Triplet therapy improves outcomes in BRAF V600E-mutant metastatic colorectal cancer

Issue: November 25, 2019

Scott Kopetz

BARCELONA, Spain — Triplet therapy with encorafenib, cetuximab and binimetinib significantly extended OS compared with standard treatment for patients with BRAF V600E mutation-positive metastatic colorectal cancer, according to results of the phase 3 BEACON CRC trial presented at European Society for Medical Oncology Congress.

Perspective from David H. Ilson, MD, PhD

“The results are practice-changing,” researcher Scott Kopetz, MD, associate professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today.

“This population represents 5% to 10% of patients with metastatic colorectal cancer. It is a very unique subgroup with aggressive disease biology, very poor responses to standard-of-care chemotherapies and much shorter survival, both in early-stage disease and metastatic disease,” Kopetz added. “We are extremely glad to see a the demonstration of a survival advantage for this population, which has such a high unmet need.”

A large body of preclinical work demonstrated that colorectal tumors do not respond well to BRAF inhibition or EGFR inhibition alone, but that when a BRAF inhibitor is given, the tumor adapts by activating the EGFR pathway, Kopetz said.

Due to the substantial synergy, the randomized BEACON CRC trial was designed to explore whether “maximal inhibition” with BRAF and EGFR inhibitors could prolong OS compared with standard-of-care therapy, Kopetz said.

The three-arm study assigned 665 patients to one of the following: triplet therapy with encorafenib (Bravtofi, Array Pharmaceuticals), cetuximab (Erbitux, Bristol-Myers Squibb) and binimetinib (Mektovi, Array Pharmaceuticals; n = 224); doublet therapy with encorafenib and cetuximab (n = 220); or a control regimen consisting of investigator’s choice of either irinotecan or FOLFIRI plus cetuximab (n = 221).

Results showed the triplet regimen significantly extended median OS (9 months vs. 5.4 months; HR = 0.52; P < .0001) and objective response rate (26% vs. 2%; P < .0001) compared with the control regimen among patients with metastatic colorectal cancer who had BRAF V600E mutations. The triplet also extended PFS compared with the control regimen.

The triplet regimen appeared well-tolerated, and researchers observed no unexpected toxicities.

Grade 3 or higher adverse events occurred among 58% of patients assigned triplet therapy, 50% of those assigned doublet therapy and 61% of those in the control group.

Seven percent of patients assigned triplet therapy discontinued due to adverse events, compared with 8% of those assigned doublet therapy and 11% of those in the control group.

“Based in part on these results, the regimen has been added to the National Comprehensive Cancer Network guideline as a standard-of-care option for these patients,” Kopetz said. “We’re pleased that this study was able to confirm the OS advantage with the triplet, as well as demonstrate the safety of the regimen.”

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Kopetz and colleagues also presented results of a comparison between the triplet and doublet regimens with regard to efficacy, safety and quality of life.

The efficacy comparison was a secondary endpoint and was not sufficiently powered. However, results favored the triplet therapy group for median OS (9 months vs. 8.4 months; HR = 0.79; 95% CI, 0.59-1.06), ORR for all patients (26% vs. 20%), and ORR for patients with one prior therapy (34% vs. 22%).

Grade 3 or higher adverse events (58% vs. 50%) and discontinuation due to adverse events (7% vs. 8%) were comparable between the triplet and doublet groups.

Investigators reported no differences in quality of life between groups.

“The next steps will include exploring options in the advanced disease or even the adjuvant settings to try to improve outcomes for these patients,” Kopetz said. “At the same time, we’ll wait for additional data from BEACON. This is an initial report based on early survival data, so we’ll still learn more as the data mature.” – by Mark Leiser

Reference: Tabernero J, et al. Abstract LBA32. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

Disclosures: Array BioPharma funded this study. Kopetz reports shareholder/stockholder interests or stock options in, consultant/advisory roles with, or research grants or funding to his institution from Amal Therapeutics, Amgen, Array BioPharma, Biocartis, Boehringer Ingelheim, Eli Lilly, EMD Serono, Genentech/Roche, Guardian Health, Holy Stone, Karyopharm, MedImmune, Merck, Molecular Match, Navire, Novartis, Sanofi and Symphogen. Please see the abstract for all other authors’ relevant financial disclosures.

Perspective

David H. Ilson, MD, PhD

The advent of genomic profiling in colorectal cancer has improved our ability to tailor therapy for patients with advanced disease. Identification of RAS mutation determines the efficacy and use of EGFR-targeted agents, and the presence of microsatellite instability determines the efficacy and use of immune checkpoint inhibitors.

BRAF mutation, present in between 8% and 12% of patients with metastatic colorectal cancer, initially was described as an adverse prognostic marker in advanced disease with poorer outcomes to chemotherapy. Data suggest that intensification of first-line therapy with irinotecan, oxaliplatin, 5-FU and bevacizumab (Avastin, Genentech) might confer better outcomes among patients with BRAF mutations compared with a two-drug therapy plus bevacizumab. This finding resulted in National Comprehensive Cancer Network guidelines recommending use of first-line triplet chemotherapy for these patients. More recent studies, however, have failed to validate a benefit for the two- vs. three-drug regimens.

With the publication of the BEACON trial, BRAF V600E mutation has now been identified as a viable target for both BRAF inhibitors and downstream inhibitors of MEK mutation. Previously, single-agent BRAF inhibitors tested in the most common subtype of BRAF V600E mutation failed to achieve efficacy, because BRAF inhibition results in feedback activation upstream of the EGFR pathway. Preclinical and clinical data, however, indicate that combining a BRAF inhibitor with an EGFR inhibitor may lead to meaningful clinical activity. A recent trial combining irinotecan with cetuximab and the BRAF inhibitor vemurafenib (Zelboraf, Genentech) indicated clinical activity for this strategy.

The BEACON trial, an industry-sponsored, international, multicenter, open-label randomized, phase 3 trial, has built on this experience, treating patients with BRAF V600E-mutant metastatic colorectal cancer progressing on one to two prior lines of chemotherapy. Of the 665 patients treated, between 50% and 56% had right-sided primaries, between 58% and 64% had liver metastases, between 65% and 66% had received one prior line of therapy, and between 5% and 9% had microsatellite instability-high tumors.

All endpoints showed superiority for inclusion of a BRAF inhibitor with cetuximab compared with irinotecan/cetuximab. Although the study was not powered to compare cetuximab and encorafenib with the addition of binimetinib, OS trended superior for three-drug therapy, as did depth of response.

Based on these results, the combination of a BRAF inhibitor with cetuximab is a new standard of care in BRAF V600E-mutant colorectal cancer, with superior outcomes trending for the additional inclusion of a MEK inhibitor. Final maturation of the outcomes with the MEK inhibitor are pending, as well as economic analysis given the likely higher cost of adding a MEK inhibitor to a BRAF inhibitor with cetuximab.

David H. Ilson, MD, PhD

HemOnc Today Editorial Board Member

Memorial Sloan Kettering Cancer Center

Disclosures: Ilson reports no relevant financial disclosures.

European Society for Medical Oncology Congress

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Triplet therapy improves outcomes in BRAF V600E-mutant metastatic colorectal cancer

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