Have Results of Recent Randomized Trials Changed the Role of mtor Inhibitors?

Have Results of Recent Randomized Trials Changed the Role of mtor Inhibitors? Bernard Escudier Institut Gustave Roussy Villejuif, France EIKCS Lyon April 2015

What is the current role of mtor inhibitors? Temsirolimus is currently the recommended option in poor risk patients Temsirolimus is an option for non clear cell RCC Everolimus is one recommended standard after TKI failure: In second line after one TKI In third line after two TKIs

Escudier, Porta, Schmidinger et al Ann Oncol 2014 ESMO 2014 guidelines Histology and setting First line Risk group Standard Option Clear-cell Good / intermediate Sunitinib [I, A] Bevacizumab + IFN [I, A] Pazopanib [I, A] High dose IL2[III, C] Sorafenib [II, B] Bevacizumab + low dose IFN [III, B] No mtor recommended

Escudier, Porta, Schmidinger et al Ann Oncol 2014 ESMO 2014 guidelines Histology and setting First line Risk group Standard Option Non Clear-cell Temsirolimus [III, B] Sunitinib [III, B] Sorafenib [III, B] Is there an alternative?

Escudier, Porta, Schmidinger et al Ann Oncol 2014 ESMO 2014 guidelines Histology and setting Second line Risk group Standard Option Clear-cell Post cytokines Axitinib [I, A] Sorafenib [I, A] Pazopanib [II, A] Sunitinib [III, A] Post TKIs Axitinib [I, B] Everolimus [II, A] Sorafenib [II, A] Are mtor better that TKIs?

Escudier, Porta, Schmidinger et al Ann Oncol 2014 ESMO 2014 guidelines Histology and setting Third line Risk group Standard Option Clear-cell Post 2 TKIs Everolimus [II, A] Any change?

What is the mechanism of mtor inhibitors? VEGF Akt TSC1 TSC2 PTEN MET Receptor mtor VHL HIF-1α VEGF Angiogenesis Cyclin D1 Cell Proliferation GLUT-1 Metabolism

Temsirolimus Everolimus Sunitinib Sorafenib Pazopanib Axitinib Rini BI, Campbel S and Escudier B. Lancet. 2009;373(9669):1119-1132.

Which questions have been raised in recent randomized trials? Are mtor inhibitors good first line options? RECORD 3 trial Are mtor inhibitors better that TKIs after sunitinib? Should mtor inhibitors be standard in non clear cell histology? Can we improve efficacy in mrcc by combining mtor inhibitors and VEGF inhibitors?

Which questions have been raised in recent randomized trials? S C R E E N Are mtor inhibitors good first line options? RECORD 3 trial R A N D O M I Z E** N = 471 1 : 1 Everolimus 10 mg/day Sunitinib 50 mg/day*** 1 st Line Cross-over upon progression Sunitinib 50 mg/day*** Everolimus 10 mg/day 2 nd Line Study endpoints Primary PFS-1 st line Secondary Combined PFS ORR-1 st line OS Safety *NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off. Motzer ASCO 2013

Cumulative event-free probability (%) Primary End Point: First-line PFS 100 90 80 70 60 50 40 30 20 10 0 Everolimus Sunitinib Everolimus (events/n = 182/238) Sunitinib (events/n = 158/233) 0 3 6 9 12 15 18 21 24 27 30 33 Time (months) Number of patients still at risk 238 233 164 181 118 145 88 108 68 84 44 55 31 42 Everolimus K-M Median PFS (mo) 23 28 12 15 Sunitinib 7.85 10.71 Hazard Ratio = 1.43 Two-sided 95% CI [1.15, 1.77] Everolimus is not better that sunitinib in first line setting 5 9 0 3 0 0

Which questions have been raised in recent randomized trials? Are mtor inhibitors better that TKIs after sunitinib? 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 1:1 Temsirolimus 25 mg IV weekly (n=259) Sorafenib 400 mg oral BID (n=253) N=512 112 sites in 20 countries Treat until PD, unacceptable toxicity Hutson T et al, JCO 2014

Overall Survival (probability) Overall survival Hutson et al, JCO 2014 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Temsirolimus Sorafenib 0 10 20 30 40 50 Time (months) Median OS, months 12.27 Sorafenib is better that temsirolimus afetr sunitinib failure 95% CI 10.13, 14.80 16.64 13.55, 18.72 P=0.014 (log-rank) Stratified HR: 1.31 (95% CI: 1.05, 1.63)

Which questions have been raised in recent randomized trials? Should mtor inhibitors be standard in non clear cell? ELIGIBILITY CRITERIA: Histology Papillary Chromophobe Unclassified Translocation Clear-cell w/ 20% sarc PS 0/1 Measurable disease Adequate organ function No prior systemic therapy No uncontrolled brain metastasis Stratification: 1. MSKCC risk group 2. Papillary vs other R A N D O M I Z A T I O N 1:1 Everolimus Sunitinib C R O S S O V E R Progressive Disease Everolimus Sunitinib Tannir N et al, ASCO 2014

