Pembrolizumab therapy for chemotherapy-resistant urothelial carcinoma

Developing effective second-line therapies for patients with advanced urothelial cancer with progression after platinum-based chemotherapy is an important medical need. The FDA recently approved two immune-checkpoint inhibitors in this setting: atezolizumab and nivolumab, although nivolumab is not yet fully approved, based on Phase 2 data only.

A landmark phase III clinical trial by Bellmunt et al. recently published in the New England Journal of Medicine compared the efficacy and safety of pembrolizumab (a humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) and chemotherapy in urothelial cancer patients who recurred or progressed on first-line platinum-based chemotherapy.

The trial randomized 542 patients tor receive either pembrolizumab or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The primary endpoints were overall survival and progression-free survival. Patients treated with pembrolizumab had superior median overall survival of 10.3 months (95% confidence interval [CI], 8.0 to 11.8) compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P = 0.002). Pembrolizumab was also associated with fewer treatment-related adverse events (60.9% vs. 90.2%). Interestingly, there were no differences in progression free-survival between the two groups. The authors suggest that progression-free survival may not be an appropriate endpoint for future assessments of clinical benefit from immune-checkpoint inhibitors.

This key study demonstrated a clear efficacy and safety advantage for pembrolizumab over second-line chemotherapy for patients with platinum-resistant urothelial cancer. Ongoing studies will assess pembrolizumab in the first-line and adjuvant settings.

Identifying optimal biomarkers and strategies for increasing clinical benefit are expected to ultimately translate to improved clinical outcomes for urothelial carcinoma patients.

Read the Abstract

Author: Bishoy M. Faltas MD

Reference:

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683. [Epub ahead of print]

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