Updated BEACON: Doublet as Good as Triplet in Metastatic CRC

Liam Davenport

June 02, 2020

The BEACON study tested both a doublet and a triplet of drugs for patients with previously treated BRAF V600E–mutated metastatic colorectal cancer (CRC).

New results from that trial, with an updated survival analysis, show that the doublet is sufficient and that patients can safely be treated with a combination of the BRAF inhibitor encorafenib (Braftovi, Array BioPharma) and the EGFR inhibitor monoclonal antibody cetuximab (Erbitux, Eli Lilly).

This means that the increased toxicity from the addition of the MEK inhibitor binimetinib (Mektovi, Array BioPharma) can be avoided and that good outcomes can be maintained.

The new results were presented as part of the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study discussant Michael S. Lee, MD, from the UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, said he "would consider encorafenib and cetuximab now the standard of care in the second line and beyond in BRAF-mutant colorectal cancer.

"I would give the doublet rather than the triplet because of the comparable survival and better side effect profile," he said.

"This is immediately practice changing, given the FDA approval of encorafenib and cetuximab," commented Autumn J. McRee, MD, UNC Lineberger Comprehensive Cancer Center. (This doublet has also been approved in Europe.)

This is a "clinically relevant" trial, and it demonstrates that the "poorest prognostic group in colorectal cancer now has viable options," she said at a Highlights of the Day session.

"We will await the results of the ANCHOR-CRC trial to see if we should be using this targeted approach in earlier lines of therapy," she added.

New Survival Data

The primary analysis of BEACON CRC, presented at the 2019 World Conference on Gastrointestinal Cancer, showed that use of the triplet therapy was associated with a 48% improvement in overall survival in comparison with standard chemotherapy.

Although that was also linked to improved quality of life, questions have been raised as to whether the benefits are worth the cost, and one commentator singled the study out for harsh criticism.

Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston, presented the updated survival results from BEACON CRC, which included data from an additional 6 months of follow-up.

"We know that the V600E mutation in BRAF occurs in about 10% to 15% of patients and is associated with a poor prognosis," Kopetz commented.

"BRAF inhibitors alone are not effective," he noted. He said preclinical models point toward an approach that targets multiple pathways, including BRAF, MEK, and EGFR.

THE BEACON study had three arms, each with 205 patients, as follows:

  • encorafenib plus binimetinib plus cetuximab;

  • encorafenib plus cetixumab; and

  • a control arm of FOLFIRI plus cetuximab or irinotecan plus cetuximab.

The three arms of the trial were relatively well balanced with respect to patient characteristics, Kopetz commented. The median age of the patients ranged from 60 to 62 years, and 48% to 57% of the patients were women.

Of note, between 5% and 10% of the cases were characterized by high microsatellite instability, and 34% to 35% of patients had received more than one prior line of therapy.

The data now presented at ASCO represent a post hoc updated analysis that includes 6 months of additional follow-up since the primary analysis was presented, Kopetz explained.

After a median follow-up of 12.8 months, 13% of triplet therapy patients, 14% of those who received doublet therapy, and 3% of control patients were still on treatment.

The updated analysis shows that median overall survival with the doublet therapy was 9.3 months, vs 5.9 months for the control group (hazard ratio [HR], 0.61). The benefit was seen across all subgroups, including those based on the number of prior regimens.

Kopetz pointed out that overall survival was numerically superior to that seen in the primary analysis, which was 8.4 months.

The updated survival analysis for the triplet therapy indicated that the median overall survival was 9.3 months, vs 5.9 months in the control arm (HR, 0.60). Again, this was consistent across subgroups.

In the primary analysis, the median overall survival with the triplet therapy was 9.0 months.

The team also compared the triplet and doublet therapies, finding that, "in contrast to what was seen in the primary analysis...we see numerically identical median overall survival with the two arms." The result was sustained across subgroups.

However, there were indications that there may be survival benefits with the triplet in certain patient subgroups, including those with ECOG performance status 1, those in whom three or more organs are involved, those with higher baseline levels of C-reactive protein, and those with partially resected or unresected disease.

Progression-free survival was comparable between the two treatment groups, at 4.5 months with the triplet therapy and 4.3 months with the doublet, compared to just 1.5 months in the control arm.

The updated analysis also showed that the objective response rate was 27% with triplet therapy, vs 20% with the doublet and 2% in the control arm. In both the doublet and triplet arms, the majority of responses were partial.

With regard to safety, Kopetz said that the updated data regarding adverse events were in general "consistent with the previously reported safety profile."

He added it is "notable" that the triplet therapy "had slightly higher rates of GI toxicity and anemia," which was not seen with the doublet, something that is "again associated with the known safety profile of a MEK inhibitor."

The study was funded by Pfizer Inc. Kopetz has stock and other ownership interests with numerous pharmaceutical companies. Other authors, as well as Lee and McRee, have also reported relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2020: Abstract 4001

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