A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679/ECHO-302)

• Published in: BMC cancer 2024-07, Vol.23 (Suppl 1), p.1253-12, Article 1253
• Main Authors: Lara, Jr, Primo N, Villanueva, Luis, Ibanez, Carolina, Erman, Mustafa, Lee, Jae Lyun, Heinrich, Daniel, Lipatov, Oleg Nikolaevich, Gedye, Craig, Gokmen, Erhan, Acevedo, Alejandro, Semenov, Andrey, Park, Se Hoon, Gafanov, Rustem Airatovich, Kose, Fatih, Jones, Mark, Du, Xiaoqi, Munteanu, Mihaela, Perini, Rodolfo, Choueiri, Toni K, Motzer, Robert J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Binomial distribution; Cancer therapies; Carcinoma, Renal cell; Carcinoma, Renal Cell - drug therapy; Care and treatment; Clinical trials; Comparative analysis; Drug therapy; Drug therapy, Combination; Female; Humans; IDO1; Immunotherapy; Indazoles - administration & dosage; Indazoles - therapeutic use; Indoleamine 2,3-deoxygenase 1; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Kinases; Lung cancer; Lymphocytes; Male; Medical prognosis; Melanoma; Metastases; Metastasis; Middle Aged; Oximes; Patients; PD-1; PD-1 protein; Pembrolizumab; Product development; Programmed death 1; Pyrimidines - administration & dosage; Pyrimidines - therapeutic use; Renal cell carcinoma; Septic shock; Solid tumors; Standard of care; Statistical analysis; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - therapeutic use; Sunitinib - administration & dosage; Sunitinib - therapeutic use; Testing; Tumors
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-023-10971-7

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 pembrolizu