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

Sebastian Mondaca; Mario Lacouture; Jonathan Hersch; Rona Yaeger


JCO Precis Oncol. 2018;2018(2) 

In This Article

Abstract and Introduction


Recent years have seen dramatic clinical advances in targeting the ERK pathway with the US Food and Drug Administration approval of several selective inhibitors of RAF and MEK.[1–5] Clinical trials of these agents indicate that near-complete inhibition of pathway signaling is necessary to effectively inhibit tumor growth.[6] 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 epidermal growth factor receptor [EGFR] inhibitors for BRAF V600E colorectal cancer) to profoundly inhibit ERK signaling has led to improved antitumor activity.[7] Combination therapy has also been shown to offset the toxicities caused by RAF inhibitors, such as the development of keratoacanthoma and squamous cell carcinoma, resulting from paradoxical ERK activation with these agents.

The role of RAF inhibitors in offsetting 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 resulting 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 dermatitis.[8,9] Combinations of RAF and EGFR inhibitors have also had a lower incidence of acneiform rash than seen with EGFR inhibitors alone.[7,10,11] This is also likely because of 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 with clinically efficacious doses have not been studied. We now report the course of a patient with BRAF V600E colorectal cancer treated with dabrafenib, trametinib, and panitumumab in a phase II clinical trial and characterize the effect on toxicities of different dose levels of these agents in this patient. Furthermore, 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.