Regorafenib with a fluoropyrimidine for metastatic colorectal cancer after progression on multiple 5-FU-containing combination therapies and regorafenib monotherapy

We present 2 patients with metastatic colorectal cancer who had progressed despite treatment with first-line FOLFOX and second-line FOLFIRI combination chemotherapy regimens. After failing these fluoropyrimidine-based regimens, both patients received additional cytotoxic and targeted therapies with eventual disease progression. These therapies included capecitabine plus dabrafenib and trametinib, regorafenib monotherapy, and regorafenib with panitumumab. After exhausting available options, both patients were offered regorafenib with either 5-fluorouracil (5-FU) or capecitabine. These therapies are individually approved for the treatment of colorectal cancer but have not yet been studied in combination. This regimen produced stable disease in both patients with acceptable toxicity. One patient continued therapy for 17 months. Although these patients previously progressed during treatment with regorafenib, capecitabine or 5-FU, the combination had some activity in both cases of refractory metastatic colorectal cancer and may be considered in the palliative setting. In bedside-to-bench cell culture experiments performed after the clinical observations, we observed sensitivity of human colorectal cancer cell lines (N = 4) to single agent regorafenib or 5-FU and evidence of synergy with the combination therapy. Synergistic effects were noted in colorectal cancer cells with KRAS mutation, BRAF mutation, and p53 mutation, as well as mismatch repair deficient cells. Regorafenib suppressed Mcl-1 and Bcl-XL in treated cancer cells that may have contributed to the anticancer efficacy including in combination with 5-FU. The safety and efficacy of regorafenib with 5-FU or capecitabine in combination should be further investigated as a therapy for patients with refractory metastatic colorectal cancer, including individuals who had progressed on regorafenib monotherapy.