CUA 2018: Checkpoint Inhibitors Across the Disease Spectrum: Metastatic Urothelial Carcinoma

Halifax, Nova Scotia ( Dr. Scott North provided a review of checkpoint inhibitors for patients with metastatic urothelial carcinoma at CUOG 6th annual multidisciplinary session at CUA 2018.  Dr. North started by discussing the IMvigor 210 trial arm assessing atezolizumab in platinum ineligible patients [1]. Atezolizumab was given as first-line treatment in 119 cisplatin-ineligible patients. At a median follow-up of 17.2 months, the ORR was 23% (95%CI 16-31%), the complete response rate (CRR) was 9%, and 19 of 27 responses were ongoing. Furthermore, the median PFS was 2.7 months (95%CI 2.1-4.2) and median OS was 15.9 months (95%CI 10.4-NR). 

Last year, initial outcomes of the phase II KEYNOTE-052 study reported 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) [2]. 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. Based on these results, pembrolizumab was granted FDA approval for the treatment of cisplatin-ineligible patients with advanced urothelial carcinoma. In the first-line cisplatin ineligible patient, Dr. North concluded: 

  • Pembrolizumab and atezolizumab have promising results  
  • These agents are approved in the US for these indications, but are not currently approved in Canada – no immunotherapy agent is approved or available for cisplatin ineligible as a first line treatment in Canada 
  • In Canada, medical oncologists are left to either pursue clinical trials or carboplatin-based therapy 
  • Cisplatin eligible patients are still treated with chemotherapy in the first-line 
In the second line, after progressing on cisplatin-based therapy, several studies have reported outcomes of immunotherapy agents. The IMvigor 210 arm had 310 patients treated with atezolizumab after progressing on first line platinum based chemotherapy [3]. 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 III IMvigor211 study tested the efficacy of atezolizumab versus chemotherapy among patients progressing on platinum-based chemotherapy [4]. 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). Dr. North’s thoughts on IMvigor 211 are as follows: 
  • This was a negative phase III trial for OS in the second line setting, although a confounding factor is that the chemotherapy group did better than expected and the benefit seems to be driven by vinflunine 
  • Atezolizumab appears to still be better than taxanes, which is what would commonly be used in the second-line setting since vinflunine is not approved in North America 
  • Further investigation of post-protocol treatment may be informative to assess if there are differences based on what chemotherapy was given 
  • Atezolizumab is still a viable option in the Canadian context, although funding will be an uphill battle with the negative phase III trial 
The phase 3 KEYNOTE-045 study compared pembrolizumab and investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in the second line setting; this trial was stopped after reporting the second planned interim analysis [5]. The study found a median 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). Based on these results, pembrolizumab was FDA approved for the treatment of locally advanced or metastatic urothelial carcinoma in the second line. According to Dr. North, since KEYNOTE-045 was positive in the phase III post-cisplatin trial, pembrolizumab is the de facto standard of care agent in this setting. Furthermore, both atezolizumab and pembrolizumab have a toxicity profile that is favorable and generally better than chemotherapy in the second-line setting. 

Dr. North notes that there are multiple first-line trials underway/completed enrolling, including DANUBE (durvalumab vs durvalumab/tremelimumab vs chemotherapy) and IMvigor 130 (atezolizumab vs chemotherapy vs atezolizumab/chemotherapy). He concluded with several summary points: 

  • There are promising results seen using immunotherapy in the first-line setting for cisplatin ineligible patients but drugs are currently not available in Canada in this setting 
  • Pembrolizumab has become the standard of care second-line agent given the positive KEYNOTE-045 study 
  • Atezolizumab is an active agent and further review of the IMvigor 211 trial will be needed to understand its results 
  • Access programs in the second-line setting exist for pembrolizumab and durvalumab pending an approval process 
  • Many trials are completed and waiting to report in the first-line setting 
Presented By: Scott North, Cross Cancer Centre, Edmonton, Alberta, Canada 

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia

1. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet 2017;389(10064):67-76. 
2. 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. 
3. 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. 
4. 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. 
5. 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.