Cancer Treatment Today

The BRAF V600E mutation is present in approximately 15% of patients with early-stage CRC and 6% of those with metastatic CRC. The prognosis of patients who have metastatic disease with the BRAF V600E mutation is very poor; the length of their survival is approximately half that of patients who have metastatic disease without the mutation.

The BRAF mutated  colorectal cancer is a developing story. Three trials had looked into this subtype of colorectal cancer. SWOG S1406 was presented at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. For this phase 2 study, the investigators randomly assigned 106 patients with mutations in BRAF V600 and extended RAS wild-type metastatic CRC to either the standard of care with irinotecan/cetuximab (Erbitux, Lilly) or irinotecan/cetuximab plus the BRAF inhibitor vemurafenib (Zelboraf, Genentech/Daiichi Sankyo). They found that PFS was longer in the vemurafenib group than in the control group: 4.4 vs 2 months, respectively (hazard ratio [HR], 0.42; P=.0002). However, even though the PFS was significantly longer with the addition of vemurafenib, opportunities for improvement remain. Based on these results, the combination was recently added to the National Comprehensive Cancer Network guidelines as a new standard-of-care option. But his study used vemurafenib, not Cotellic.

Atreya CE, Van Cutsem E, Bendell JC, et al. Updated efficacy of the MEK inhibitor trametinib, BRAF inhibitor dabrafenib, and anti-EGFR antibody panitumumab in patients with BRAFV600E mutated metastatic colorectal cancer [ASCO abstract 103]. J Clin Oncol. 2015;33(15)(suppl).

Corcoran RB, André T, Yoshino T, et al. Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E–mutated (BRAFm) metastatic colorectal cancer (mCRC) [ESMO abstract 455O]. Ann Oncol. 2016;27(6)(suppl).

Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33(34):4023-4031.

Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893-1901.

Gomez-Roca CA, Delord J, Robert C, et al. Encorafenib (LGX818), an oral BRAF inhibitor, in patients (pts) with BRAF V600E metastatic colorectal cancer (mCRC): results of dose expansion in an open-label, phase 1 study [ESMO abstract 535P]. Ann Oncol. 2014;25(suppl 4):iv182-iv183.

Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726-736.

Kopetz S, Desai J, Chan E, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 2015;33(34):4032-4038.

Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406) [ASCO GI abstract 520]. J Clin Oncol. 2017;35(6)(suppl).

More recently, the results from the safety lead-in of the BEACON CRC trial were presented at the 2018 ASCO Gastrointestinal Cancers Symposium. The lead-in included 29 patients from the phase 2 BEACON study who had BRAF V600–mutant metastatic CRC that had progressed after 1 or 2 prior regimens. Patients received a combination of the BRAF inhibitor encorafenib, the anti-EGFR antibody cetuximab, and the MEK inhibitor binimetinib. The overall response rate was 48%, and the median PFS was 8 months. These results are substantially better than those seen historically in this population. The phase 3 portion of BEACON CRC is ongoing, with patients being randomly assigned either to encorafenib/cetuximab with or without binimetinib or to a standard-of-care arm.

A third study of interest is one that Dr Ryan Corcoran of Massachusetts General Hospital presented at the European Society for Medical Oncology (ESMO) annual meeting in 2016. This phase 1/2 study examined a combination of the BRAF inhibitor dabrafenib (Tafinlar, Novartis), the EGFR inhibitor panitumumab (Vectibix, Amgen), and the MEK inhibitor trametinib (Mekinist, Novartis) in 35 patients with BRAF V600E–mutated metastatic CRC and found a response rate of 32%. In contrast, the response rate was just 10% among patients who received dabrafenib and panitumumab alone.

A phase 1b study by van Geel and colleagues, which appeared in Cancer Discovery in 2017, did not find that adding the PI3K inhibitor alpelisib to treatment with encorafenib and cetuximab achieved meaningful improvement in the response rate or durability.