Abstract
Immunotherapy achieved remarkable results in patients with deficient mismatch repair (dMMR)/microsatellite instable (MSI) metastatic colorectal carcinoma (mCRC). However, its efficacy in proficient MMR (pMMR)/microsatellite stable (MSS) mCRC remains limited. In the phase II NIVACOR trial, we evaluated the activity and safety of FOLFOXIRI/bevacizumab plus nivolumab as first-line therapy in patients with RAS/BRAF-mutated mCRC (NCT04072198). The primary endpoint of the trial was the Objective Response Rate (ORR) whereas secondary endpoints were safety profile, overall survival (OS), progression free survival (PFS), duration of response (DoR) and quality of life. The primary endpoint was met. Among the 73 enrolled patients, 76.7% achieved an objective response (95% CI, 65.4 to 85.8%), while the disease control rate was 97.3% (95% CI, 90.5 to 99.7%). The median progression-free survival (mPFS) was 10.1 months (95% CI, 9.0 to 14.3 months), and the median overall survival (mOS) was not reached. Treatment-related adverse events of grade 3 or higher occurred in 48 patients out 73 enrolled patients (65.8%). Comprehensive genomic profiling and RNA sequencing analysis revealed genomic and transcriptomic profiles associated with treatment response in pMMR/MSS patients. Alterations in pathways such as PI3K/AKT, chemokine signaling and DNA repair showed correlation with treatment activity. These findings highlight the potential synergy between immune checkpoint inhibitors and cytotoxic chemotherapy in selected patients with pMMR/MSS mCRC.
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Data availability
Data supporting the findings of this study are available within the article. To protect the privacy of the patients in the study, clinical information of individual RAS and BRAF mutated mCRC patients have been anonymized and reported in Fig. 1, Supplementary Fig. 2 and in the Supplementary Data file. Source data and further clinical data can be requested to the corresponding author within the limitations of the patient informed consent. De-identified sequencing data have been deposited in the Genome Sequencing Archive (accession code HRA016779). The access is restricted and requires approval by the NGDC Data Access Committee upon request to the corresponding author. The accession request will be reviewed within a timeframe of 2-4 weeks and data will be available in accordance with participant consent and applicable regulations. Sequencing data will be also available in the Zenodo repository (https://doi.org/10.5281/zenodo.17358523).
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Acknowledgements
This was a nonprofit study, conducted in the GOIRC clinical research network. Bristol Myers Squibb partially covered the costs of the study. The study was also supported by Ricerca Corrente grant L3/8 from Ministero della Salute to REA. NN have received support from Ministero della Salute (Project T3-AN-06 “Sviluppo di una piattaforma per la implementazione clinica della oncologia di precisione nelle regioni del centro-sud Italia”). We thank all patients and their families, all caregivers, the referring oncologists and the GOIRC group for the participating centers.
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Conceptualization: F.I., N.N., C.P. and A.D. Data Curation: S.T., A.D. and G.M. Investigation: R.E.A., S.T., F.B., L.A., G.N., F.P., G.T., T.L., R.B., G.R., E.G., M.L., E.M., S.L. and A.R. Validation: R.E.A. and S.T. Resources: D.F., M.R.M. and A.D.L. Formal analysis: R.E.A., D.R., and G.M. Funding acquisition: C.P. and A.D. Supervision: N.N., C.P. and A.D. Writing – original draft: R.E.A., N.N., A.D. and G.M. Writing–review & editing All authors.
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Angela Damato: outside the submitted work, has received personal fees for the advisory role, speaker engagements, and travel and accommodation expenses from Ipsen, Servier, BMS, Merck Serono, Amgen, and Daiichi Sankyo. Francesca Bergamo: received personal honoraria as invited speaker from Eli-Lilly, MSD, Bristol Myers Squibb, AstraZeneca, Bayer, Pierre Fabre; participation in advisory board for AAA Novartis, Takeda, Teysuno. Filippo Pietrantonio: honoraria: Servier, Bayer, AstraZeneca, Lilly, MSD, Amgen, Pierre-Fabre, Merck-Serono, BMS, Astellas. Consulting or Advisory Role: Merck-Serono, Amgen, Servier, MSD, Organon, Bayer. Research Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Incyte, Agenus. Giuseppe Tonini: advisory board member of Molteni, MSD, Novartis, Roche, and Pharmamar. Elisa Giommoni: advisory board of Eli Lilly, Amgen, Viatris, BMS, Servier. Sara Leonardi: received honoraria (as invited speaker) from Roche, Eli Lilly, BMS, Servier, Merck Serono, Pierre Fabre, GSK, and Amgen; consulting fee (advisory boards) from Amgen, Astellas, Bayer, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, BMS, Servier, Merck Sharp & Dohme (MSD), GSK, Takeda, Rottapharm, and Beigene; as well as grants or funds (to institution) from Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, and BMS. Nicola Normanno: outside the submitted work personal fees for the advisory role, speaker engagements, and travel and accommodation expenses from AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Eli Lilly, Illumina, Incyte, MERCK, Merck Sharp & Dohme, Novartis, Roche, Servier, Thermofisher; financial support to research projects from Astrazeneca, Biocartis, Illumina, MERCK, QIAGEN, Roche, Sophia Genetics, Thermofisher. Carmine Pinto: outside the submitted work personal fees for the advisory role, speaker engagements, and travel and accommodation expenses from Amgen, Astellas, AstraZeneca, Bayer, Bristol Meyer Squibb, Celgene, Clovis Oncology, Eisai, Ipsen, Janssen, Incyte, Merck-Serono, Merck Sharp and Dohme, Novartis, Roche, Sandoz, Sanofi, and Servier. The other authors have no conflicts of interest to declare.
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Damato, A., Esposito Abate, R., Tessitore, S. et al. First-line Nivolumab plus FOLFOXIRI/Bevacizumab in advanced RAS/BRAF-mutated colorectal cancer: efficacy, safety and biomarker discovery from the phase II NIVACOR trial. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70620-y
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DOI: https://doi.org/10.1038/s41467-026-70620-y
