Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. Results: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Conclusions: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.
Bibliographical noteFunding Information:
R.J. Kelly is an advisory board member/paid consultant for AstraZeneca, Bristol-Myers Squibb, Merck, Eli Lilly, Astellas, and Novartis. Y. Bang is an employee/paid consultant for AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, Bristol-Myers Squibb, Eli Lilly, Taiho, Daiichi-Sankyo, Astellas, BeiGene, Green-Cross, Samyang Biopharm, Hanmi, Genexine, and GlaxoSmithKline, and reports receiving commercial research grants from AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Eli Lilly, Boeringer-Ingelheiim, Macrogenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Ono, Daiichi-Sankyo, Astellas, BeiGene, GreenCross, CKD Biopharma, and Genexine. D.V.T. Catenacci is an employee/paid consultant for Bristol-Myers Squibb, Merck, Taiho, Gritstone, Lilly, Genentech/Roche, Seattle Genetics, and Daichii Sankyo, and reports receiving speakers bureau honoraria from Foundation Medicine, Merck, Lilly, Guardant Health, Tempus, and Genentech/Roche. Zev A. Wainberg is an employee/paid consultant for AstraZeneca, Bayer, Merck, Lilly, and Bristol-Myers Squibb. J.C. Bendell is an employee/paid consultant for Gilead, Genetech/Roche, Bristol-Myers Squibb, Five Prime, Lilly, Merck, MedIumme, Celgene, Taiho, Macro-genics, GlaxoSmithKline, Novartis, OncoMed, LEAP, TG Thearpeutics, AstraZenca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, ARMO, Ipsen, Merrimack, Oncogenex, FORMA, Arch Oncology, Prelude Therapeutics, Phoenix Bio, Cyteir, Molecular Partners, Innate, Torque, Tizona, Janssen, Tolero, Translational Drug Development, Amgen, Settle Genetics, Moderna therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, and Agois, reports receiving commercial research grants from Gilead, Genentech/Roche, Bristol-Myers Squibb, Five Prime, Lilly, Merck, MedImmune, Celgene, EMD Serono, Taiho, Marcogenics, GlaxoS-mithKline, Novartis, OncMed, LEAP, TG Therapeutics, AstraZenca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRex, Forty Seven, AbbVie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, Boston Biomedical, Ispen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall Edwards, Pieries, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude Oncology, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, ImClone, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, and Arcus Bio, and other remuneration from Gilead, Genetech/Roche, Bristol-Myers Squibb, Lilly, Merck, Medimmune, Celgene, Taiho, Novartis, OncoMed, BI, ARMO, Ipsen, Oncogenex, and FORMA. C.S. Denlinger is an employee/paid consultant for Merck, Bristol-Myers Squibb, Eli Lilly, Astellas, Exelixis, QED Therapeutics, Carevive, Bayer, and Beigene. R. Leidner reports receiving commercial research grants from Bristol-Myers Squibb. H. Lenz is an advisory board member/unpaid consultant for Bristol-Myers Squibb, Merck KG, and Bayer. M.C. Rebelatto is an employee/paid consultant for and holds ownership interest (including patents) in AstraZeneca. P. Brohawn is an employee/paid consultant for AstraZeneca and Immunocore Ltd. P. He is an employee/paid consultant for AstraZeneca. J. McDevitt is an employee/paid consultant for Medimmune. J.M. Englert is an employee/paid consultant for Medimmune/AstraZeneca. G.Y. Ku is an employee/paid consultant for Merck, Pieris, Bristol-Myers Squibb, and Eli Lilly, reports receiving commercial research grants from AstraZeneca and Arog, other commercial research support from Bristol-Myers Squibb, Pieris, and Zymeworks, and speakers bureau honoraria from Dava Oncology. No potential conflicts of interest were disclosed by the other authors.
The authors thank the patients, their families and caregivers, and the site investigators and staff for their participation in this study, and Christopher More-house of AstraZeneca for performing biomarker analyses. This study was funded by
All Science Journal Classification (ASJC) codes
- Cancer Research