Negative Trials in RCC: Where Did We Go Wrong? Can We Do Better?

Negative Trials in RCC: Where Did We Go Wrong? Can We Do Better? 9 th European Kidney Cancer Symposium, Dublin, April 2014 Tim Eisen

Tim Eisen - Disclosures Company Research Support Advisory Board Trial Management Group Honoraria Astra Zeneca + + + Astellas + + Aveo + + + Bayer + + + + GSK + + + + Immatics + Pfizer + + + Roche + +

Appraisal

40 Years of Developing mrcc Treatments Cytokines IL-2 and IFN-α High-dose IL-2 FDA approval based on phase II data Pazopanib Everolimus Bevacizumab+IFN-α Temsirolimus Sorafenib Sunitinib Axitinib 1980 1990 2000 2010 2020 VHL tumour suppressor gene isolated Chromatin Remodelling Gene Mutations

Failed studies a BIG issue 935 / 7776 Phase II / III studies did not complete Accrual 38.7% Sponsor decision 10.7% Interim analysis 9.9% Toxicity 8.2% Funding 5.6% Stensland et al., GU ASCO 2014

Nephrectomy in mrcc: Key Questions in the TKI Era Is cytoreductive nephrectomy benefical? If so, should nephrectomy or TKI come first?

CARMENA V SURTIME

There are many ongoing Phase III studies of adjuvant targeted therapy in RCC... Trial Treatment arms and duration Patients N SORCE 1 Sorafenib (3 years) Sorafenib (1 year) then placebo (2 years) Placebo (3 years) Resected clear-cell/non-clear-cell RCC and intermediate- or high-risk disease 1656 ASSURE 2 Sorafenib Sunitinib Placebo 1 year Resected clear-cell/non-clear-cell RCC and intermediate-high- or very-high-risk disease 1923 S-TRAC 3 Sunitinib Placebo 1 year Resected predominantly clear-cell RCC and high-risk disease 720 PROTECT 4 Pazopanib Placebo 1 year Resected (predominantly) clear-cell RCC with high or moderately high risk of recurrence 1500 EVEREST 5 Everolimus Placebo 54 weeks Resected clear-cell/non-clear-cell RCC and intermediate-high- or very-high-risk disease 1218 1. www.clinicaltrials.gov. NCT00492258; 2. www.clinicaltrials.gov. NCT00326898; 3. www.clinicaltrials.gov. NCT00375674; 4. www.clinicaltrials.gov. NCT01235962; 5. www.clinicaltrials.gov. NCT01120249.

Adjuvant studies in RCC: Divided we fall? Placebo / control 3143 Sorafenib 1yr (SORCE)1242 Pazopanib (PROTECT) 750 Sorafenib (ASSURE) 641 Sunitinib (ASSURE) 641 Everolimus (EVEREST) 609 Sunitinib (S-TRAC) 300

ARISER (G250 v Placebo) Metastases at baseline in 11% Median DFS 71 months 5 year OS 78% Risk Group Staging % of total Leibovich Score 1 T3/4; N0/X; M0 75% 4-9 2 Any T; N+; M0 8% 2 11 3 T1b/2; N0/NX; M0; G>3 17% 3-8 Belldegrun et al., ASCO 2013

MAMS vs traditional Traditional Approach Multi-arm, Multi-stage Phase II T1 T2 T3 T4 C T1 T2 T3 T4 Phase II Phase III C T1 C T3 C T4 Phase III

Predictors of Successful Phase III Trials Strong Phase II signal / scientific rationale Predictive marker Robust outcome magnitude and relevance Efficient and effective design Clin Cancer Res. 2010 Dec 15;16(24):5951-5. doi: 10.1158/1078-0432.CCR-10-2632. Translating clinical trials into meaningful outcomes. LoRusso PM 1, Schnipper LE, Stewart DJ, Boerner SA, Averbuch SD, Wolf W.

Recent Negative Trials in mrcc Study Setting Experimental Arm Standard Arm INTORSECT 2 nd line Temsirolimus Sorafenib INTORACT 1 st line Bev/Tem Bev/IFN RECORD 2 1 st line Bev/Evero Bev/IFN GOLD 3 rd line Dovitinib Sorafenib AGILE 1 st line Axitinib Sorafenib TIVO 1 1 st line Tivozanib Sorafenib Comment

INTORSECT Phase III Study Design 1 Key eligibility criteria: mrcc PD on 1st-line sunitinib Stratification factors: Duration of sunitinib therapy ( or > 6 mos) MSKCC risk group Histology (clear cell or non clear-cell) Nephrectomy status R A N D O M I Z A T I O N 1:1 N = 512 Temsirolimus 25 mg IV weekly a n = 259 Sorafenib 400 mg oral BID a n = 253 Primary end point: PFS (IRC) Secondary end points: OS, PFS (investigator), PFS at 12, 24, and 36 weeks, ORR, duration of response a Dose reductions were allowed: temsirolimus (to 20 mg then 15 mg); sorafenib (to 400 mg/day, then every other day) 1. Hutson TE et al ESMO 2012; abstract LBA22_PR

