Phase 1/2 study of epacadostat in combination with durvalumab in patients with metastatic solid tumors

• Published in: Cancer Vol. 129; no. 1; pp. 71 - 81
• Main Authors: Naing, Aung, Algazi, Alain P., Falchook, Gerald S., Creelan, Benjamin C., Powderly, John, Rosen, Seth, Barve, Minal, Mettu, Niharika B., Triozzi, Pierre L., Hamm, John, Zhou, Gongfu, Walker, Chris, Dong, Zhiwan, Patel, Manish R.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2023; John Wiley and Sons Inc
• Subjects: Adult; Antibodies, Monoclonal - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Apoptosis; Appetite loss; Cell death; Diarrhea; Dioxygenase; durvalumab; epacadostat; Humans; Immune checkpoint inhibitors; Immunotherapy; Inhibitors; kynurenine; Metastases; Monoclonal antibodies; neoplasms; Neoplasms - pathology; Neoplasms, Second Primary - etiology; Oncology; Original; ORIGINAL ARTICLES; Oximes; Patients; PD-1 protein; PD-L1 protein; PD‐1; Pharmacodynamics; Pruritus; Solid tumors; Sulfonamides; Targeted cancer therapy; Tumors; durvalumab; epacadostat; kynurenine; neoplasms; PD-1
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.34512

BACKGROUND Targeting programmed cell death protein 1 (PD‐1) and indoleamine 2,3‐dioxygenase (IDO1) pathways is an appealing option for cancer treatment. METHODS The open‐label, phase 1/2 ECHO‐203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti–PD‐L1 monoclonal antibody in adult patients with advanced solid tumors. RESULTS The most common treatment‐related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)‐naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300‐mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained. CONCLUSIONS Epacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect. Clinical trial information A study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO‐203) (NCT02318277). Epacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. Objective response rate was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested that >300 mg twice daily of epacadostat is needed to ensure sufficient drug effect.