Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial

Author(s): Prof Thierry André, MD^a,b; Elena Elez, MD^c; Heinz-Josef Lenz, MD^d; Lars Henrik Jensen, MD^e; Prof Yann Touchefeu, MD^f; Eric Van Cutsem, MD^g; Rocio Garcia-Carbonero, MD^h; David Tougeron, MDⁱ; Guillermo Ariel Mendez, MD^j; Michael Schenker, MD^k,l; Christelle de la Fouchardiere, MD^m; Maria Luisa Limon, MDⁿ; Takayuki Yoshino, MD^o; Jin Li, MD^p; Jose Luis Manzano Mozo, MD^q; Laetitia Dahan, MD^r; Giampaolo Tortora, MD^s; Myriam Chalabi, MD^t; Eray Goekkurt, MD^u; Maria Ignez Braghiroli, PhD^v; Rohit Joshi, MD^w; Timucin Cil, MD^x; Francine Aubin, MD^y; Elvis Cela, PhD^z; Tian Chen, PhD^z; Ming Lei, PhD^z; Lixian Jin, MD^z; Steven I Blum, PhD^z; Sara Lonardi, MD^aa

Source: DOI: 10.1016/S0140-6736(24)02848-4

Dr. Maen Hussein's Thoughts

Combination beat monotherapy is another option for MSI patients. Is combo better then pembro?

BACKGROUND

CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In our previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, we report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines.

METHODS

CheckMate 8HW is a randomised, open-label, international, phase 3 trial at 128 hospitals and cancer centres across 23 countries. Immunotherapy-naive adults with unresectable or metastatic colorectal cancer across different lines of therapy and microsatellite instability-high or mismatch repair-deficient status per local testing were randomly assigned (2:2:1) to nivolumab plus ipilimumab (nivolumab 240 mg, ipilimumab 1 mg/kg, every 3 weeks for four doses; then nivolumab 480 mg every 4 weeks; all intravenously), nivolumab (240 mg every 2 weeks for six doses, then 480 mg every 4 weeks; all intravenously), or chemotherapy with or without targeted therapies. The dual independent primary endpoints were progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus chemotherapy (first line) and progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus nivolumab (all lines) in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. This study is registered with ClinicalTrials.gov (NCT04008030).

FINDINGS

Between Aug 16, 2019, and April 10, 2023, 707 patients were randomly assigned to nivolumab plus ipilimumab (n=354) or nivolumab alone (n=353). 296 (84%) of 354 patients in the nivolumab plus ipilimumab group and 286 (81%) of 353 patients in the nivolumab group were centrally confirmed to have microsatellite instability-high or mismatch repair-deficient status. At the data cutoff on Aug 28, 2024, median follow-up (from randomisation to data cutoff) was 47·0 months (IQR 38·4 to 53·2). Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in progression-free survival versus nivolumab (hazard ratio 0·62, 95% CI 0·48–0·81; p=0·0003). Median progression-free survival was not reached with nivolumab plus ipilimumab (95% CI 53·8 to not estimable) and was 39·3 months with nivolumab (22·1 to not estimable). Treatment-related adverse events of any grade occurred in 285 (81%) of 352 patients receiving nivolumab plus ipilimumab and in 249 (71%) of 351 patients receiving nivolumab; grade 3 or 4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) patients, respectively. There were three treatment-related deaths: one event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab group and one pneumonitis event in the nivolumab group.

INTERPRETATION

Nivolumab plus ipilimumab showed superior progression-free survival versus nivolumab across all treatment lines, with a manageable safety profile, in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These results, together with the first-line results of superior progression-free survival with nivolumab plus ipilimumab versus chemotherapy, suggest nivolumab plus ipilimumab as a potential new standard of care for patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.

FUNDING

Bristol Myers Squibb and Ono Pharmaceutical.

Author Affiliations

^a Sorbonne Université, Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris, Paris, France; ^b Unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, Paris, France; ^c Vall d’Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; ^d University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; ^e University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark; ^f Institut des Maladies de l’Appareil Digestif, Centre Hospitalier Universitaire de Nantes, Nantes, France; ^g University Hospitals Gasthuisberg and University of Leuven, Leuven, Belgium; ^h Hospital Universitario 12 de Octubre Imas12, Facultad de Medicina, UCM, Madrid, Spain; ⁱ Centre Hospitalier Universitaire de Poitiers Site de la Miletrie, Poitiers, France; ^j Hospital Universitario Fundacion Favaloro, Buenos Aires, Argentina; ^k Centrul de Oncologie Sf Nectarie, Craiova, Romania; ^l University of Medicine and Pharmacy, Craiova, Romania; ^m Centre Léon Bérard, Lyon, France; ⁿ Hospital Universitario Virgen del Rocío, Seville, Spain; ^o National Cancer Center Hospital East, Chiba, Japan; ^p Shanghai East Hospital, Shanghai, China; ^q Institut Català d’Oncologia, Hospital Universitario Germans Trias i Pujol, Badalona, Spain; ^r La Timone, Aix Marseille Université, Marseille, France; ^s Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; ^t Netherlands Cancer Institute, Amsterdam, Netherlands; ^u Hematology-Oncology Practice Eppendorf and University Cancer Center Hamburg, Hamburg, Germany; ^v Instituto do Cancer de São Paulo, Universidade de São Paulo, São Paulo, Brazil; ^w Cancer Research SA, Adelaide, SA, Australia; ^x University of Health Sciences, Adana Faculty of Medicine, Adana City Education and Research Hospital, Adana, Turkey; ^y Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada; ^z Bristol Myers Squibb, Princeton, NJ, USA; ^aa Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy

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