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The safety and tolerability of epacadostat alone and in combination with pembrolizumab in patients with advanced solid tumors: results from a first-in-Japanese phase I study (KEYNOTE-434)

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Summary

Purpose

Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors.

Methods

Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab.

Results

Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis—a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data.

Conclusion

Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors.

Clinical trial registration NCT02862457.

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Acknowledgments

The authors thank all the nurses, data managers, patients, and their families for their outstanding dedicated patient care, careful data collection, participation, and time, respectively. The authors also thank Xiaohua Gong from Incyte for assistance with pharmacokinetic epacadostat assessments, and Kahori Sasahara, Yu Sakai, and Takashi Sawada from MSD K.K. for study management. Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, CMPP, and Brian Szente, PhD, of the ApotheCom pembrolizumab team (Yardley, PA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Incyte Corporation, Wilmington, DE, USA.

Funding

Funding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Incyte Corporation, Wilmington, DE, USA.

Author information

Authors and Affiliations

  1. Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan

    Toshihiko Doi, Kohei Shitara, Nobuaki Matsubara, Izumi Ohno, Takahiro Kogawa & Yoichi Naito

  2. Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan

    Yutaka Fujiwara, Toshio Shimizu, Kan Yonemori & Noboru Yamamoto

  3. Department of Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, Japan

    Yutaka Fujiwara

  4. Incyte Corporation, Clinical Development, Wilmington, DE, USA

    Lance Leopold & Mihaela Munteanu

  5. MSD K.K. Oncology Science Unit, Tokyo, Japan

    Naoyoshi Yatsuzuka & Shi Rong Han

  6. Department of Clinical Oncology, Merck & Co., Inc., Kenilworth, NJ, USA

    Ayman Samkari

Authors
  1. Toshihiko Doi
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Contributions

Conception, design, or planning of the study: T.D., K.S., L.L., S.R.H., A.S.

Acquisition and analysis of data: T.D., Y.F., K.S., T.S., K.Y., N.M., I.O., T.K., Y.N., L.L., M.M., S.R.H., N.Yamamoto.

Interpretation of results: T.D., K.S., N.M., L.L., M.M., N.Yatsuzuka, A.S., N.Yamamoto.

Drafting of the manuscript: T.D., A.S.

Critically reviewing or revising the manuscript for important intellectual content: All authors.

Review of final version and agreement with content and decision to submit: All authors.

Corresponding author

Correspondence to Toshihiko Doi.

Ethics declarations

Conflict of interest

T.D. received grants and personal fees from Eli Lilly, Kyowa Hakko Kirin, MSD, Daiichi Sankyo, Sumitomo Dainippon, Taiho, Novartis, Boehringer Ingelheim, Chugai Pharma, Bristol-Myers Squibb, AbbVie, personal fees from Amgen, Takeda, Bayer, Rakuten Medical, Ono Pharmaceutical, Astellas Pharma, Oncolys BioPharma, grants from Merck Serono, Janssen, Pfizer, Quintiles, and Eisai.

Y.F. received grants from MSD, AbbVie, AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Incyte, and Novartis for research funding; personal fees from AstraZeneca for advisory role and participation in speakers’ bureau, personal fees from Daiichi Sankyo for advisory role.

K.S. reports paid consulting or advisory roles for Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho, Novartis, AbbVie, and GlaxoSmithKline; honoraria from Novartis, AbbVie, and Yakult; and research funding from Astellas, Lilly, Ono Pharmaceutical, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD and Medi Science.

T.S. received research grant (Institute) from Novartis, Eli Lilly, Bristol-Myers Squibb, Daiichi Sankyo, Takeda Oncology, Eisai, AstraZeneca, AbbVie, Incyte, Astellas Pharma, Symbio Pharmaceuticals, 3D-Medicine, Five Prime, PharmaMar, and Chordia Therapeutics.

K.Y. received personal fees for advisory role and lecture from Eisai, personal fees for advisory role from Novartis, Chugai, and Ono Pharmaceutical, lecture fee from Taiho, personal fee for lecture from Pfizer.

N.M. received grants and personal fees from Janssen, MSD, Astra-Zeneca, grants from Roche, Lilly, Taiho, Bristol-Myers Squibb, and personal fees from Sanofi.

I.O., S.R.H., T.K., M.M., N.Yatsuzuka: have nothing to disclose.

L.L. reports employment at Incyte Corporation.

A.S. reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Y.N. received other for participation in speakers’ bureau from Pfizer, Taiho, Nippon Kayaku, Eli Lilly, AstraZeneca, Merck Serono, Bayer, Meiji Seika, Roche Diagnostics, Novartis, Taiho, Chugai Pharmaceutical, Eisai, and Fuji Film Toyama Chemistry; other for research funding from Roche Diagnostics.

N.Yamamoto received research grants from Chugai, Taiho, Eisai, Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical, Takeda, Janssen Pharmaceutical, MSD, Merck, GSK, honoraria from Ono Pharmaceutical, Chugai, AstraZeneca, Pfizer, Lilly, Bristol-Myers Squibb, Sysmex, personal fees for consulting from Eisai, Otsuka, Takeda, Boehringer Ingelheim, and Cimic.

Ethical approval

The study protocol and all amendments were approved by the institutional review board or ethics committee at each center. The study was conducted in accordance with the protocol and its amendments, all relevant local and national regulations, the provisions of the Declaration of Helsinki, and Good Clinical Practice guidelines.

Informed consent

All participants provided written and informed consent before enrollment.

Availability of data and material

The data sharing policy of Merck Sharp & Dohme, including restrictions, is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

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Doi, T., Fujiwara, Y., Shitara, K. et al. The safety and tolerability of epacadostat alone and in combination with pembrolizumab in patients with advanced solid tumors: results from a first-in-Japanese phase I study (KEYNOTE-434). Invest New Drugs 39, 152–162 (2021). https://doi.org/10.1007/s10637-020-00942-1

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