18 th Annual Advances in Oncology - 2017
Prostate cancer Management of metastatic castration sensitive cancer Urothelial carcinoma Non-muscle invasive urothelial carcinoma Updates in metastatic urothelial carcinoma management Renal cell carcinoma Evolution of front-line therapy in mrcc
Prior to 2017: Androgen deprivation therapy (ADT) [continuous or intermittent] STAMPEDE and CHAARTED trials established role of ADT + docetaxel Some suggestion of increased benefit with heavy disease burden CJ Sweeney et al, NEJM 2015
Cyp17 inhibition Approved for metastatic castration resistant prostate cancer (CRPC) based on results of Phase III studies in docetaxel-pretreated and docetaxel-naïve patients Studied in castration sensitive prostate cancer in two studies LATITUDE- aggressive metastatic disease STAMPEDE- high risk locally advanced to metastatic disease
Patients Treatment Metastatic castration sensitive prostate cancer Two or more: - Gleason > 8 - > 3 bony lesions - Visceral metastases Randomize 1:1 Arm A Androgen deprivation therapy + abiraterone + prednisone Arm B Androgen deprivation therapy alone Treatment until radiographic progression Primary endpoints: - Overall survival - Radiographic progressionfree survival K. Fizazi et al NEJM 2017
Median OS benefit: Not reached v 34.7 months HR = 0.62 (95% CI 0.51-0.76); p=0.001 Radiographic PFS 33.0 v 14.8 months HR= 0.47 (95% CI: 0.39-0.55); p=0.001 K Fizazi et al. NEJM 2017
Patients Treatment Metastatic OR node positive OR locally advanced high risk with > 2 of: - T3 or T4 - Gleason 8-10 - PSA > 40 Randomize 1:1 Arm A Androgen deprivation therapy + abiraterone + prednisolone Treatment until PSA, clinical or radiographic progression (or for 2 years if nonmetastatic) OR relapsed disease treated with ADT < 12 months and >12 months since treatment Arm B Androgen deprivation therapy alone Primary outcome: Overall Survival ND James et al NEJM 2017
Characteristic ADT alone (n=957) ADT alone + abi (n=960) Median age (range) 67 (62-72) 67 (63-72) Node-negative non-metastatic 256 (27%) 253 (26%) Node-positive non-metastatic 187 (20%) 182 (19%) Metastatic 476 (50%) 465 (48%) Previously treated nonmetastatic 12 (1%) 25 (3%) Previously treated metastatic 26 (3%) 35 (4%) No hypertension 571 (60%) 557 (58%) Hypertension but fit for trial 385 (40%) 401 (42%) ND James NEJM 2017
OS HR: 0.63 (95% CI: 0.52-0.76); p<0.001 Treatment failure HR: 0.29 (95% CI: 0.25-0.34); p <0.001 ND James NEJM 2017
ADT +/- docetaxel Newly diagnosed metastatic prostate cancer patients Randomize Node positive only allowed if: 1 extra pelvic LN > 2cm OR 1 pelvic LN > 2 cm + 1 extrapelvic LN > 1 cm ADT + abi/pred +/- docetaxel ADT +/- docetaxel + local RT ADT+ abi/pred +/- docetaxel + local RT Treatment until progression Target accrual n=916 Primary endpoint OS Started enrollment 2013-2014 Expecting 5.5 years from first accrual NCT01957436
For castration sensitive prostate cancer patients ADT ADT + docetaxel (for 6 cycles) ADT + abiraterone + prednisone Biomarkers to identify who most benefits given Cost considerations Toxicities associated with docetaxel, abiraterone + prednisone Potential for limiting treatments in castration resistant setting
Non-muscle invasive urothelial carcinoma treatment SWOG S0337 Metastatic urothelial carcinoma (muc) First-line treatment with ddmvac or gemcitabine + cisplatin Second-line treatment: atezolizumab accelerated approval in May 2016 for platinum-refractory muc Keynote 045
Patients Treatment Cystoscopy with new diagnosis, suspected low grade nonmuscle invasive bladder cancer Randomize 1:1 One instillation of intravesicular gemcitabine (2 g/100 ml saline) Instillation of saline alone Cystoscopy every 3 months for 2 years, then every 6 months for 2 years Primary endpoint: time to recurrence (TTR) E Messing et al AUA 2017
