RT Journal Article SR Electronic T1 Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e008872 DO 10.1136/jitc-2024-008872 VO 12 IS 8 A1 Schenker, Michael A1 Burotto, Mauricio A1 Richardet, Martin A1 Ciuleanu, Tudor-Eliade A1 Gonçalves, Anthony A1 Steeghs, Neeltje A1 Schoffski, Patrick A1 Ascierto, Paolo A A1 Maio, Michele A1 Lugowska, Iwona A1 Lupinacci, Lorena A1 Leary, Alexandra A1 Delord, Jean-Pierre A1 Grasselli, Julieta A1 Tan, David S P A1 Friedmann, Jennifer A1 Vuky, Jacqueline A1 Tschaika, Marina A1 Konduru, Somasekhar A1 Vemula, Sai Vikram A1 Slepetis, Ruta A1 Kollia, Georgia A1 Pacius, Misena A1 Duong, Quyen A1 Huang, Ning A1 Doshi, Parul A1 Baden, Jonathan A1 Di Nicola, Massimo YR 2024 UL http://jitc.bmj.com/content/12/8/e008872.abstract AB Background Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).Patients and methods Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab.Results In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.Conclusions Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.Trial registration number NCT03668119.Data are available on reasonable request. Data may be obtained from a third party and are not publicly available. Bristol Myers Squibb will honor legitimate requests for clinical trial data from qualified researchers with a clearly defined scientific objective. Data sharing requests will be considered for phases II–IV interventional clinical trials that completed on or after January 1, 2008. In addition, primary results must have been published in peer-reviewed journals and the medicines or indications approved in the USA, EU, and other designated markets. Sharing is also subject to protection of patient privacy and respect for the patient’s informed consent. Data considered for sharing may include non-identifiable patient-level and study-level clinical trial data, full clinical study reports, and protocols. Requests to access clinical trial data may be submitted using the enquiry form at https://vivli.org/ourmember/bristol-myers-squibb/.