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Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Publication: Journal of Clinical Oncology

Abstract

Purpose

Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported.

Patients and Methods

Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks.

Results

Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies.

Conclusion

Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

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Authors' Disclosures of Potential Conflicts of Interest

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Tara C. Mitchell

Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Incyte, Aduro Biotech, Regeneron
Research Funding: Merck (Inst), Incyte (Inst), Bristol-Myers Squibb (Inst), Roche (Inst)

Omid Hamid

Consulting or Advisory Role: Amgen, Novartis, Roche, Bristol-Myers Squibb, Merck
Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Novartis, Amgen, Array BioPharma
Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Celldex (Inst), Genentech (Inst), Immunocore (Inst), Incyte (Inst), Merck (Inst), Merck Serono (Inst), MedImmune (Inst), Novartis (Inst), Pfizer (Inst), Rinat Neuroscience (Inst), Roche (Inst)

David C. Smith

Research Funding: Agensys (Inst), Atterocor (Inst), Bayer AG (Inst), Boston Biomedical (Inst), Exelixis (Inst), Incyte (Inst), Eli Lilly (Inst), MedImmune (Inst), Novartis (Inst), OncoMed Pharmaceuticals (Inst), Seattle Genetics (Inst), Bristol-Myers Squibb (Inst), Medarex (Inst), ESSA Pharma (Inst), Genentech (Inst), Medivation (Inst), Astellas Pharma (Inst), Merck (Inst)

Todd M. Bauer

Employment: Tennessee Oncology, Sarah Cannon Research Institute
Consulting or Advisory Role: Ignyta (Inst), Guardant Health, Loxo Oncology, Pfizer
Research Funding: Daiichi Sankyo (Inst), MedPacto (Inst), Incyte (Inst), Mirati Therapeutics (Inst), MedImmune (Inst), AbbVie (Inst), AstraZeneca (Inst), Leap Therapeutics (Inst), MabVax Therapeutics (Inst), Stemline Therapeutics (Inst), Merck (Inst), Eli Lilly (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Pfizer (Inst), Principia Biopharma (Inst), Genentech (Inst), Roche (Inst), Deciphera Pharmaceuticals (Inst), Merrimack (Inst), Immunogen (Inst), Millennium Pharmaceuticals (Inst), Ignyta (Inst), Calithera Bioscience (Inst), Kolltan Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Immunocore (Inst), Roche (Inst), Aileron Therapeutics (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), Moderna Therapeutics (Inst), Sanofi (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst)

Jeffrey S. Wasser

Stock or Other Ownership: Johnson & Johnson, Bristol-Myers Squibb, Eli Lilly, Biogen, AbbVie, Merck (I), Pfizer (I)
Honoraria: Amgen, Novartis
Consulting or Advisory Role: Amgen, Novartis
Speakers’ Bureau: Novartis
Research Funding: Merck, Guardant Health, Incyte, Pfizer

Anthony J. Olszanski

Consulting or Advisory Role: EMD Serono, Takeda Pharmaceuticals, Bristol-Myers Squibb, G1 Therapeutics, Pfizer, Array BioPharma, Iovance Biotherapeutics
Research Funding: Takeda Pharmaceuticals (Inst), Immunocore (Inst), EMD Serono (Inst), Amgen (Inst), Incyte (Inst), Kyowa Hakko Kirin (Inst), Eli Lilly (Inst), Advaxis Immunotherapies (Inst), Mirati Therapeutics (Inst), Ignyta (Inst), Novartis (Inst), Pfizer (Inst), Bristol-Myers Squibb (Inst), Kura Oncology (Inst)
Travel, Accommodations, Expenses: Takeda Pharmaceuticals

