Dr. Petros Grivas gave a presentation advocating for first-line immunotherapy for this patient. In the gemcitabine/cisplatin vs MVAC trial, von der Maase et al.1 reported on 405 patients with metastatic urothelial carcinoma randomized 1:1 to receive gemcitabine/cisplatin or standard MVAC every 28 days for a maximum of six cycles. Overall survival was similar in both arms (HR 1.04, 95%CI 0.82-1.32), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (gemcitabine/cisplatin 49%; MVAC 46%). However, Dr. Grivas notes that this trial was designed to assess whether gemcitabine/cisplatin is superior to MVAC and was not powered to demonstrate non-inferiority. Second, he notes that outcomes were worse in cisplatin-unfit patients with a median overall survival of 9 months.
Dr. Grivas notes that atezolizumab is ideal in this setting. The IMvigor210 phase II trial treated 310 patients with atezolizumab after progressing on first line platinum based chemotherapy2. 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. Also as part of the IMvigor210 trial was a cohort of patients (n=119) that were treated with atezolizumab as first-line treatment secondary to being cisplatin-ineligible. 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).
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)3. 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 at a median follow-up of 11.5 months demonstrated durable responses in this population (6-month OS rate: 67%; 12-month OS rate: 48%).
Dr. Grivas notes that there are many ongoing IO studies among patients with metastatic urothelial carcinoma. One study he highlighted is the GU 14-182 randomized phase II trial of maintenance pembrolizumab vs placebo. Patients with metastatic urothelial carcinoma with at least stable disease after first-line platinum-based chemotherapy will be randomized (n=200) to pembrolizumab 200 mg IV q3 weeks vs placebo. Another maintenance study where Dr. Grivas is the US lead, will randomize patients (n=668) with stable disease, partial or complete responses on first-line chemotherapy to either avelumab (10 mg/kg IV q2 weeks) vs best supportive care.
Dr. Grivas concluded with several take-home messages from this talk supporting the role of immunotherapy for this patient:
- The premise of longer OS and ORR, especially in PD-L1 positive patients, has to be confirmed in phase III trials
- Less toxicity and better quality of life is achievable with immunotherapy compared to chemotherapy
- Concurrent combinations vs sequential therapy on an individual patient level may be the future
- The role of biomarkers needs to be clarified for optimal patient selection, as one size (treatment) may not fit all
Presented by: Wassim Kassouf, Professor, Department of Surgery in Urology, McGill University, Montreal Canada and Petros Grivas, MD, PhD, medical oncologist at Seattle Cancer Care Alliance, Clinical Director, Genitourinary Cancers Program, University of Washington Medicine, Associate Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Washington
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia Twitter: @zklaassen_md at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona Spain, March 15-19, 2019.
- Von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000 Sep;18(17):3068-3077.
- 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.
- 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.
Chemotherapy - In a PDL1 Positive Patient with Good Performance Status and GFR with Lung Metastases