT )

23 Combination studies of checkpoint inhibitors in RCC: Summary of efficacy and safety Line Treatment PD-L1 Select. n RR (%) PFS (months) S (months) Adverse events (All grades) 1/2L ivolumab (2mg/kg or 5mg/kg Q3W) + sunitinib 1 one (1% & 5%) A Fatigue (82%) Diarrhoea (61%) Hypertension (49 %) ncreased ALT (39%) ncreased AST (36%) 2L+ ivolumab (2mg/kg Q3W) + Pazopanib 1 one (1% & 5%) A Fatigue (60%) Diarrhoea (60%) ncreased AST (30%) ncreased ALT (25%) Hypertension (25%) 1/2L ivolumab (3mg/kg) + pilimumab (1mg/kg Q3Wx4) 2 one A Fatigue (52%) Pruritus (38%) Rash (29%) Diarrhoea (29%) 1/2L ivolumab (1mg/kg) + pilimumab (3mg/kg Q3Wx4) 2 one A Fatigue (70%) ncreased ALT (39%) ncreased AST (39%) ausea (39%) Diarrhoea (35%) 1L MPDL3280A + bevacizumab (15mg/kg Q3W) 3,4 one (HC 1,2,3) A A Fatigue (46%) Pyrexia (37%) ausea (37%) Diarrhoea (31%) Decreased appetite (26%) Amin et al. ASC 2014; 2. Hammers et al. ASC 2014; 3. McDermott et al. ESM Lieu et al. ESM 2014

24 CheckMate 214: Phase study of nivolumab in combination with ipilimumab in first-line mrcc Eligibility: Patients with advanced RCC Treatment-naive =1070 RA D M Z A T ivolumab 3 mg/kg + ipilimumab 1 mg/kg q3wk* Sunitinib 50 mg (4 wk on/ 2 wk off) Primary end points: PFS, S Secondary end points: RR, adverse event rate *ivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks for 4 doses then nivolumab 3 mg/kg. (CT )

25 RAPD: Phase study of MPDL3280A as monotherapy or in combination with bevacizumab vs sunitinib in untreated advanced RCC Eligibility Locally advanced or mrcc with clear-cell and/or sarcomatoid component Previously untreated with any systemic therapy Karnofsky PS 70 = R A D M S A T MPDL3280A 1200 mg V q3w + bevacizumab 15 mg/kg V q3w MPDL3280A 1200 mg V q3w Sunitinib 50 mg/day 4/2 Primary endpoints: PFS per RECST v.1.1 via central CR assessment Secondary endpoints: PFS using investigator assessment per immune-related criteria, RR, duration of response, S, duration of response and PFS in patients progressing on sunitinib and MPDL alone arms who subsequently cross over to combination, safety, PK of MPDL3280A alone and in combination with bevacizumab (CT )

26 A phase, open-label, randomized study of MPDL3280A in combination with bevacizumab versus sunitinib in patients with untreated mrcc Eligibility: Unresectable advanced or metastatic RCC with clear-cell histology and/or sarcomatoid carcinoma Treatment-naïve All MSKCC risk scores are included =550 R A D M Z A T MPDL3280A 1200 mg V q3w + bevacizumab 15 mg/kg V q3w Sunitinib 50 mg (4 wk on/ 2 wk off) Stratification factors: Liver metastases (yes/no) MSKCC risk (0, 1-2, 3+) PD-L1 expression (C0, C1/2/3) Primary end point: PFS Secondary end points: RR, S, QL, toxicity profile

27 ivolumab (anti-pd-1) in combination with sunitinib/ pazopanib has shown encouraging anti-tumour activity Phase study of sunitinib/pazopanib + nivolumab in mrcc utcome Sunitinib + nivolumab (5 mg/kg) (n=33) Pazopanib + nivolumab (2 mg/kg) (n=20) RR, % Stable disease rate, % PFS rate at 24 weeks, % Grade 3 4 related AEs leading to discontinuation, % Four DLTs were observed in the pazopanib arm, leading to closure of this arm DLT, dose limiting toxicity; PD-1, programmed cell death 1 Amin et al. ASC 2014