Prospective Data: INTORSECT Phase III Study Efficacy 1 No significant difference in PFS between temsirolimus and sorafenib OS significantly longer with sorafenib (P=0.014) Median PFS, 1.0 months 95% CI 0.9 0.8 0.7 Temsirolimus Sorafenib 4.28 3.91 4.01, 5.43 2.80, 4.21 0.6 0.5 0.4 P=0.1933 (log-rank) Stratified HR: 0.87 (95% CI: 0.71, 1.07) 0.3 0.2 0.1 0 0 5 10 15 20 25 Patients at risk, n Time (months) Sorafenib 252 72 22 11 6 0 Temsirolimus 259 96 28 9 5 0 PFS (probability) Progression-Free Survival (IRC Assessment) Median OS, 1.0 months 95% CI 0.9 0.8 0.7 Temsirolimus Sorafenib 12.27 16.64 10.13,14.80 13.55, 18.72 0.6 0.5 0.4 P=0.014 (log-rank) Stratified HR: 1.31 (95% CI: 1.05, 1.63) 0.3 0.2 0.1 0 0 10 20 30 40 50 Patients at risk, n Time (months) Sorafenib 253 158 74 34 13 0 Temsirolimus 259 132 54 22 8 0 Overall Survival (probability) Overall Survival CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; OS, overall survival; PFS, progression-free survival 1. Hutson TE et al ESMO 2012; abstract LBA22_PR

Recent Negative Trials in mrcc Study Important question? Strong rationale? Predictive marker? INTORSECT Yes Yes No Yes INTORACT RECORD 2 GOLD AGILE TIVO 1 Good design?

Rationale for Bevacizumab / Temsirolimus combination Phase I study: N = 12, all ECOG 0-1 Prior therapy: n = 7, cytokines in 6/7 RR: NO CR PR=7 (60 %) SD = 3 (25 %) PFS: n/a Combination feasible with both agents given at full dose High response rate further testing recommended Merchan ASCO 2007 www.esmo2012.org

Rationale for Everolimus/Bevacizumab combination Phase II study: N = 30 untreated patients in preliminary report N = 50 untreated patients in final report Median PFS: 12 months in ASCO 2008 presentation (9 months in abstract) 9.1 months in the final report (JCO 2010) RR: NO CR PR=23 % SD = 53 % Combination feasible with both agents given at full dose Very active ( 12 months PFS ) further testing recommended Whorf et al ASCO 2008; Hainsworth et al JCO 2010 www.esmo2012.org

Recent Negative Trials in mrcc Study Setting Experimental Arm Standard Arm Comment INTORSECT 2 nd line Temsirolimus Sorafenib Positive INTORACT 1 st line Bev/Tem Bev/IFN Ph I signal RECORD 2 Large Ph II 1 st line Bev/Evero Bev/IFN Ph II signal +/- GOLD 3 rd line Dovitinib Sorafenib True negative AGILE 1 st line Axitinib Sorafenib TIVO 1 1 st line Tivozanib Sorafenib

AGILE Study Design* Previously untreated metastatic RCC R A N D O M I Z E 2:1 Axitinib 5 mg BID (n=192) Sorafenib 400 mg BID (n=96) Primary endpoint: PFS Randomization stratified by ECOG PS (0 vs 1). * ClinicalTrials.gov: NCT00920816. Titrated stepwise to 7 mg BID and then 10 mg BID in patients without grade 3 or 4 (CTCAE v3.0) axitinib-related AEs for a consecutive 2-week period, unless BP >150/90 mmhg. 22

PFS (probability) Progression-free Survival (IRC Assessment) No. events (%) 1.0 Axitinib 111 (58) 0.9 Sorafenib 60 (63) 0.8 0.7 0.6 1-sided P=0.038 0.5 0.4 0.3 0.2 = censored for axitinib 0.1 = censored for sorafenib 0.0 0 2 4 6 8 10 12 14 16 18 20 Time (months) Stratified HR, 0.77* (95% CI 0.56 1.05) mpfs, mo (95%CI) 10.1 (7.2 12.1) 6.5 (4.7 8.3) * Stratified by ECOG PS; assuming proportional hazards, HR <1 indicates a reduction in favor of axitinib and HR >1 indicates a reduction in favor of sorafenib. IRC = independent radiology committee; mpfs = median progression-free survival 22 24 Patients at risk, n Axitinib 192 154 132 114 91 78 63 54 34 19 6 1 0 Sorafenib 96 73 60 43 34 24 20 19 13 10 0 0 0 23

