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Triplet therapy extends survival in BRAF V600E-mutant metastatic colorectal cancer
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A combination of encorafenib, binimetinib and cetuxumab significantly improved OS and overall response rate compared with standard-of-care chemotherapy among patients with BRAF V600E-mutant metastatic colorectal cancer, according to findings from the randomized phase 3 BEACON CRC study presented at ESMO World Congress on Gastrointestinal Cancer.
The triplet therapy also exhibited a safety profile concordant with the known safety profiles of each individual agent.
One in seven patients with metastatic colorectal cancer has a BRAF mutation. According to the researchers, the study findings suggest that the three-drug combination should replace chemotherapy as standard of care for these patients.
“These are very exciting results, because we’ve been trying to target BRAF-mutant colorectal cancer for many years,” Scott Kopetz, MD, PhD, associate professor in the department of gastrointestinal medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said in a press release. “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.”
In a lead-in to the multicenter, open-label, phase 3 BEACON CRC study, the triplet showed acceptable safety and promising activity among 30 patients with BRAF V600E-mutant metastatic colorectal cancer who failed one or two previous regimens.
The randomized portion of the study included 665 such patients assigned to one of the following: encorafenib (Bravtofi, Array Pharmaceuticals), cetuximab (Erbitux, Bristol-Myers Squibb) and binimetinib (Mektovi, Array Pharmaceuticals; n = 224); a doublet combination of encorafenib and cetuximab (n = 220); or a control regimen consisting of investigator’s choice of either irinotecan or FOLFIRI plus cetuximab (n = 221).
OS and ORR comparing the triplet group with the control group, determined by blinded central review, served as the study’s primary endpoints. OS for the doublet group vs. the control group, as well as PFS, duration of response and safety, served as secondary endpoints.
Patients on the triplet regimen achieved median OS of 9 months (95% CI, 8-11.4) compared with 5.4 months (95% CI, 4.8-6.6) for the control group (HR = 0.52; 95% CI, 0.39-0.7).
Patients assigned the doublet combination achieved median OS of 8.4 months (95% CI, 7.5-11), also significantly longer than that of the control group (HR = 0.6; 95% CI, 0.45-0.79).
ORR was 26% (95% CI, 18-35) with the triplet therapy vs. 2% (95% CI, 0-7) with the control regimen.
Future analyses will investigate the potential benefits of the triplet vs. doublet combinations, according to researchers.
The targeted therapies appeared well-tolerated, with adverse events consistent with those observed in previous trials with each combination. Grade 3 or higher adverse events occurred among 58% of patients in the triplet group, 50% in the doublet group and 61% in the control group.
The findings underscore the need for patients with metastatic colorectal cancer to be tested for BRAF mutations, according to Andrés Cervantes, MD, PhD, of the biomedical research institute INCLIVA at University of Valencia in Spain.
“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,” Cervantes, who was not involved with the study, said in the press release.
Cervantes said these findings ultimately may have broader implications for patients with BRAF mutations.
“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,” he said in the release. “However, it is important that we investigate its use in other settings where more patients with BRAF mutations may benefit, including those with less advanced metastatic disease and possibly in the adjuvant setting after primary surgery with curative intent.” – by Jennifer Byrne
Reference:
Kopetz S, et al. Abstract LBA-006. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.
Disclosures: HemOnc Today could not confirm the authors’ relevant financial disclosures at the time of publication.
Photo credit: European Society of Medical Oncology.
Perspective
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Michael S. Lee, MD
Activating BRAF V600E mutations are found in approximately 10% to 15% of patients with colorectal cancer and have long been known to be a strong prognostic biomarker for inferior survival. However, until recently, there was not clear evidence indicating that BRAF V600E mutations could predict for benefit from any particular therapy. Indeed, there was significant disappointment with the failure of BRAF inhibitor monotherapy to yield any significant effect in colorectal cancer.
However, the BEACON CRC trial definitively demonstrates the actionability of BRAF mutations in metastatic colorectal cancer to predict for effective targeted therapies and provide a new treatment option for patients. The results of BEACON CRC clearly show a significant improvement in OS and PFS with either the triplet of encorafenib/cetuximab/binimetinib or the doublet of encorafenib/cetuximab over the alternative standard-of-care control arm of irinotecan-based chemotherapy plus cetuximab. The response rate was an impressive 26% with the triplet and 20% with the doublet, including 4% to 5% complete responses; however, response rate was noticeably better among patients receiving trial treatment in the second line rather than the third-line setting. Toxicities also were as expected for these agents and were manageable.
The results of BEACON CRC are practice-changing. First, all patients with metastatic colorectal cancer should be evaluated for BRAF V600E mutations, which is now not only prognostic but also predictive for effectiveness of targeted therapies. Second, treatment with doublet or triplet therapy should be used in the second- or third-line setting; given higher response rates seen in the second-line setting, I would likely counsel patients for second-line use. Third, treatment with a chemotherapy-free targeted regimen as in BEACON CRC would be preferred over a chemotherapy-including regimen.
Although cross-trial comparisons are not reliable, the SWOG1406 trial showed patients receiving the combination of vemurafenib (Zelboraf, Genentech), cetuximab and irinotecan had a median PFS of 4.3 months (95% CI, 3.6-5.7), which is comparable to the PFS in the BEACON CRC trial. Thus, with the current data we have, I would favor giving treatment with a doublet or triplet therapy without including irinotecan.
There are several opportunities to continue exploring. We are awaiting more results from BEACON CRC to better describe outcomes comparing the doublet and triplet therapies to determine which patients would be best served with doublet vs. triplet therapy, in particular with an eye toward toxicity profiles, cost and quality of life. Additionally, BRAF mutations are enriched among microsatellite instability-high colorectal cancer, and the optimal sequence or combination of immunotherapy and targeted therapy remains to be determined. Moreover, non-V600E BRAF mutations, with very different cell signaling, are found in a small group of patients with colorectal cancer. At present the best treatment approach for these patients is not well defined, and studies of doublet or triplet therapy in these patients would be valuable.
Finally, it is not known whether doublet or triplet therapy should be used in other contexts for BRAF V600E-mutant colorectal cancer, such as the first-line or adjuvant settings. Ongoing investigation will be helpful to determine these answers.
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