Impact of histology on the efficacy and safety of pembrolizumab (pembro) monotherapy for advanced urothelial carcinoma (UC) in the phase 3 KEYNOTE-045 and KEYNOTE-361 trials.

person Patrizia Giannatempo Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy info_outline Patrizia Giannatempo, Jean-Pascal H. Machiels, Naoto Sassa, Jose Angel Arranz Arija, Yasuhisa Fujii, Wen-Pin Su, Bhumsuk Keam, Stephane Culine, Ying-Chun Shen, José Muñoz-Langa, David Leonid Sarid, Maureen J.B. Aarts, Fabio Calabro, Eli Rosenbaum, Olesya Goldman, Blanca Homet Moreno, Abhishek Amar Bavle, Jin Zhi Xu, Sun Young Rha

Authors person Patrizia Giannatempo Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy info_outline Patrizia Giannatempo, Jean-Pascal H. Machiels, Naoto Sassa, Jose Angel Arranz Arija, Yasuhisa Fujii, Wen-Pin Su, Bhumsuk Keam, Stephane Culine, Ying-Chun Shen, José Muñoz-Langa, David Leonid Sarid, Maureen J.B. Aarts, Fabio Calabro, Eli Rosenbaum, Olesya Goldman, Blanca Homet Moreno, Abhishek Amar Bavle, Jin Zhi Xu, Sun Young Rha Organizations Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Cliniques Universitaires Saint-Luc (UCLouvain), Brussels, Belgium, Aichi Medical University, Nagakute, Japan, Hospital General Universitario Gregorio Marañón, Madrid, Spain, Tokyo Medical and Dental University Hospital, Tokyo, Japan, National Cheng Kung University Hospital, Tainan, Taiwan, Seoul National University Hospital, Seoul, South Korea, Saint-Louis Hospital, Paris, France, National Taiwan University Hospital, Taipei, Taiwan, Hospital Universitario Y Politécnico La Fe, Valencia, Spain, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Maastricht University Medical Centre, Maastricht, Netherlands, UPMC Salvator Mundi International Hospital, Rome, Italy, Institute of Oncology Clinical Trials Department, Rabin Medical Center, Petah Tikva, Israel, Meir Medical Center- Oncology Institute, Kefar Sava, Israel, Merck & Co., Inc., Rahway, NJ, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea, Republic of (South) Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Background: For patients (pts) with advanced UC, pembro monotherapy has shown antitumor activity as first-line (1L) therapy in the phase 3 KEYNOTE-361 (NCT02853305) study of pembro ± platinum-based chemotherapy (chemo) vs platinum-based chemo and as second-line therapy in the phase 3 KEYNOTE-045 (NCT02256436) study of pembro vs investigator’s choice chemo. This exploratory analysis evaluated efficacy and safety of pembro monotherapy by UC histology in KEYNOTE-361 and KEYNOTE-045. Methods: KEYNOTE-361 enrolled pts with advanced UC and no prior systemic therapy; KEYNOTE-045 enrolled pts with advanced UC whose disease progressed or relapsed after 1L platinum-based chemo. Pure transitional cell (TC) and mixed predominant TC histology, as assessed by investigator, were allowed. Pembro monotherapy was given at a dose of 200 mg IV Q3W for up to 2 y or until disease progression, unacceptable toxicity, or withdrawal of consent in both studies. End points for this exploratory analysis were ORR, DOR, and PFS per RECIST v1.1 by central radiology assessment, and OS and safety in pts with pure TC or mixed predominant TC allocated to receive pembro monotherapy. Results: A total of 307 randomly assigned pts (280 [91.2%] pure TC histology; 27 [8.8%] mixed predominant TC histology) from KEYNOTE-361 and 268 pts (186 [69.4%] pure TC histology; 82 [30.6%] mixed predominant TC histology) from KEYNOTE-045 were included. Median follow-up for both studies was ≥32 mo. PFS, ORR, DOR, and OS for pembro were generally similar in pts with mixed predominant TC histology and pts with pure TC histology. In treated pts, grade 3-5 treatment-related AEs occurred at similar rates in KEYNOTE-361 (17.3% [48/277] pure TC; 18.5% [5/27] mixed predominant TC) and KEYNOTE-045 (16.9% [31/183] pure TC; 17.3% [14/81] mixed predominant TC). Conclusions: The observed clinical activity and safety profile of pembro monotherapy was generally consistent irrespective of histology in pts with UC in the KEYNOTE-361 and KEYNOTE-045 studies. Small sample size in some subgroups and limited data available to classify histology subgroups were limitations of this exploratory analysis. Clinical trial information: NCT02256436; NCT02853305. KEYNOTE-361 pure TC (n = 280) KEYNOTE-361 mixed predominant TC (n = 27) KEYNOTE-045 pure TC (n = 186) KEYNOTE-045 mixed predominant TC (n = 82) ORR, % (95% CI) 29.3 (24.0-35.0) 40.7 (22.4-61.2) 21.0 (15.4-27.5) 24.4 (15.6-35.1) DOR, median (range), mo a 28.2 (2.1+ to 36.1+) 24-mo: 50.0% NR (4.0+ to 30.4+) 24-mo: 60.0% 19.7 (1.6 to 60.5+) 24-mo: 47.4% NR (2.8+ to 60.1+) 24-mo: 76.5% OS, median (95% CI), mo 14.8 (11.8-17.9) 24-mo: 36.8% 16.2 (5.5-NR) 24-mo: 44.4% 9.7 (7.5-11.8) 24-mo: 25.2% 11.6 (7.4-16.4) 24-mo: 31.5% PFS, median (95% CI), mo 3.9 (2.3-5.5) 24-mo: 15.9% 2.2 (2.1-18.0) 24-mo: 24.2% 2.1 (2.0-2.2) 24-mo: 11.0% 2.1 (2.0-3.5) 24-mo: 18.9% NR, not reached. a + indicates no PD at time of last disease assessment

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