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SAN FRANCISCO -- Only the two-drug combination of encorafenib (Braftovi) plus cetuximab (Erbitux) will undergo regulatory review by the FDA for metastatic BRAF-mutant colorectal cancer at this time, a researcher reported here.

The decision follows updated results from the three-arm BEACON CRC trial, a phase III study showing that the BRAF/EGFR-inhibiting doublet reached a median overall survival (OS) of 9.3 months, identical to the arm that also included the MEK inhibitor binimetinib (Mektovi), said Scott Kopetz, MD, PhD, of MD Anderson Cancer Center in Houston.

"We felt it was important to share this information with the community," he told the audience at the Gastrointestinal Cancers Symposium (GICS). "On the basis of these results, the decision's been made not to submit the binimetinib [triplet] to the FDA, and the doublet of encorafenib plus cetuximab and is now under review."

At a median follow-up of 12.8 months, both the chemotherapy-free doublet and triplet showed a significant improvement in median OS compared with the study's control arm (5.9 months), an investigator's choice of cetuximab plus either irinotecan or FOLFIRI (folinic acid, fluorouracil, and irinotecan).

"There's really no discernable difference in the survival curves," Kopetz said during a Q&A following his presentation. "So in my practice right now, I'm using the doublet."

An earlier analysis of BEACON CRC appeared to show a slight OS edge favoring the triplet over the doublet (9.0 vs 8.4 months, respectively), with both significantly better than the control arm (5.4 months at that time). "Encouragingly ... the overall survival for the doublet improved by almost a month with the additional mature follow-up," said Kopetz.

GICS discussant Christopher Booth, MD, of Queen's University in Kingston, Canada, questioned the cost-effectiveness of either treatment regimen, and noted that BRAF-mutant disease effects few colorectal cancer patients to begin with (around 400 in the U.S. each year), would likely be unaffordable to most, and would only benefit a small subgroup within this rare subset. Response rates in the updated analysis were 20% with the doublet and 27% with the triplet, versus 2% with the control regimen (P<0.0001 for both).

Booth calculated the "financial toxicity" based on Red Book costs, estimating that a 28-day supply would reach $23,000 for the doublet and $32,000 for the triplet, an average treatment course would cost $109,000 and $168,000, respectively, and annual costs would balloon to $280,000 and $305,000.

"That's a very, very expensive package of treatment," he said, after being asked what he would do if left in charge of approval.

"We have to be pragmatic about the resources we have for cancer care and think very carefully about the magnitude of benefit relative to the price, so I think I would leave the answer to a formal cost-effectiveness analysis," Booth said, and suggested that the data may not meet the criteria for regulatory approval in many countries in Northern Europe or jurisdictions in Canada.

Kopetz's presentation was primarily devoted to quality of life (QOL) and patient-reported outcomes data from BEACON CRC (he dropped the updated OS news at the tail end), and here both the doublet and triplet combinations demonstrated longer maintenance of QOL on standardized questionnaires versus the control arm, as measured by the time to definitive 10% deterioration.

On the European Organisation for Research and Treatment of Cancer QOL Questionnaire (QLQ-C30) -- which measures a patients' global health status -- 10% deterioration occurred at 4.60 months with the doublet (HR 0.54, 95% CI 0.43-0.69) and 4.96 months with the triplet (HR 0.55, 95% CI 0.43-0.70), versus 2.2 months with the control regimen.

On the Functional Assessment of Cancer Therapy Colon Cancer (FACT C) questionnaire -- a measure of physical, social, emotional, and functional well-being -- time to deterioration occurred at 5.36 months with the doublet (HR 0.46, 95% CI 0.36-0.59) and 5.56 months with the triplet (HR 0.48, 95% CI 0.38-0.62), versus 2 months in the control arm.

On EuroQol 5D 5L -- which measures patients' mobility, ability to self-care, engage in usual activities, pain or discomfort, and anxiety or depression -- time to deterioration was 5.36 months with the doublet (HR 0.49, 95% CI 0.39-0.63) and 5.59 months with the triplet (HR 0.49, 95% CI 0.38-0.63), versus 2.37 months in the control arm.

Finally, on the Patient Global Impression of Change -- which asks the degree to which patients symptoms worsened or improved on treatment -- 58% and 53% of patients on the doublet and triplet, respectively, had at least some improvement in symptoms, compared to 36% of patients on the control arm.

"There really was no discernable difference between the quality of life between the doublet or the triplet across the four instruments," said Kopetz.

Booth, however, questioned whether the single timepoint used to capture patient deterioration was adequate, and suggested further analysis with repeated measures would be needed to definitively say that QOL was improved with either combination.

BEACON CRC was a global, open-label study that from May 2015 to January 2019 that randomized 665 patients with BRAF V600E-positive metastatic colorectal cancer to one of thee arms in the second-line setting: encorafenib (300 mg daily) plus cetuximab (400 mg/m² as an initial dose, then 250 mg/m²) and binimetinib (45 mg twice daily) in the triplet arm, encorafenib plus cetuximab in the doublet arm (same doses), or investigator's choice of cetuximab plus either irinotecan or FOLFIRI in the control arm.

Kopetz noted that no new safety signals were seen in the updated analysis. In the prior analysis, grade 3/4 toxicities were common and occurred in a similar proportion of patients randomized to the doublet (50%), triplet (58%), and control treatment (61%).

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