28 Change in baseline target lesions (%) Maximum tumour burden reduction in baseline target lesions by nivolumab dose Treatment S + 2 (n=7) S + 5 (n=22) P + 2 (n=19) Patient Positive change in tumour burden indicates tumour growth; negative change indicates tumour change 2, nivolumab 2 mg/kg intravenous every 3 weeks; 5, nivolumab 5 mg/kg intravenous every 3 weeks; P, pazopanib; S, sunitinib Amin et al. ASC 2014

29 What can we expect in a short term in the field of mrcc SURTME PRTECT CARMEA EVEREST SRCE S-TRAC ATLAS CheckMate 214 (ipi + nivo vs sun) ASSURE ADAPT ALLACE A (cabo vs sun) MPRT RAPD MPDL3280 +/- bevacizumab METER (cabo vs evero) CheckMate 25 (nivo vs evero) ephrectomy Y/ Adjuvancy Vaccines Targeted agents mmune Checkpoint

30 METER: Phase study of second-line treatment with cabozantinib vs everolimus in mrcc Eligibility: mrcc with clear-cell component ne prior VEGF-targeted therapy =650 RA D M SA T Cabozantinib 60 mg orally daily Everolimus 10 mg orally daily Primary end point: PFS Study assumes mpfs of 5 months for everolimus and 7.5 months for cabozantinib. This provides for a HR of 0.67 and 90% power and requires 259 PFS events among the first 375 patients randomized Secondary end points: S, RR Assumes a median S of 15 months for everolimus and 20 months for cabozantinib. This provides for a HR of 0.75 and 80% power and requires 413 events Exploratory end points: patient-reported outcomes, biomarkers, safety, PK (CT )

31 ALLACE A031203: Randomized Phase Study Comparing Cabozantinib with Sunitinib in Patients with Previously Untreated Metastatic RCC Eligibility: patients with previously untreated clear cell mrcc with intermediate/poor risk =140 R A D M S A T Cabozantinib 60 mg orally daily Sunitinib 50 mg 4/2 schedule Primary end point: PFS Secondary end points: S, RR, Proportion of patients with unacceptable treatment related grade 3 or higher toxicity Exploratory end point: association between high MET expression and better PFS and S P: T. Choueri (CT )

32 The DART Study: Part 1 results of dalantercept plus axitinib dose escalation and expansion cohorts in advanced RCC Presented By Martin Voss at 2015 Genitourinary Cancers Symposium

33 Do not forget angiogenesis in mrcc: Axitinib + Dalantercept Presented By Martin Voss at 2015 Genitourinary Cancers Symposium

34 ESM 2014 RCC clinical guidelines Setting Risk group Standard ption First line Good/ntermediate risk Sunitinib [,A] Bevacizumab + F-α [,A] Pazopanib [,A] High-dose L2 [,C] Sorafenib [,B] Bevacizumab + low-dose F-α [,A] Poor risk Temsirolimus [,A] Sunitinib [,B] Sorafenib [,B] Second line Post cytokines Post VEGFR-TK Axitinib [,A] Sorafenib [,A] Pazopanib [,A] Axitinib [,B] Everolimus [,A] Sunitinib [,A] Sorafenib [,A] Third line Post two VEGFR-TKs Post VEGFR-TK and mtr inhibitor Everolimus [,A] Sorafenib [,B] ther VEGFR-TK [V,B] Rechallenge [V,B] Escudier B, et al. Ann ncol. 2014;25(Suppl. 3):iii49 iii56

35 Future ESM Guidelines?... Setting Tumour markers Treatment choice First-line therapy PD-L1 expression PD-L1/VHL null, BAP-1 WT PD-L1/VHL null, BAP-1 mutant mtr activation, high LDH ther mutation Anti-PD-1-based therapy Selective VEGF inhibitor VEGF inhibitor + agent X TR inhibitor Specific inhibitor Second-line therapy Same again? Presented by Atkins. KCS 2012

36 Muchas gracias