Jonathan E. Rosenberg, MD

THE TREATMENT OF metastatic urothelial carcinoma experienced a long period of stagnation until the recognition that targeting the programmed cell death protein 1 (PD-1) pathway could yield deep and durable responses.^1-3 Cisplatin-based combination chemotherapy has been the reference standard for front-line therapy, leading to a survival improvement compared to single-agent treatment and noncisplatin regimens. However, no agents had been unequivocally demonstrated to prolong survival in patients previously treated with platinum chemotherapy. 

In the past few years, multiple agents targeting the PD-1 pathway have been tested and shown significant promise. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), all anti– programmed cell death ligand 1 (PD-L1) antibodies, and nivolumab (Opdivo), an anti–PD-1 antibody, received accelerated approval from the U.S. Food and Drug Administration based on single-arm phase I or II studies for patients treated with prior platinum therapy.^4-7 However, none of these agents have been tested in a randomized trial. A recent press release reported that the phase III study of atezolizumab patients with prior platinum therapy did not reach its primary endpoint of improved overall survival compared to chemotherapy.⁸ 

As reported by Bellmunt and colleagues in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, pembrolizumab (Keytruda) was tested in a randomized phase III trial compared to second- and third-line chemotherapy.⁹ Patients were randomized with equal probability to pembrolizumab or chemotherapy, which consisted of the investigator preference of docetaxel, paclitaxel, or vinflunine. Patients who experienced clinical progression but were clinically well were allowed to continue treatment at the discretion of the treating investigator. 

PD-L1 status was tested based on a “combined positive score,” which was measured as the percentage of PD-L1–positive immune and tumor cells compared to the number of tumor cells. Patients were allowed to enroll on the study regardless of the PD-L1 score, but determination of that score was required for all patients. 

Key Findings 

PATIENTS TREATED with pembrolizumab on this study demonstrated a shorter progression-free survival compared to chemotherapy. However, median overall survival was 2.9 months longer in the pembrolizumab arm than the chemotherapy arm (10.3 vs 7.4, hazard ratio = 0.73, P = .002). 

Twenty-one percent of patients treated with pembrolizumab achieved Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1– defined objective responses, compared to 11.4% treated with chemotherapy. In addition, the durability of responses to pembrolizumab was impressive: At the time of data analysis, 18.4% of pembrolizumab-treated patients were still receiving pembrolizumab, compared to the 1.2% of patients assigned to chemotherapy who were still receiving chemotherapy. 

Patients with PD-L1–overexpressing tumors had an improved hazard ratio for death over chemotherapy compared to the entire study population. However, the median survival of 8 months in the PD-L1– high-expression group treated with pembrolizumab suggests that this biomarker in this trial highlighted a poor-prognosis group of patients, since this subgroup had a shorter median survival than the entire pembrolizumab arm (10.3 months). Furthermore, the objective response rates were not different between patients with PD-L1–overexpressing tumors and the entire population (21.6% vs 21.1%). Therefore, PD-L1 status using the 10% combined positive score threshold with the 22C3 antibody should not be used to select which patients with previously treated metastatic urothelial carcinoma should receive pembrolizumab. 

“With four agents already approved in this patient population, the major question is which agent is the safest and most effective in this context. Unfortunately, the lack of comparative data prevents any worthwhile conclusions from being drawn.”

— Jonathan E. Rosenberg, MD

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Safety Profile 

SAFETY FAVORED pembrolizumab over chemotherapy. Severe treatment-related adverse events were about one-third less common in pembrolizumab-treated patients, and treatment-related deaths were similar. These results suggest that pembrolizumab will become a reference standard for the treatment of metastatic urothelial carcinoma in patients who have been previously treated with platinum-based chemotherapy. 

With four agents already approved in this patient population, the major question is which agent is the safest and most effective in this context. Unfortunately, the lack of comparative data prevents any worthwhile conclusions from being drawn. ■

DISCLOSURE: Dr. Rosenberg is a consultant for Bristol-Myers Squibb, Roche/ Genentech, AstraZeneca, EMD-Serono, Astellas/Agensys, Seattle Genetics, Bayer, Inovio, and Gritstone; and owns stock in Merck. 

REFERENCES 

1. Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558-562, 2014. 

2. Petrylak DP, Powles T, Bellmunt J, et al: A phase Ia study of MPDL3280A (anti-PDL1): Updated response and survival data in urothelial bladder cancer (UBC). 2015 ASCO Annual Meeting. Abstract 4501. Presented June 1, 2015. 

3. Plimack ER, Bellmunt J, Gupta S, et al: Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): A non-randomised, open-label, phase 1b study. Lancet Oncol 18:212-220, 2017. 

4. 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 389:67-76, 2017. 

5. Massard C, Gordon MS, Sharma S, et al: Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 34:3119-3125, 2016. 

6. Gulley JL, Rajan A, Spigel DR, et al: Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): Dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 18:599-610, 2017. 

7. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312-322, 2017. 

8. Genentech provides update of phase III study of Tecentriq (atezolizumab) in people with previously treated advanced bladder cancer. May 10, 2017. Available at http://www.businesswire.com/news/home/20170509006887/en/Genentech-Update-Phase-III-Study-TECENTRIQ-Atezolizumab. Accessed July 21, 2017. 

9. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015-1026, 2017.