Balancing RAF, MEK, and EGFR Inhibitor Doses to Achieve Clinical Responses and Modulate Toxicity in BRAF V600E Colorectal Cancer

Recent years have seen dramatic clinical advances in targeting the ERK pathway with the FDA approval of several selective inhibitors of RAF and MEK1–5. Clinical trials of these agents indicate that near complete inhibition of pathway signaling is necessary to effectively inhibit tumor growth6. Targeted approaches have been most successful in BRAF V600E tumors because of the relatively wide therapeutic index of RAF inhibitors (vemurafenib and dabrafenib), which inhibit signaling in cells with BRAF V600 mutants but cause “paradoxical activation” of ERK signaling in normal cells that are wild-type for RAF kinases. In contrast, MEK inhibitors (trametinib and cobimetinib) suppress ERK signaling in all cells, and their clinical activity has been limited by a narrow therapeutic index. Combining these agents – with RAF and MEK inhibitors for BRAF V600E melanoma or lung cancer and with RAF, MEK, and EGFR inhibitors for BRAF V600E colorectal cancer – to profoundly inhibit ERK signaling has led to improved antitumor activity7. Combination therapy has also been shown to offset the toxicities caused by RAF inhibitors, such as the development of keratoacanthomas and squamous cell carcinoma, resulting from paradoxical ERK activation with these agents. The role of RAF inhibitors to offset MEK inhibitor toxicity and the need for dose intensity to modulate opposing toxicities is less clear. Recent observations in clinical trials have suggested that RAF inhibitors offset dermatologic toxicity from MEK or EGFR inhibitors. In the phase III trial of trametinib in melanoma, grade 3 or 4 acneiform dermatitis occurred in 8% of trametinib-treated patients, whereas in the phase III trial of the combination of dabrafenib and trametinib, no patient had grade 3 or 4 acneiform dermatitis8,9. Combinations of RAF and EGFR inhibitors have also had a lower incidence of acneiform rash than seen with EGFR inhibitors alone7,10,11. This is also likely due to the opposite effects of RAF and EGFR inhibitors on MEK activation in normal cells. However, the doses of RAF inhibitors needed for these clinically opposing effects and how these doses compare to clinically efficacious doses have not been studied. We now report the course of a patient with BRAF V600E CRC treated with dabrafenib, trametinib, and panitumumab in a phase II clinical trial, and within this patient characterize the effect on toxicities of different dose levels of these agents. Further, we find that, within the clinical dose range, there is a RAF inhibitor dose that is an inflection point for the toxicity and efficacy of this regimen.