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A triplet of targeted therapies in second-line led to significant improvement in survival for patients with BRAF-mutated metastatic colorectal cancer (mCRC), a randomized trial showed.

Patients had a median overall survival (OS) of 9 months with the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) as compared with 5.4 months for patients treated with physician's choice of standard therapy. One-fourth of patients responded to the triple-drug combination versus 2% of those randomized to the current standard of care. A third treatment arm consisting of encorafenib and cetuximab also improved survival and response rate versus standard therapy.

The results made a compelling case for the targeted triplet to supplant existing therapies as the standard of care, Scott Kopetz, MD, of the University of Texas MD Anderson Cancer Center in Houston, said at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer in Barcelona.

"This study builds on a decade of research into the tumor biology of BRAF-mutated colorectal cancer and reflects a rational combination to address the vulnerabilities unique to this tumor," Kopetz . "Colorectal cancer does not respond to BRAF therapy alone because tumor cells adapt through other mechanisms after initial treatment. With this triple targeted therapy, we are using a very scientifically logical combination to inhibit BRAF and these other mechanisms."

About 15% of CRCs arise in association with a mutation in the BRAF gene. For years, standard chemotherapy plus the EGFR inhibitor cetuximab has represented standard of care for mCRC that has progressed beyond initial therapy. As Kopetz noted, trials of BRAF inhibition alone failed to produce meaningful improvement in survival.

The BRAF inhibitor encorafenib already has approval for treatment of BRAF-mutated melanoma in combination with the MEK inhibitor binimetinib. Monotherapy with a BRAF inhibitor represented a significant advance in the treatment of melanoma as compared with previous options, but the benefits were short lived. The addition of a MEK inhibitor significantly improved outcomes as compared with a BRAF inhibitor alone, providing a rationale for evaluating the combination in other BRAF-mutated cancers.

Kopetz reported findings from the randomized, phase III . Investigators in the international trial randomized 665 patients with BRAF-mutated mCRC to three treatment arms: encorafenib plus cetuximab, with or without binimetinib, or investigator's choice of chemotherapy plus cetuximab. The primary endpoints were OS and objective response rate for the comparison of the triplet therapy to standard therapy (control arm). Secondary endpoints included progression-free survival, duration of response, OS for the doublet arm versus control arm, and safety.

The results showed that the three-drug targeted combination reduced the survival hazard by 48% as compared with physician's choice of standard therapy (95% CI 0.39-0.70, P<0.0001). A subgroup analysis showed a consistent advantage for the targeted triplet. The difference in response rate also achieved a high level of statistical significance (P<0.0001). Patients randomized to encorafenib and cetuximab had a median OS of 8.4 months, representing a 40% reduction in the survival hazard versus standard therapy (95% CI 0.45-0.79, P=0.0003).

The trial lacked the statistical power to compare OS for the three-drug targeted regimen versus encorafenib and cetuximab, but preliminary analyses yielded a trend in favor of the three-drug regimen on the order of a 20-25% reduction in relative risk. A preliminary analysis of response rate (331 patients) showed that both encorafenib regimens outperformed the control arm (26%, 20%, 2%; P<0.0001 for the triplet and doublet encorafenib groups versus control).

The vast majority of patients treated with the encorafenib triplet or doublet had some reduction in tumor size, somewhat greater with the three-drug regimen (P=0.033). Median PFS increased significantly with both encorafenib regimens versus control (4.3, 4.2, 1.5 months; P<0.0001 for both comparisons).

Grade 3/4 adverse events were common and occurred in a similar proportion of patients randomized to the encorafenib triplet (58%), the encorafenib doublet (50%), or standard therapy (61%). Serious adverse events, adverse events leading to discontinuation of all therapy, and adverse events leading to discontinuation of any one drug occurred in a similar proportion of the three treatment groups.

In light of the BEACON CRC results, all patients with mCRC should be tested for BRAF mutations, ESMO expert Andres Cervantes, MD, said in a statement.

"We now have a specific treatment that can change the natural course of the disease in patients with BRAF mutations and is better than previous therapy, so it is essential that patients are routinely tested," said Cervantes, of the University of Valencia in Spain.

The chemotherapy-free triplet regimen should be considered an additional benefit of the triplet combination, he added. "In many other types of cancer, and particularly colorectal cancer, it is common for biological targeted therapies to be used in combination with chemotherapy. The fact that we can give this targeted combination without the need for chemotherapy is very good news for patients."

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