Jason J. Luke

Honoraria: Intellisphere
Consulting or Advisory Role: Amgen, Array BioPharma, Bristol-Myers Squibb, Merck, EMD Serono, Benevir Biopharm, Checkmate Pharmaceuticals, Novartis, AstraZeneca, MedImmune, 7 Hills Pharma, Castle Biosciences, Actym Therapeutics, Gilead Sciences, Janssen Pharmaceuticals, NewLink Genetics, RefleXion Medical, Syndax, Tempest Therapeutics
Research Funding: Merck, Bristol-Myers Squibb, Boston Biomedical, MedImmune, Incyte, Celldex, Genentech, Roche, Pharmacyclics, Five Prime Therapeutics, Corvus Pharmaceuticals, Delcath Systems, AbbVie, Immunocore, Palleon Pharmaceuticals, Checkmate Pharmaceuticals, Macrogenics, Novartis, Tesaro
Travel, Accommodations, Expenses: Amgen, Bristol-Myers Squibb, Array BioPharma, AstraZeneca, MedImmune, Benevir Biopharm, Castle Biosciences, Checkmate Pharmaceuticals, EMD Serono, Gilead Sciences, Janssen Pharmaceuticals, Merck, Novartis, RefleXion Medical

Ani S. Balmanoukian

Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Merck, AstraZeneca

Emmett V. Schmidt

Employment: Merck
Stock or Other Ownership: Merck, Merck (I)

Yufan Zhao

Employment: Incyte, Amgen
Stock or Other Ownership: Incyte, Amgen

Xiaohua Gong

Employment: Incyte
Stock or Other Ownership: Incyte
Travel, Accommodations, Expenses: Incyte

Janet Maleski

Employment: Incyte
Stock or Other Ownership: Incyte
Travel, Accommodations, Expenses: Incyte

Lance Leopold

Employment: Incyte
Stock or Other Ownership: Incyte

Thomas F. Gajewski

Consulting or Advisory Role: Merck, Roche, Genentech, Jounce Therapeutics, Bayer AG, AbbVie, Aduro Biotech, Evelo Biosciences, FogPharma, Adaptimmune, Five Prime Therapeutics
Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), Roche (Inst), Genentech (Inst), Incyte (Inst), Seattle Genetics (Inst), Ono Pharmaceutical (Inst)
Patents, Royalties, Other Intellectual Property: Licensing to Evelo Bioscience (Inst), licensing to Aduro Biotech (Inst)

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 3223 - 3230
PubMed: 30265610

History

Published online: September 28, 2018
Published in print: November 10, 2018

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Authors

Affiliations

Tara C. Mitchell [email protected]
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Omid Hamid
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
David C. Smith
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Todd M. Bauer
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Jeffrey S. Wasser
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Anthony J. Olszanski
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Jason J. Luke
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Ani S. Balmanoukian
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Emmett V. Schmidt
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Yufan Zhao
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Xiaohua Gong
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Janet Maleski
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Lance Leopold
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.
Thomas F. Gajewski
Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.

Notes

Correspondence to: Tara C. Mitchell, MD, Abramson Cancer Center, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: [email protected].

Author Contributions

Conception and design: Tara C. Mitchell, Anthony J. Olszanski, Emmett V. Schmidt, Janet Maleski, Lance Leopold, Thomas F. Gajewski
Provision of study materials or patient: David C. Smith, Todd M. Bauer, Jason J. Luke
Collection and assembly of data: Tara C. Mitchell, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason J. Luke, Ani S. Balmanoukian, Emmett V. Schmidt, Yufan Zhao, Janet Maleski, Lance Leopold, Thomas F. Gajewski
Data analysis and interpretation: Tara C. Mitchell, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason J. Luke, Emmett V. Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, Lance Leopold, Thomas F. Gajewski
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

Funding Information

Supported by Incyte and Merck & Co.

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Tara C. Mitchell, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Anthony J. Olszanski, Jason J. Luke, Ani S. Balmanoukian, Emmett V. Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, Lance Leopold, Thomas F. Gajewski
Journal of Clinical Oncology 2018 36:32, 3223-3230

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