Probability 0 0.2 0.4 0.6 0.8 1.0 Probability 0 0.2 0.4 0.6 0.8 1.0 Everolimus versus sunitinib in nccrcc Final Analysis (05/2014) Final Analysis 05/2014 Sunitinib (Events 25/33) Everolimus (Events 26/35) Sunitinib Median (95% CI)= Everolimus 6.1 mos (4.2, 9.4) is not Everolimus Median (95% Sunitinib Median (95% CI): 16.2 mos (14.2, NA) Everolimus Median (95% CI): 14.9 mos (8.0, 23.4) CI)= 4.1 mos (2.7, 10.5) better that sunitinib in non clear cell histology Stratified logrank P-value = 0.6 0 5 10 15 20 25 Stratified logrank P-value = 0.18 0 10 20 30 40

Which questions have been raised in recent randomized trials? Can we improve efficacy in mrcc by combining mtor inhibitors and VEGF inhibitors? Patients with previously untreated advanced RCC (N=791) Stratification factors: MSKCC risk group Nephrectomy status R A N D O M I Z E TEM + BEV TEM: 25 mg IV weekly BEV: 10 mg/kg IV every 2 wk (n=400) IFN + BEV IFN: 9 MU SC 3 x wk BEV: 10 mg/kg IV every 2 wk (n=391) Treat until PD, unacceptable toxicity, or discontinuation for any other reason April 2008 October 2012 1:1 Rini et al. JCO 2014

Probability of PFS INTORACT RESULTS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 TEM + BEV IFN + BEV Median PFS, months 9.1 9.3 1-sided P=0.759 (log-rank) Stratified HR: 1.07 (95% CI: 0.89, 1.28) 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Time (months) 95% CI 8.1, 10.2 9.0, 11.2 Rini et al. JCO 2014

And Everolimus is not better.. PFS. Combining mtor and VEGF inhibition is not recommended Ravaud et al. Ann Oncol 2015

Which questions have not been raised? Is Temsirolimus the best option for poor risk patients? Is Everolimus better that axitinib after TKI failure? Are mtor inhibitors better that TKIs in papillary or in chromophobe cancers?

Which questions have not been raised? Is Temsirolimus the best option for poor risk patients? Histology and setting First line Risk group Standard Option Clear-cell Poor risk Temsirolimus [II, A] Sunitinib [II, B] Sorafenib [III, B]

Treatment of poor risk patients remain questionable Very few poor risk patients enrolled in randomized trials No randomized trial is currently investigating whether temsirolimus should remain standard of care Everolimus does not appear to be better that temsirolimus (Escudier et al, GU ASCO 2015) Immune therapy are currently evaluated in this setting, but

With sunitinib as control arm! Checkmate study

Which questions have not been raised? Is Temsirolimus the best option for poor risk patients? Is Everolimus better that axitinib after TKI failure? Temsirolimus and Everolimus have different PK profile Cross trial comparisons suggest similar efficacy

Cross trial comparison Axitinib Sorafenib Sorafenib Temsirolimus Everolimus N 194 195 253 259 277 PFS OS Axis Intorsect Record 1

Cross trial comparison Axitinib Sorafenib Sorafenib Temsirolimus Everolimus N 194 195 253 259 277 PFS 4.8 3.4 3.9 4.3 3.9 (4.6*) OS Axis Intorsect Record 1 * 2 nd line post sunitinib only

Cross trial comparison Axis Intorsect Record 1 Axitinib Sorafenib Sorafenib Temsirolimus Everolimus N 194 195 253 259 277 PFS 4.8 3.4 3.9 4.3 3.9 (4.6*) OS 15.2 16.5 16.4 12.3 14.8

Which questions have not been raised? Is Temsirolimus the best option for poor risk patients? Is Everolimus better that axitinib after TKI failure? Are mtor inhibitors better that TKIs in papillary or in chromophobe cancers?

nccrcc is very heterogenous Everolimus n=35 Sunitinib n=33 Age (median, range) 58 (23-73) 60 (28-76) 0.72 Gender (M:F) 24:11 19:14 0.45 Nephrectomy 27 25 1.0 Histology Papillary Sarcomatoid Chromophobe Unclassified Translocation ECOG Performance Status 0 1 13 6 6 6 4 15 20 14 6 6 4 3 18 15 P-value 0.97 0.47 Tannir N et al, ASCO 2014

Subgroup analyses are unacceptable Subtype Everolimus Median, mos (95% CI) Sunitinib Median, mos (95% CI) Papillary 14.9 (7.1, 22.7) n=13 16.6 (5.9, NA) n=14 Chromophobe 25.1(4.7, NA) n=6 31.6 (14.2, NA) n=6 Unclassified NA n=6 15.4 (NA) n=4 Translocation 8.1 (5.5, 23) n=4 16.2 (8.8, NA) n=3 Sarcomatoid w/ clear-cell 11.1 (2.0, NA) n=6 7.0 (5.4, 10.4) n=6 Tannir N et al, ASCO 2014

Conclusions Recent randomized data have not significantly changed the role of mtor However: The use of temsirolimus in second line should be discouraged Combination of mtor with VEGF inhibitors is not a good option Randomized trials should be designed to: Compare everolimus and axitinib Compare TKIs to temsirolimus in poor risk patients