ASCO 2018: Pembrolizumab versus Investigator’s Choice (Paclitaxel, Docetaxel, or Vinflunine) in Recurrent, Advanced Urothelial Cancer: 2-Year Follow-Up from KEYNOTE-045 Trial

Chicago, IL ( Recurrent, advanced urothelial carcinoma remains a dismal prognosis. Additional chemotherapy after failing platinum-based chemotherapy has historically been palliative. Last year, 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) 1. 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. At the 2018 ASCO annual meeting, Yves Fradet, MD, and KEYNOTE-045 colleagues presented two-year follow-up data from this trial. 

For KEYNOTE-045, 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy were randomly assigned to receive pembrolizumab (n=270; 200 mg every 3 weeks) or the investigator's choice of chemotherapy (n=272) with paclitaxel (175 mg/m2 every 3 weeks), docetaxel (75 mg/m2 every 3 weeks), or vinflunine (320 mg/m2 every 3 weeks). The co-primary end points were OS and PFS. The secondary endpoint was ORR (RECIST v1.1, blinded central review) Eligibility requirements included: 

  • Histologically or cytologically confirmed urothelial carcinoma
  • Progression after platinum-based chemotherapy
  • ECOG performance status 0-2
  • Measurable disease per RECIST v1.1 criteria
  • ≤2 lines of systemic therapy
At the cutoff point of October 26, 2017, the median follow-up for the 542 included patients was 27.7 months. The median OS was significantly longer for patients receiving pembrolizumab vs chemotherapy (10.3 vs 7.3 months; HR 0.70, 95%CI 0.57-0.85). Importantly, the OS benefit with pembrolizumab was seen in all PD-L1 expression subgroups. Specifically, for CPS ≥10 the median OS was 8.0 (95%CI 5.0-12.3) months for pembrolizumab and 4.9 (95%CI 4.0-7.4) months for chemotherapy (HR 0.55, 95%CI 0.37-0.81).  This survival benefit remained regardless of age, ECOG performance status, prior therapy, liver metastases, baseline hemoglobin, time from last chemotherapy, histology, risk factor group, and choice of chemotherapy. Similar to the second interim analysis, there was no difference in PFS between the two arms (2.1 vs 3.3 months; HR 0.96, 95%CI 0.79-1.16), however, pembrolizumab was associated with a higher ORR compared to the chemotherapy group (21.1% vs 11.0%). The median duration of response was longer with pembrolizumab (not reached, 95%CI 1.6-30.3 months vs 4.4 months, 95%CI 1.4-29.9 months), and a greater proportion of responses lasted ≥12 months (68% vs 35%) with pembrolizumab. Finally, there were fewer patients with pembrolizumab compared to chemotherapy who experienced a treatment-related adverse event of any grade (62.0% vs 90.6%) and a grade ≥3 adverse event (16.5% vs 50.2%).

The authors concluded that at the two-year follow-up point, 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. In addition to FDA approval, pembrolizumab has also been approved in this disease space irrespective of PD-L1 status by the European Medicines Agency, and the Japanese Ministry of Health, Labor, and Welfare. These results are encouraging, considering the dismal prognosis associated with platinum-refractory locally advanced or metastatic urothelial carcinoma. This trial demonstrates not just extended life, but also the quality of life for patients receiving pembrolizumab with respect to fewer adverse events. Clinical trial information: NCT02256436

1. 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.

Presented by: Yves Fradet, MD, CHU de Québec - Université Laval, Québec City, QC, Canada
Co-Authors: Joaquim Bellmunt, Ronald De Wit, David J. Vaughn, Jae-Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang, Miguel A. Climent, Daniel Peter Petrylak, Toni K. Choueiri, Andrea Necchi, Winald R. Gerritsen, Howard Gurney, David I. Quinn, Stephane Culine, Cora N. Sternberg, Kijoeng Nam, Tara L. Frenkl, Rodolfo F. Perini, Dean F. Bajorin; CHU de Québec - Université Laval, Québec City, QC, Canada; Dana-Farber Cancer Institute, Boston, MA; Erasmus MC Cancer Institute, Rotterdam, Netherlands; Abramson Cancer Center, Penn Medicine, Philadelphia, PA; Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea, Republic of (South); University of California, San Francisco, San Francisco, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Fundación Instituto Valenciano de Oncología, Valencia, Spain; Smilow Cancer Hospital at Yale University, New Haven, CT; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Radboud University Medical Center, Nijmegen, Netherlands; Westmead Hospital and Macquarie University, Sydney, Australia; USC Norris Comprehensive Cancer Center, Los Angeles, CA; Hôpital Saint-Louis, Paris, France; San Camillo-Forlanini Hospital, Rome, Italy; Merck & Co., Inc., Kenilworth, NJ; Memorial Sloan Kettering Cancer Center, New York, NY

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
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