N=406 Intention to treat analysis Intravesicular gemcitabine with decreased risk of recurrence compared to saline: HR = 0.66; 95% CI 0.48-0.90, p=0.010 In low-grade non-muscle invasive urothelial cancer patients enrolled HR = 050; 95% CI 0.33-0.76, p=0.001 E Messing AUA 2017
Patients Treatment Advanced urothelial carcinoma with predominantly transitional cell histology - Progressed after 1-2 platinumbased CT - ECOG 0-2 Randomize 1:1 Pembrolizumab 200 mg IV q3weekly Paclitaxel 175 mg/m2 IV q3weekly OR docetaxel 75 mg/m2 IV q3weekly OR vinflunine 320 mg/m2 IV q3weekly Treatment for 2 years or until progression, toxicity or withdrawal of consent Primary outcome: Overall Survival Progression- Free Survival DF Bajorin et al ASCO 2017
HR: 0.70 (95% CI 0.57-0.86) P= 0.0004 OS (%) 100 80 60 40 Median OS, mos (95% CI) 44.4% 30.2% Pembro (n = 270) 10.3 (8.0-12.3) 36.1% 20.5% CT (n = 272) 7.4 (6.1-8.1) 20 Pembro CT 0 0 4 8 12 16 20 24 Mos 270 272 194 171 147 109 116 73 79 46 27 15 4 1 DF Bajorin et al. ASCO 2017
Drug Target Efficacy Phase Type & Date of approval atezolizumab Anti-PD- L1 ORR: 14.8% (95% CI: 11.1-19.3) nivolumab Anti-PD-1 ORR: 19.6% (95% CI: 15.1-24.9) avelumab durvalumab Anti-PD- L1 Anti-PD- L1 ORR: 13.3% (95% CI: 9.1-18.4) ORR: 17.0% (95% CI: 11.9-23.3) pembrolizumab Anti-PD-1 HR: 0.70 (95% CI 0.57-0.86); p=0.0004 I/II I/II I/II I/II III Accelerated May 2016 Accelerated Feb 2017 Accelerated May 2017 Accelerated May 2017 Full May 2017
CheckMate 214: Study design Patients Treatment Treatment-naïve advanced or metastatic clearcell RCC Measurable disease KPS 70% Tumor tissue available for PD- L1 testing Randomize 1:1 Stratified by IMDC prognostic score (0 vs 1 2 vs 3 6) Region (US vs Canada/Europe vs Rest of World) Arm A 3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W for four doses, then 3 mg/kg nivolumab IV Q2W Arm B 50 mg sunitinib orally once daily for 4 weeks (6-week cycles) Treatment until progression or unacceptable toxicity Escudier et al ESMO 2017
Median duration of response, months (95% CI) Patients with ongoing response, % Outcome NIVO + IPI N = 425 N = 847 SUN N = 422 Confirmed ORR, % (95% CI) 42 (37 47) 27 (22 31) Confirmed BOR, a % Complete response Partial response Stable disease Progressive disease Unable to determine/not reported 9 32 31 20 8 P < 0.0001 1 25 45 17 12 Duration of Response (Probability) NIVO + IPI NR (21.8 NE) 72 SUN 18.2 (14.8 NE) 63 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 No. at Risk NIVO + IPI SUN 0.0 0 6 12 18 24 Months 177 146 120 55 3 112 75 52 17 0 Escudier et al ESMO 2017
Median OS, months (95% CI) NIVO + IPI NR (28.2 NE) 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 No. at Risk NIVO + IPI SUN 0 3 6 9 12 SUN 26.0 (22.1 NE) Hazard ratio (99.8% CI), 0.63 (0.44 0.89) P < 0.0001 15 18 21 24 27 30 33 Months 425 399 372 348 332 318 300 241 119 44 2 0 422 387 352 315 288 253 225 179 89 34 3 0 Escudier et al ESMO 2017
Trial/ drugs Comparator N Results Phase JAVELIN Avelumab + axitinib IMmotion 150 Atezolizumab + bevacizumab Study 111 Lenvatinib + pembrolizumab Echo- 202/Keynote- 037 Epocadostat + pembrolizumab None 55 ORR: 58.2% (44.1-71.3) Atezolizum ab OR Sunitinib 305 PFS HR: 0.64; p=0.095 None 30 ORR: 63% (44-80) None 19 ORR: 47% I Ib II II
Combination Comparators planned n Bevacizumab + atezolizumab Axitinib + avelumab Axitinib + pembrolizumab Lenvatinib + pembrolizumab Nivolumab + ipilimumab + cabozantinib Endpoint Expected to finish Sunitinib 900 PFS 2020 Sunitinib 583 PFS 2020 Sunitinib 840 PFS 2020 Lenvatinib + everolimus OR Sunitinib Nivolumab + ipilimumab OR Sunitinib 735 PFS 2020?? PFS 2021