A single-arm, phase Ib/II MEDITREME study evaluated clinical and biological response with first-line chemo-immunotherapy combination of modified FOLFOX6 (mFOLFOX6) regimen combined with durvalumab and tremelimumab as induction therapy, followed by maintenance therapy with durvalumab until progression for RAS-mutated metastatic colorectal cancer (mCRC). The study reached its primary objective, with 3-month progression-free survival (PFS) of 90.7%, 6-month PFS of 60% and median PFS of 8.2 months, whereas the expected median PFS for such a population is 5–6 months with FOLFOX regimen alone.
Favourable clinical efficacy of first-line chemo-immunotherapy for unresectable microsatellite stable (MSS) mCRC with in-depth molecular and immune analyses, provide clues for better selection of patients with MSS mCRC for chemo-immunotherapy, with potentially broad clinical implications according to drs. Marion Thibaudin and François Ghiringhelli of the Université Bourgogne Franche-Comté and Cancer Biology Transfer Platform, Department of Biology and Pathology of Tumors, Georges-François Leclerc Anticancer Center, UNICANCER in Dijon, France, and colleagues who published the findings on 10 August 2023 in the Nature Medicine.
The authors wrote in the background that although patients with microsatellite instable mCRC benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for MSS tumours, as immunotherapy is ineffective as monotherapy in that setting.
Many studies have underlined that the immune system recognises CRC, and high CD8 T cell infiltrates are associated with better prognosis in localised or mCRC. Preclinical data suggest that combining a PD1/PD-L1 inhibitor with an immunogenic cell death inducer, such as oxaliplatin, could enhance immunotherapy efficacy. 5-fluorouracil (5-FU) could eliminate myeloid-derived suppressor cells and limit tumour-induced immunosuppression. Thus, combining 5-FU and oxaliplatin could improve antitumour immune response. In mouse CRC models, a synergistic effect was observed with an anti-PD-L1 plus FOLFOX combination.
Based on these data, the investigators designed the phase Ib/II MEDITREME study with aim to investigate feasibility and efficacy and to explore the genomic and immunologic features of response in MSS mCRC. To obtain homogenous response rates and PFS, the study team focused on patients with RAS-mutated tumours.
In MEDITREME, the study team evaluated the safety and efficacy of durvalumab plus tremelimumab combined in first-line treatment with mFOLFOX6 chemotherapy in 57 patients with RAS-mutatded unresectable mCRC. Safety was the primary objective of phase Ib with no safety issue observed. The phase II primary objective of efficacy in terms of 3-month PFS in patients with MSS tumours was met, with 3-month PFS of 90.7% (95% confidence interval [CI] 79.2–96%).
For secondary objectives, response rate was 64.5%, median PFS was 8.2 months (95% CI 5.9–8.6) and overall survival was not reached in patients with MSS tumours. The study investigators observed higher tumour mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial–mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumour-specific T cell response associated with better PFS.
The authors commented that the study is limited by its small sample size and the absence of a FOLFOX monotherapy control arm. However, the clinical data compared favourable to previous studies of doublet chemotherapy alone. Because of the lack of control group and small sample size, genomic and transcriptomic data must be taken as exploratory, and the predictive versus prognostic nature of the results warrants confirmation in larger randomised studies. Due to the absence of a control group without oxaliplatin, the role of immunogenic cell death has not been directly proven.
The authors acknowledged GenomEast platform, a member of the ‘France Génomique’ consortium for scRNA-seq and RNA-seq, the Cytometry platform (IGBMC, Strasbourg) for the sorting experiments related to scRNA-seq, the Burgundy Regional Council for supporting the facility, and the biomonitoring platform of UMR 1098 for technical support. The study was supported by grants from AstraZeneca and from Georges-François Leclerc Cancer Center.
Reference
Thibaudin M, Fumet J-D, Chibaudel B, et al. First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial. Nature Medicine 2023;29:2087-2098.
