NEW YORK – A triple-pronged therapy that simultaneously targets BRAF, EGFR, and MEK seems to stretch out overall survival times in BRAF-mutated metastatic colorectal cancer cases, according to results from a randomized Phase III clinical trial called BEACON.
"We're hopeful that this will give new options for our [BRAF-mutated metastatic CRC] patients," said Scott Kopetz, a gastrointestinal medical oncologist at the University of Texas MD Anderson Cancer Center, principal investigator on BEACON and co-lead for MD Anderson's Cancer Moon Shot effort in CRC.
For that multicenter, open label clinical trial, investigators randomized 665 metastatic CRC patients with BRAF V600E mutant tumors — enrolled at hundreds of sites in 15 countries — to receive the BRAF inhibitor encorafenib (Braftovi from Array Biopharma) and the EGFR inhibitor cetuximab (Erbitux from Eli Lilly; also distributed by Merck and/or Bristol-Myers Squibb elsewhere) with or without the MEK inhibitor binimetinib (Array Biopharma's Mektovi) or else standard therapy.
The trial participants all had advanced disease and had progressed after one or two previous rounds of treatment. The precise form of standard therapy that was compared to the doublet (cetuximab and encorafenib) or triplet (cetuximab, encorafenib, and binimetinib) therapies in BEACON were left up to clinicians, to some extent, but included single or combination chemotherapy and cetuximab.
"The standard treatment in this setting is traditional chemotherapy — cytotoxic chemotherapy — sometimes in combination with cetuximab, [which is] an EGFR inhibition," Kopetz explained. "That was the foundation for the BEACON control arm."
The trial built on roughly a decade of research demonstrating that BRAF-mutated tumors can adapt to BRAF inhibition via EGFR and MEK pathways, explained Kopetz.
Researchers first recognized that the combination of BRAF and EGFR inhibitors demonstrated a benefit. However, they then saw that tumors still developed resistance by acquiring alterations that may be attenuated by a MEK inhibitor.
"That led to the finding [that] we needed to do the triplet of BRAF, EGFR, and MEK [inhibitors] to optimize outcomes for patients," said Kopetz, who presented findings from the BEACON trial at a European Society for Medical Oncology World Congress on Gastrointestinal Cancer in Barcelona over the weekend (the abstract for that presentation appeared in the Annals of Oncology late last week).
Kopetz and his team reported that BRAF-mutated metastatic CRC patients receiving the triple drug therapy had a median overall survival time of 9 months, relative to 5.4 months in patients receiving the standard therapy at the interim analysis point. That coincided with a hazard ratio of 0.52, or a 48 percent decrease in deaths versus standard therapy over the time frame considered.
The magnitude of that overall survival effect compared to standard treatment "is something we really haven't seen in metastatic colorectal cancer trials previously," Kopetz said.
He noted that progression-free survival, a secondary endpoint for the trial, was extended from 1.5 months in the standard treatment control arm to 4.3 months following the three-drug treatment.
In the double treatment arm, involving BRAF and EGFR inhibitors without the MEK inhibitor, the median overall survival came in at 8.4 months, though the investigators cautioned that the current trial was not sufficiently powered to identify differences between the two- and three-drug arms.
Based on blinded central review, the investigators saw an objective response rate of 26 percent in the advanced CRC patients treated with encorafenib, cetuximab, and binimetinib. In contrast, just 2 percent saw their tumors shrink with the standard treatment.
The team documented adverse events in 58 percent of the metastatic CRC patients who received all three targeted drugs, compared with 50 percent of those in the encorafenib and cetuximab double drug regimen, and 61 percent of patients in the standard treatment control arm. Kopetz noted that toxicities were manageable, and the team saw very low rates of treatment discontinuation.
BRAF V600E mutations have been documented in 8 percent to 15 percent of CRC cases, Kopetz explained, and often correspond to more aggressive cases with poor outcomes. Guidelines in the US and other parts of the world already recommend testing for BRAF V600E mutations in CRC tumors, though he expects the uptake of such testing may rise based on treatment options revealed by the BEACON trial results.
"I think uptake will definitely increase, as awareness of the study and the overall survival benefit becomes evident," Kopetz said.
National Comprehensive Cancer Network guidance currently includes the three-drug treatment as an option for CRC in the US, and BEACON results are expected to support regulatory approval for the combination regimen.
Based on BEACON trial safety lead-in data, published in a rapid communication in the Journal of Clinical Oncology in June, the US Food and Drug Administration granted encorafenib a breakthrough therapy designation last August, giving the okay to use that drug in combination with cetuximab and binimetinib for previously-treated metastatic CRC patients.
Prior FDA approval for encorafenib and binimetinib in unresectable or metastatic melanoma named the bioMerieux THxID BRAF kit as a companion diagnostic for picking up BRAF V600E mutations in those skin cancer cases.
For the BEACON trial itself, "there was no companion diagnostic, but obviously that will be part of [future] regulatory steps" in the commercial setting, Kopetz said.
In the trial, BRAF mutation testing was done with approaches being used in clinical practice at the participating center — most often next-generation sequencing panel assays — followed by central confirmation of the BRAF V600E status.
Though the primary outcome for the BEACON trial has been met, the team expects to do additional analyses on the Phase III trial data as it matures to get a better handle on the magnitude of benefit for the combined treatments.
Kopetz noted that there is also interest in looking at a similar treatment regimen in the first- or second-line treatment settings.
The ANCHOR-CRC trial is currently recruiting untreated individuals with BRAF V600E-mutated metastatic CRC for a Phase II trial of first-line encorafenib, binimetinib, and cetuximab treatment. So far, trials in primary BRAF-mutated CRCs have been discussed, though none are in the works or announced yet, Kopetz noted.
"At present, targeted therapy should probably be limited to the patient group treated in the BEACON CRC trial, who had progressed after one or two previous lines of chemotherapy," Andres Cervantes, head of medical oncology at the University Hospital in Valencia, Spain, a BEACON study location, said in a statement.
"However," Cervantes said, "it is important that we investigate its use in other settings where more patients with BRAF mutations may also benefit, including those with less advanced metastatic disease and possibly in the adjuvant setting after primary surgery with curative intent."