Discussion
tumor, melanoma, CRC
TUMOR, MELANOMA
We present preclinical, clinical and translational evidence of cooperativity between BRAF/MAPK pathway inhibition and the immune response in BRAFThe primary focus of the study was efficacy in the MSS BRAFIn what we believe is one of the first clinical trials to incorporate systematic scRNAseq analysis of paired pre- and on-treatment tumor biopsies from all patients, we identified a potential mechanism underlying the cooperativity observed between BRAF/MAPK inhibition and immune response. We find evidence of tumor cell-intrinsic induction of key immune programs (types I and II IFN response, antigen presenting genes and T cell recruiting chemokines) triggered by MAPK pathway inhibition. These gene expression changes are similar to a gene expression program recently discovered in malignant cells from immunologically active MSI CRC and associated with activated and chronically stimulated T cellsBy performing parallel studies with matched patient-derived organoids generated from the same patients, we confirmed that induction of immune genes by BRAF/MAPK inhibition is tumor cell intrinsic and does not depend on cells in the tumor microenvironment. Indeed, induction of these immune programs was observed even in organoid cultures, which consist of pure tumor cell populations. These data provide important mechanistic insight, as the potential cooperativity of MAPK pathway inhibition and the immune response has previously been hypothesized to involve a direct effect of MAPK inhibition on cells in the tumor microenvironmentNotably, organoids derived from patients with PFS > 6 months also retained the pattern of increased induction of immune programs upon BRAF/MEK treatment relative to organoids from patients with PFS < 6 months, as observed in our scRNAseq dataset. This observation allowed us to use these matched organoids as representative models to probe the mechanisms underlying tumor cell-intrinsic immune program induction. Interestingly, our scRNAseq data suggested that patients with PFS < 6 months failed to achieve robust MAPK inhibition in tumor cells with DT compared with patients with PFS > 6 months. This same pattern was observed in matched patient-derived organoid models, allowing us to test the hypothesis that failure to induce immune programs was a direct consequence of inadequate BRAF/MAPK inhibition and that more optimal MAPK inhibition may lead to improved induction of key immune genes, even in tumor cells from patients who did not benefit from therapy. As noted above, a limitation of the study was the use of a BRAF/MEK inhibitor combination for this proof-of-concept study, which was based on the availability of established dosing and safety data for this regimen from patients with melanoma at the time that this study was initiated; this preceded the results of the BEACON study that demonstrated the efficacy of encorafenib and cetuximab in this population. Notably, the BEACON study also showed that while the addition of an MEK inhibitor increased the overall response rate relative to the BRAF/EGFR doublet (27% versus 20%), it did not improve survival. Thus, BRAF/MEK is likely not the optimal BRAF-targeting core in this population, and these data suggest that more effective BRAF-targeting combinations could further augment the cooperativity with ICB. Remarkably, using a combination of BRAF and ERK inhibitors that led to more robust BRAF/MAPK inhibition across all organoids, we found that immune program induction could be achieved in all models, regardless of PFS. This finding has important and immediate clinical implications, suggesting that combining ICB with a more effective BRAF/MAPK-targeting core, such as BRAF/EGFR or BRAF/ERK, may further enhance the immune cooperativity and clinical benefit observed and that such strategies warrant further exploration in future clinical trials. This potential for enhanced clinical activity from targeting the BRAF pathway in combination with ICB is further supported by early data from an ongoing clinical trial adding the anti-PD-1 antibody nivolumab to the current standard of care of encorafenib plus cetuximab, yielding a 50% ORR in the first 21 patients compared with an expected 20% ORR for encorafenib plus cetuximab aloneFinally, it will be important to determine whether this potential mechanism of immune cooperativity is limited to BRAF