Starting with the FDA approval of cisplatin in 1978 for metastatic bladder cancer, there have been few exciting advances with regards to systemic therapy for bladder cancer until the recent approval of atezolizumab in 2016, quickly followed by four more immunotherapy options in 2017 (pembrolizumab, nivolumab, durvalumab, avelumab).
The IMvigor210 phase II trial treated 310 patients with atezolizumab after progressing on first line platinum-based chemotherapy . Compared with a historical control objective response rate (ORR) of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 ORR (15%, 95%CI 11-20, p=0.0058), as well as for each prespecified immune cell group: IC 2/3 - 27%, 95%CI 19-37, p<0·0001; IC1/2/3 - 18%, 95%CI 13-24, p=0.0004. Furthermore, over a median follow-up of 11.7 months (95%CI 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders.
The phase 3 KEYNOTE-045 study comparing pembrolizumab and investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) reported results after the second planned interim analysis (at which point the trial was stopped) . The study found a median overall survival (OS) of 10.3 months (95%CI 8.0-11.8) in the pembrolizumab group, compared with 7.4 months (95%CI 6.1-8.3) in the chemotherapy group (HR 0.73, 95%CI 0.59-0.91). Furthermore, the median OS among patients who had a tumor PD-L1 combined positive score (CPS) of ≥10% was 8.0 months (95%CI 5.0-12.3) in the pembrolizumab group, as compared with 5.2 months (95%CI 4.0-7.4) in the chemotherapy group (HR 0.57, 95%CI 0.37-0.88). Updated two-year outcomes presented at this meeting demonstrate that the results of the interim analysis that resulted in FDA approval for pembrolizumab remained, specifically for an OS benefit and superior safety, compared to chemotherapy.
The phase III IMvigor211 study tested the efficacy of atezolizumab versus chemotherapy among patients progressing on platinum-based chemotherapy . There were 931 patients randomized to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11.1 months, 95%CI 8.6-15.5 vs 10.6 months 95%CI 8.4-12.2) (HR 0.87, 95%CI 0.63-1.21). An exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase II data from IMvigor 210 for atezolizumab in this setting. Unfortunately, atezolizumab was not associated with significantly longer OS than chemotherapy in patients overexpressing PD-L1 (IC2/3).
Srinivas’ summary of all of the check-point inhibitor studies in platinum-refractory disease is:
- All inhibitors evaluated in this setting are active
- ORR ranges from 15-26%
- There are a handful of patients with complete responses
- Pembrolizumab has demonstrated superiority to chemotherapy in this setting
The phase II KEYNOTE-052 study was also for patients ineligible for cisplatin, reporting that among 370 patients receiving at least one dose of pembrolizumab, 89 (24%, 95%CI 20-29) patients had a centrally assessed objective response, and 74 (83%) of 89 patients had ongoing responses over a median follow-up of 5 months (IQR 3.0-8.6) . Additionally, a PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab: 42 (38%, 95%CI 29-48) of 110 patients had an objective response. Updated efficacy results presented at this meeting demonstrate durable responses in this population. As Srinivas notes, this is comparable to our best chemotherapy regimen in this setting (carboplatin/gemcitabine), which demonstrates ORRs of 36%, PFS of 5.8 months, and OS of 9.3 months.
Srinivas also highlighted that there are several ongoing trials in the adjuvant setting for urothelial carcinoma, summarized as follows:
There are several challenges that Srinivas notes moving forward in the clinical trial landscape of immunotherapy:
- There are no reliable, predictive biomarkers
- There is a relatively low number of responders and we are unclear as to the duration of therapy for those that do respond
- We are still unsure what the best setting to use immunotherapy is
- Will sequence therapy matter?
- Is re-treatment an option?
1. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016;387(10031):1909-1920.
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. Powles T, Duran I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomized controlled trial. Lancet 2018;391:748-757.
4. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18(11):1483-1492.
Presented by: Sandy Srinivas, MD, Department of Oncology, Stanford University School of Medicine/Stanford Cancer Center, Stanford, CA
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA