BRAF-Mutant CRC: 'Practice-Changing' Data Support New Combos

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


September 19, 2019

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine from the University of Oxford in England. Today I want to comment on the recently reported BEACON trial.[1] Scott Kopetz ably presented the results of this trial on behalf of colleagues from MD Anderson and around the world at the 2019 ESMO (European Society for Medical Oncology) World Congress on Gastrointestinal Cancer in Barcelona, Spain.

The BEACON trial addressed a thorny problem for those of us interested in the treatment of colorectal cancer, namely that subset of patients—around 1 in 7—with advanced disease that is BRAF mutant. We know that this particular biology carries a bad prognosis and is relatively less responsive to conventional chemotherapy.

Based on rather nice fundamental biology and basic science that enabled an understanding of the mechanism of resistance to BRAF inhibitors in colorectal cancer, the BEACON investigators put together a triplet therapy combining a MEK inhibitor, a BRAF inhibitor, and an epidermal growth factor receptor (EGFR) inhibitor. They have taken the therapy through phase 2 trials; BEACON is the first large, global, well-designed, and well-conducted randomized trial of this therapy regimen.

Investigators recruited 665 patients, all with the BRAF V600E mutation, from around the world. Patients were randomly assigned to one of three arms: triplet therapy with binimetinib (the MEK inhibitor), encorafenib (the BRAF inhibitor), and cetuximab (the EGFR inhibitor); doublet therapy with encorafenib and cetuximab; or conventional chemotherapy, either irinotecan or FOLFIRI in combination with cetuximab. All of these patients had disease that previously progressed after one or two lines of conventional chemotherapy.

The key finding was that median overall survival was 9 months for the triplet-therapy group. This stood in stark contrast to patients who had received chemotherapy and cetuximab, for whom the median survival was only 5.4 months, a big statistical difference.

It was also intriguing that in patients who received the doublet therapy with encorafenib and cetuximab, the median overall survival was 8.4 months—again, statistically significantly better by about 3 months compared with the conventional chemotherapy.

The study was powered to look at conventional chemotherapy versus the biological combinations but not to look at the difference between doublet and triplet therapy, so this comparison is an open question that I'm sure will be addressed subsequently. Moreover, I have no doubt that this triplet therapy combination will be brought further into first-line treatment. Ongoing trials are looking at that.

Is this practice-changing? Yes, I believe it is. With that degree of survival benefit in a tumor with a biology we know to be inimical to conventional chemotherapy, this is a step forward. For me, there's still a question about whether we should go for the triplet or doublet combinations. If one were working in a resource-constrained environment, if one had difficulty getting access to the drugs, it does look as though there is significant advantage to using the doublet on its own, without the MEK inhibitor.

This is an important piece of work based on plausible biology, delivered by one of the world's leading groups, and a wonderful expression of a global collaborative trial. These patients were recruited very quickly. I believe that the results are practice-changing.

Have a look at the presentation, and please send us your comments. For now, Medscapers, ahoy. Thank you.

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