The Checkmate-025 study randomized 821 previously treated clear cell mRCC patients 1:1 to nivolumab vs everolimus and treated until progression or intolerable drug toxicity [1]. The median overall survival (OS) was 25 months (95%CI 21.8 to NR) for nivolumab and 19.6 (95%CI 17.6-23.1) with everolimus, with a HR for death with nivolumab vs everolimus of 0.73 (98.5%CI 0.57-0.93). However, the median progression-free survival (PFS) was not significant between the two groups (HR 0.88, 95%CI 0.75-1.03). Since this landmark trial, we have subsequently seen combination phase Ib trials demonstrating encouraging objective response rates (ORR): pembrolizumab + axitinib (ORR 58.2%, 95%CI 44.1-71.3%) and axitinib + avelumab (ORR 100%). We eagerly await currently accruing first line and neoadjuvant/adjuvant immunotherapy trials for patients with RCC:
Given the high somatic mutation frequency observed in bladder cancer and the potential for many neoantigens to be seen as foreign by the host immune system, Dr. Chi notes that this malignancy is ripe for success with immunotherapy. Across five clinical trials of immunotherapy in bladder cancer (testing atezolizumab, nivolumab, durvalumab, pembrolizumab, avelumab vs chemotherapy), we have seen consistent response rates across different PD-1/PD-L1 agents. However, although the PD-L1 expression enriches for response, it is not currently suitable as a predictive biomarker as of yet according to Dr. Chi. In a phase III study published earlier this year, 542 patients with advanced urothelial cancer progressing on first line platinum-based chemotherapy were randomized to pembrolizumab vs additional chemotherapy (paclitaxel, docetaxel or vinflunine) [2]. Patients receiving pembrolizumab had an improved median OS (10.3 months, 95%CI 8.0-11.8) compared to 7.4 months (95%CI 6.1-8.3) for patients receiving chemotherapy (HR 0.73, 95%CI 0.59-0.91). However, similar to Checkmate-025 for RCC, there was no difference in PFS (HR 0.98, 95%CI 0.81-1.19). There are exciting clinical trials undergoing for urothelial carcinoma in the first line metastatic state, adjuvant setting after radical cystectomy and non-muscle invasive setting:
Since the approval of immunotherapy therapy Sipuleucel-T for mCRPC, immunotherapy lost favor in the prostate cancer arena until recently according to Dr. Chi. Beer et al. earlier this year reported findings of their phase III trial randomizing 602 patients (2:1) with metastatic chemotherapy-naïve castration-resistant prostate cancer (CRPC) to ipilimumab vs placebo [3]. Although there was no difference in OS between the groups (HR 1.11, 95.87%CI 0.88-1.39), men receiving ipilimumab had improved PFS (5.6 months vs 3.8; HR 0.67, 95.87% CI 0.55-0.81) compared to those on placebo. Since then, there has been interest for anti-PD-1 activity in enzalutamide-resistant prostate cancer, with a number of trials ongoing:
Dr. Chi concluded with a number of take home messages: (i) immunotherapy with checkpoint inhibitors and agonists are in the development across a range of genitourinary cancers, (ii) agents targeting PD-1/PD-L1 are active in genitourinary cancers, with nivolumab approved for use in RCC and atezolizumab in bladder cancer, (iii) these agents are well tolerated but can induce immune related adverse events which need to be carefully monitored for and managed with corticosteroids, (iv) now proven in the advanced disease setting, these agents are now being tested in earlier disease states: first line, neoadjuvant/adjuvant, and non-muscle-invasive bladder cancer.
Presented By: Kim Chi, BC Cancer Agency, MD, Vancouver Prostate Centre, Vancouver, BC, Canada
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 72nd Canadian Urological Association Annual Meeting - June 24 - 27, 2017 - Toronto, Ontario, Canada
References:
1. Motzer R, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal Cell Carcinoma. N Engl J Med 2015;373:1803-1813.
2. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.
3. Beer TM, Kwon ED, Drake CG, et al. Randomized, Double-Blind, Phase III Trial of Ipilimumab versus placebo in Asymptomatic or Minimally Symptomatic Patients with Metastatic Chemotherapy-Naïve Castration-Resistant Prostate Cancer. J Clin Oncol 2017;35(1):40-47.