The invited discussant of BEACON CRC, Alfredo Falcone, MD, of the Department of Oncology and Translational Medicine at the University of Pisa, Italy, commented: “The ‘story’ of BEACON represents a good example of the European Society for Medical Oncology Congress theme: Translating Science Into Better Cancer Patient Care.” In Dr. Falcone’s opinion, the data are strong enough to elevate the encorafenib/binimetinib/cetuximab triplet as the new standard of care in previously treated patients with metastatic BRAF V600E–mutated colorectal cancer, at least those with microsatellite-stable disease.

“The data suggest that this triplet, vs the doublet of encorafenib/cetuximab, has some improved efficacy, with a modest increase in toxicity (mainly diarrhea and anemia) and no detrimental effect on quality of life,” Dr. Falcone said.

Focus on Heterogeneity of Disease

Dr. Falcone acknowledged that the analysis was not formally powered to show superiority for the triplet over the doublet, and the overall survival data came from an interim analysis with short follow-up. Nevertheless, he said, “I don’t personally think we need to answer this question with a higher level of evidence, which would probably require not only a longer follow-up from BEACON, but also further prospective randomized studies. I would rather focus on the heterogeneity of BRAF-mutated metastatic colorectal cancer.”

Such heterogeneity is becoming better understood, he said. It has become clear that BRAF-mutated tumors can be further subdivided into at least two subtypes, with distinct molecular pathways, regardless of their microsatellite-stability status, and this may have treatment implications.

The BM1 subtype appears in experimental models to be more sensitive to BRAF and MEK inhibition than the BM2 subtype. And although patients with BRAF-mutated tumors are believed to have a poor prognosis, it is possible to risk-stratify patients into low-, intermediate- and high-risk groups, with vastly different median survival times. Studies that take into account BRAF heterogeneity are needed as well as studies to understand and overcome primary and secondary treatment resistance. ■

DISCLOSURE: Dr. Falcone has served as an advisor or consultant for Bayer, Bristol-Myers Squibb, Lilly, Merck, Pierre-Fabre, Roche, and Servier.