Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: Updated phase 1 results from ECHO-202/KEYNOTE-037

Background

Epacadostat (epac) is an oral, potent, selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. Preliminary phase 1 results from this ongoing study of epac with pembrolizumab (pembro) showed promising clinical activity and an acceptable safety profile (Gangadhar et al, SITC 2015; Hamid et al, SMR 2015). Updated data from all 62 phase 1 pts as of 28March2016 are reported.

Methods

Pts with advanced melanoma and select solid tumors were enrolled; pts previously treated with checkpoint inhibitors were excluded. Enrollment is complete for dose escalation (epac 25, 50, 100 mg BID + pembro 2 mg/kg IV Q3W or epac 300 mg BID + pembro 200 mg IV Q3W) and dose expansion (epac 50, 100, and 300 mg BID + pembro 200 mg IV Q3W). Safety, tolerability, and response (RECIST 1.1) were evaluated.

Results

The MTD has not been established. The most common (≥15%) all-grade treatment-related AEs (TRAEs) were fatigue, rash, arthralgia, pruritus, diarrhea, and nausea. Grade ≥3 TRAEs were observed in 18% (most common: rash [8%] and increased lipase [3%]). No treatment-related deaths occurred. Among 19 pts who were treatment-naive for advanced melanoma (M1c 53%), 4 CRs, 7 PRs, and 3 SDs were observed. Responses were observed in all epac dose cohorts ≥50 mg BID and all sites of target lesions including liver, lung, and lymph nodes. All responses are confirmed and ongoing (median follow-up [min, max]: 42 wks [31.7, 75.9]). Median PFS has not been reached. Responses were also observed in pts previously treated for advanced melanoma (n = 3; 1 CR, 1 SD) and pts with NSCLC (n = 12; 5 PRs, 2 SDs), RCC (n = 11; 3 PRs, 5 SDs), endometrial adenocarcinoma (n = 7; 1 CR, 1 PR), TCC (n = 5; 3 PRs), TNBC (n = 3; 2 SDs), SCCHN (n = 2; 1 PR, 1 SD). Based on overall safety and efficacy, epac 100 mg BID was selected as the RP2D. Biomarker evaluation is ongoing.

Conclusions

Epac with pembro continues to be well tolerated and showed promising clinical activity. Based on these results, enrollment in tumor-specific cohorts is ongoing in phase 2 of this study and a phase 3 study in pts who are treatment-naive for advanced melanoma has been initiated (NCT02752074).

Clinical trial identification

NCT02178722

Legal entity responsible for the study

Incyte Corporation and Merck & Co., Inc.

Funding

Incyte Corporation and Merck & Co., Inc.

Disclosure

T.C. Gangadhar, D.C. Smith, T.M. Bauer, J.S. Wasser: Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution). O. Hamid: Consulting - Amgen, BMS, Genentech, Merck & Co., Inc., Merck Serono, Novartis, Pfizer, Roche; Speaker - BMS, Genentech, Novartis; Corporate-sponsored Research (Institution) - Incyte Corporation, Merck & Co., Inc. A.J. Olszanski: Advisory Board - Merck & Co., Inc, BMS; Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution), BMS, Novartis, Teva, Takeda, Pfizer; Data Safety Monitoring Board: Takeda. J.J. Luke: Advisory Board - Amgen, Array; Corporate-sponsored Research (Institution) - Novartis, MedImmune, BMS, Pharmacyclics, BBI Therapeutics, Five Prime Therapeutics, Genentech, Corvus, Delcath, Abbvie, Celldex, EMD Serono, Incyte Corporation, Merck & Co., Inc. A.S. Balmanoukian: Corporate-sponsored Research - MedImmune, Merck Serono, Genentech, Pfizer, Pharmacyclics, Incyte Corporation (Institution), Merck & Co., Inc. (Institution); Speaker's Bureau - BMS and Merck & Co., Inc. D.R. Kaufman: Employment and stock ownership at Merck & Co., Inc. Y. Zhao, J. Maleski, M.J. Jones, L. Leopold: Employment and stock ownership at Incyte Corporation. T.F. Gajewski: Advisory Board - Merck & Co., Inc; Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc. (Institution).