Nivolumab combination therapies in patients with advanced gastric and gastroesophageal junction cancer: the phase II FRACTION gastric cancer study

G Ku; G M Haag; H Park; V K Lam; T J George; S S Kim; M Gutierrez; V Shankaran; S Stein; C S Denlinger; E Elimova; A Nagrial; A R He; M B Sawyer; H H Yoon; R Geva; J Starr; G Curigliano; T Golan; R von Moos; R Fritsch; D Lim; Q Wang; A Patel; T Aoyama; M Lei; D Greenawalt; M Di Bartolomeo

doi:10.1016/j.esmoop.2024.104107

Nivolumab combination therapies in patients with advanced gastric and gastroesophageal junction cancer: the phase II FRACTION gastric cancer study

ESMO Open. 2025 Jan 10;10(2):104107. doi: 10.1016/j.esmoop.2024.104107. Online ahead of print.

Authors

G Ku¹, G M Haag², H Park³, V K Lam⁴, T J George⁵, S S Kim⁶, M Gutierrez⁷, V Shankaran⁸, S Stein⁹, C S Denlinger¹⁰, E Elimova¹¹, A Nagrial¹², A R He¹³, M B Sawyer¹⁴, H H Yoon¹⁵, R Geva¹⁶, J Starr¹⁷, G Curigliano¹⁸, T Golan¹⁹, R von Moos²⁰, R Fritsch²¹, D Lim²², Q Wang²³, A Patel²³, T Aoyama²³, M Lei²³, D Greenawalt²³, M Di Bartolomeo²⁴

Affiliations

¹ Memorial Sloan Kettering Cancer Center, New York, USA. Electronic address: [email protected].
² Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital and Clinical Cooperation Unit Applied Tumor-Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³ Washington University School of Medicine, St Louis, USA.
⁴ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.
⁵ University of Florida Health Cancer Center, Gainesville, USA.
⁶ Division of Medical Oncology, University of Colorado Cancer Center, Aurora, USA.
⁷ John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, USA.
⁸ University of Washington School of Medicine, Seattle, USA.
⁹ Yale University School of Medicine, New Haven, USA.
¹⁰ Fox Chase Cancer Center, Philadelphia, USA.
¹¹ Princess Margaret Cancer Centre, Toronto, Canada.
¹² Department of Medical Oncology, Westmead Hospital, University of Sydney, Sydney, Australia.
¹³ Georgetown University Medical Center, Washington, USA.
¹⁴ Cross Cancer Institute, University of Alberta, Edmonton, Canada.
¹⁵ Mayo Clinic, Rochester, USA.
¹⁶ Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
¹⁷ Mayo Clinic, Jacksonville, USA.
¹⁸ Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy; European Institute of Oncology, IRCCS, Milan, Italy.
¹⁹ Sheba Medical Center, Tel-Aviv University, Tel Aviv, Israel.
²⁰ Cancer Center, Kantonsspital Graubünden, Chur, Switzerland.
²¹ Department of Medical Oncology and Hematology, Universitätsspital Zürich, Zurich, Switzerland.
²² City of Hope National Medical Center, Duarte, USA.
²³ Bristol Myers Squibb, Princeton, USA.
²⁴ Fondazione IRCCS Istituto Nazionale Tumori Milano, Milan, Italy.

PMID: 39798422
DOI: 10.1016/j.esmoop.2024.104107

Abstract

Background: Nivolumab-based therapies are efficacious with acceptable safety in patients with gastric cancer (GC) and gastroesophageal junction cancer (GEJC). Novel nivolumab-based combination immunotherapies may offer enhanced efficacy in these indications. FRACTION-GC was a signal-seeking, randomized, open-label, phase II adaptive-design trial assessing efficacy and safety of nivolumab in combination with ipilimumab [cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody], relatlimab (lymphocyte-activation gene 3 antibody), or IDO1i (BMS986205, an indoleamine-2,3-dioxygenase-1 inhibitor) in patients with unresectable, advanced/metastatic GC/GEJC.

Patients and methods: Previously treated patients with GC/GEJC were randomized to receive nivolumab + ipilimumab, nivolumab + relatlimab, or nivolumab + IDO1i across two tracks: anti-programmed death-(ligand) 1/anti-CTLA-4-naïve (track 1) and -experienced (track 2). Primary endpoints were objective response rate (ORR) by investigator per RECIST v1.1, duration of response, and progression-free survival (PFS) rate at 24 weeks. Secondary endpoint was safety.

Results: Eighty-one patients in track 1 and 81 in track 2 received one combination therapy. With a median follow-up of 50.2 months, ORR [95% confidence interval (CI)] by investigator for nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 was 4% (0.1% to 21.9%), 5% (0.1% to 24.9%), and 13% (4.4% to 28.1%), and for track 2 was 9% (1.1% to 28.0%), 6% (0.7% to 18.7%), and 0% (0% to 15.4%), respectively. PFS rate at 24 weeks (95% CI) was 24% (11% to 39%) for nivolumab + IDO1i track 1, 17% (16% to 32%) for nivolumab + relatlimab track 2, and not estimable for other treatment arms. Grade 3/4 treatment-related adverse events were reported in 22%, 5%, and 18% of patients receiving nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 and in 35%, 11%, and 18% of patients in track 2, respectively. No treatment-related deaths were reported.

Conclusions: While ORR did not meet prespecified expansion criteria in any treatment arm, the safety profile of the combinations was manageable. FRACTION-GC represents a novel adaptive protocol for testing multiple combination immunotherapies.

Keywords: gastric cancer; gastroesophageal junction cancer; immunomodulatory combination therapy; nivolumab; relatlimab.