BEACON Trial in BRAF-Mutant mCRC: Now Published, Criticized

Megan Brooks

October 23, 2019

The recently reported BEACON trial, which showed that some patients with colorectal cancer (CRC) can be treated without chemotherapy and that has been hailed as practice changing by gastrointestinal cancer experts, has been slammed with harsh criticism from an outspoken oncologist commentator.

Patients in the BEACON trial had metastatic CRC with a BRAF V600E mutation, which is found in 10% to 15% of patients with metastatic CRC and is usually associated with a poor prognosis.

The trial showed that for these patients, a triple combination of targeted therapy led to significantly better overall survival than traditional chemotherapy.

The triplet comprised the BRAF inhibitor encorafenib (Braftovi, Array BioPharma), the MEK inhibitor binimetinib (Mektovi, Array BioPharma), and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).

Results from the BEACON trial were presented earlier this year at the World Conference on Gastrointestinal Cancer (WCGC) and were reported at that time by Medscape Medical News.

They have now been published in full in the New England Journal of Medicine [NEJM].

At the WCGC, principal investigator Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that he was "pleased to report that really this is the first evidence of a survival benefit with a chemotherapy-free targeted therapy regimen in a prospective biomarker-defined subgroup, in this case BRAF V600E mutations in colorectal cancer.

"On the basis of this, we think it really defines a new standard of care," he added.

Kopetz noted that the triplet therapy has already been added to the National Comprehensive Cancer Network guidelines for the treatment of metastatic CRC.

The BEACON results were described as practice changing in a recent Medscape video commentary by David Kerr, MD, professor of cancer medicine at the Oxford Cancer Center, United Kingdom.

However, the study has received harsh criticism from Vinay Prasad, MD, MPH, hematologist/oncologist and assistant professor of medicine at Oregon Health and Science University in Portland.

In his podcast Plenary Session, Prasad calls it the "single worst reported randomized controlled trial" because of a failure to provide basic information, the choice of control group regimen, and for multiple redactions to the original published protocol, among other reasons.

Asked by Medscape Medical News for comment on Prasad's concerns, BEACON study investigator Josep Tabernero, MD, PhD, medical oncologist and director, Vall d'Hebron Institute of Oncology, Barcelona, Spain, said, "I prefer to comment on that in the official format of NEJM letters to the editor if they come."

Details of the Study Results

BEACON was an open-label phase 3 trial that involved 665 patients with BRAF V600E–mutated metastatic CRC whose disease had progressed after one or two prior regimens.

The trial had three treatment arms. One group of patients received triplet therapy with three targeted agents ― encorafenib, binimetinib, and cetuximab.

Another group received doublet targeted therapy with encorafenib and cetuximab.

A third (control) group received standard chemotherapy (physician choice of cetuximab and irinotecan or cetuximab and FOLFIRI [folinic acid, fluorouracil, and irinotecan]).

The median overall survival (OS) was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio [HR] for death, 0.52; 95% confidence interval [CI], 0.39 – 0.70; P < .001).

The median OS in the doublet-therapy group was 8.4 months (HR for death vs control, 0.60; 95% CI, 0.45 – 0.79; P < .001).

The objective response rate was 26% (95% CI, 18 – 35) in the triplet-therapy group vs 2% (95% CI, 0 – 7) in the control group (P < .001). It was 20% in the doublet-therapy group, which was also significantly higher than in the control group (P < .001).

Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, 50% in the doublet-therapy group, and 61% in the control group.

"The combination of three targeted therapies ― encorafenib, binimetinib, and cetuximab ― leads to significantly improved outcomes for these patients," Tabernero told Medscape Medical News.

"As we continue to seek out much needed therapeutic avenues against BRAF V600E–mutated metastatic colorectal cancer, our future research will need to better define the benefits of both the triplet and doublet combinations," said Tabernero.

"While this study was not designed to compare the triplet and doublet therapies, the doublet regimen might be sufficient for some patients. Further, these present findings could also warrant assessing the combination as first-line therapy," he added.

Article Deserves "Deep Scrutiny"

In his podcast, Prasad says the BEACON trial has "many, many flaws" that flew under the radar of the reviewers.

They include, among other factors, the choice of cetuximab as a control treatment, which has no role in BRAF V600E–mutated CRC, Prasad says. It's also unclear what proportion of patients in the control group were treated with each of the two options. In addition, full inclusion and exclusion criteria for patients in the trial are missing.

Other key unknowns, according to Prasad, are the time from metastatic diagnosis to enrollment; how long patients survived before enrollment; and what pre- and post-protocol therapies were given.

This article deserves "deep scrutiny," says Prasad. He notes that it reads more like a press release than a scientific article and that it did not answer basic questions readers would want to know.

Prasad says it's also worth noting that the manuscript was drafted with "professional medical writing assistance funded by Array BioPharma," the company that funded BEACON, along with Merck, Ono Pharmaceutical, and Pierre Fabre.

N Engl J Med. Published online September 30, 2019. Abstract

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