Statistical Design Primary endpoint for first-line comparison was PFS, assessed by independent radiology committee (IRC) 90% power to detect a 78% improvement in mpfs from 5.5 mo with sorafenib to 9.8 mo with axitinib, corresponding to an HR of 0.56 (overall 1-sided α=0.025) An estimated 247 treatment-naïve patients were needed to observe the required 148 IRC-assessed PFS events One interim futility analysis was planned at 74 (50%) investigator-assessed PFS events; independent data monitoring committee (DMC) could adjust number of IRC-assessed PFS events based on conditional power at interim analysis Number of PFS events was increased to 169 by DMC 24

Recent Negative Trials in mrcc Study Setting Experimental Arm Standard Arm Comment INTORSECT 2 nd line Temsirolimus Sorafenib True negative INTORACT 1 st line Bev/Tem Bev/IFN Ph I signal RECORD 2 Large Ph II 1 st line Bev/Evero Bev/IFN Ph II signal +/- GOLD 3 rd line Dovitinib Sorafenib True negative AGILE 1 st line Axitinib Sorafenib Statistics TIVO 1 1 st line Tivozanib Sorafenib

TIVO-1: Phase III superiority study of tivozanib vs sorafenib as first-line targeted therapy for advanced RCC Key eligibility criteria Advanced RCC Clear cell histology Measurable disease Prior nephrectomy 0 1 prior therapy for mrcc No prior VEGF or mtor therapy ECOG PS 0 1 Stratification factors Geographic region Prior treatments for mrcc Number of metastatic lesions R A N D O M I S E D 1:1 Tivozanib 1.5 mg/day p.o., 3 weeks on/1 week off (N=260) Sorafenib 400 mg p.o. b.d., continuous (N=257) Progression Crossover to tivozanib via separate protocol Motzer et al. J Clin Oncol 2012; 30(Suppl): Abstract 4501 (Oral presentation) 26

Tivozanib is superior to sorafenib for PFS (primary endpoint, independent radiological review) Probability of PFS (%) 100 80 60 40 20 Median PFS, months (95% CI) Tivozanib 11.9 (9.3 14.7) Sorafenib 9.1 (7.3 9.5) HR=0.797; P=0.042 Tivozanib Sorafenib 0 0 5 10 15 Time since randomisation (months) 20 No. at risk Tivozanib 260 257 217 210 181 179 164 163 144 140 126 117 109 100 94 68 65 29 29 2 2 0 Sorafenib 257 253 218 212 184 183 146 144 120 113 91 84 73 68 64 46 44 19 18 2 2 0 ITT population Data on file, AVEO/Astellas Pharma 2012, Study 301 CSR, Table 17 and Figure 3 Motzer et al. J Clin Oncol 2012; 30(Suppl): Abstract 4501 (Oral presentation) 27

Use of next-line treatments confounds the OS comparison Randomised to tivozanib arm (n=260) Still on tivozanib treatment 27% (n=71) Discontinued initial therapy 73% (n=189) 64% 18% 10% 8% VEGF (n=18) mtor (n=16) No therapy (n=121) Other*(n=34) Randomised to sorafenib arm (n=257) Still on sorafenib treatment 12% (n=31) * Other includes radiotherapy and cytokines Due to rounding, total does not equal 100% Discontinued initial therapy 88% (n=226) 3% 2% 26% 70% (156/158 patients received tivozanib) VEGF (n=158) mtor (n=4) No therapy (n=58) Other * (n=6) Motzer et al. J Clin Oncol 2013; 31(Suppl 6): Abstract 350 (Poster) 28 28

100 80 TIVO-1: final OS analysis Tivozanib Sorafenib (includes patients who crossed over) Median OS, months (95% CI) 28.8 (22.5 NR) 29.3 (29.3 NR) Survival (%) 60 40 20 Tivozanib arm Sorafenib arm a HR=1.25; P=0.105 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Time (months) No. at risk Tivozanib 260 256 241 227 211 198 183 170 159 148 142 133 125 89 39 2 0 Sorafenib 257 249 241 232 218 208 194 181 170 167 157 151 137 98 43 3 0 a includes patients who crossed over to tivozanib after progression on sorafenib Motzer et al. J Clin Oncol 2013; 31(Suppl 6): Abstract 350 (Poster) 29 29

Conclusions Perspective Help ourselves in difficult situations Minimise Risk & Maximise Efficiency: How persuasive will the data be? Try to foresee consequences of design Strength of Phase II / scientific rationale Realistic statistical design Novel designs Phase II: Use RECIST as a continuous variable Multi-Arm Multi-Stage