Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC.
KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1.
One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects.
ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab.
ClinicalTrials.gov; NCT03260894 .
BMC cancer. 2024 Jul 25*** epublish ***
Primo N Lara, Luis Villanueva, Carolina Ibanez, Mustafa Erman, Jae Lyun Lee, Daniel Heinrich, Oleg Nikolaevich Lipatov, Craig Gedye, Erhan Gokmen, Alejandro Acevedo, Andrey Semenov, Se Hoon Park, Rustem Airatovich Gafanov, Fatih Kose, Mark Jones, Xiaoqi Du, Mihaela Munteanu, Rodolfo Perini, Toni K Choueiri, Robert J Motzer
University of California Davis Comprehensive Cancer Center, University of California Davis, 4501 X Street, Davis, Sacramento, CA, 95817, USA. ., Oncology Department, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago, Chile., Hematology and Oncology Department, Pontificia Universidad Católica de Chile, Santiago, Chile., Department of Medical Oncology, Hacettepe University Medical Faculty, Ankara, Turkey., Department of Oncology and Internal Medicine Asan Medical Center, University of Ulsan College of Medicine, Ulsan, South Korea., Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Department of Oncology, Republican Clinical Oncology Dispensary, Ufa, Russia., Department of Medical Oncology, Calvary Mater Newcastle, Waratah, NSW, Australia., Faculty of Medicine, Ege University, Izmir, Turkey., ONCOCENTRO APYS Clinical Research Unit, Viña del Mar, Chile., Ivanovo Regional Oncology Dispensary, Ivanovo, Russia., Department of Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Russian Scientific Center of Roentgenoradiolog, Moscow, Russia., Department of Medical Oncology, Baskent University, Ankara, Turkey., Incyte Corp, Wilmington, DE, USA., Merck & Co., Inc, Rahway, NJ, USA., Dana-Farber Cancer Institute, Boston, MA, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.