The FDA has granted breakthrough therapy designation to a novel triplet combination targeting BRAF V600E-mutant metastatic colorectal cancer (mCRC), marking a significant regulatory milestone for patients with this aggressive disease subtype. The designation covers the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) for patients who have received 1 or 2 prior lines of treatment in the metastatic setting.
Promising Clinical Data Drives Regulatory Recognition
The breakthrough designation is based on compelling data from the safety lead-in phase of the ongoing randomized phase III BEACON CRC trial (NCT02928224). The triplet regimen demonstrated a confirmed overall response rate (ORR) of 48% and a 1-year overall survival (OS) rate of 62%, according to findings presented at the 20th ESMO World Congress on Gastrointestinal Cancer in June 2018.
"We are delighted that the FDA has recognized the potential of this combination for patients with BRAF V600E-mutant metastatic colorectal cancer," said Victor Sandor, MD, chief medical officer at Array BioPharma, the manufacturer of binimetinib and encorafenib. "As there are no regimens approved specifically for BRAF V600E-mutant mCRC, this designation provides us with the opportunity to work closely with the FDA to potentially accelerate our effort to bring an important treatment option to these patients in critical need."
Study Design and Patient Population
The safety lead-in phase of the open-label, global phase III BEACON CRC trial enrolled 30 patients with mCRC who had experienced disease progression following 1 or 2 prior regimens. All patients except one had a BRAF V600E mutation, with one patient having microsatellite instability-high disease. The treatment regimen consisted of encorafenib at 300 mg daily, binimetinib at 45 mg twice daily, and cetuximab administered per label instructions.
Efficacy Outcomes Show Substantial Improvement
At 12.6 months of follow-up, the median overall survival had not yet been reached. The median progression-free survival was 8 months (95% CI, 5.6-9.3) and remained consistent regardless of whether patients had received 1 or 2 prior treatment lines. Among patients who had received only 1 prior line of therapy, the overall response rate reached 62%.
Axel Grothey, MD, from the Division of Hematology/Oncology at Mayo Clinic, emphasized the clinical significance of these results: "The results of the BEACON CRC safety lead-in demonstrate substantial improvements in efficacy outcomes when compared to current approved standard of care benchmarks in patients with BRAF-mutant metastatic CRC. The median progression-free survival of 8 months is a meaningful improvement compared to the benchmark of about 2 months, and the overall survival of 62% at 12 months is very promising given that with current approved standards of care, half of patients will succumb to their disease within 4 to 6 months."
Safety Profile and Tolerability
The triplet combination demonstrated a manageable safety profile. Grade 3/4 adverse events occurring in at least 10% of patients included fatigue (13%), anemia (10%), increased blood creatine kinase (10%), and increased AST (10%).
Addressing Critical Unmet Medical Need
The breakthrough designation addresses a significant gap in treatment options for patients with BRAF-mutant mCRC. As Grothey noted, "These data underscore the potential of this triplet combination to benefit patients with BRAF V600E-mutant metastatic CRC, who, despite their poor prognosis, currently have limited effective treatment options."
Ongoing Development and Future Plans
Based on the positive results from the safety lead-in phase, enrollment in the randomized portion of BEACON CRC continues. In this phase of the study, patients are randomized to receive encorafenib/binimetinib plus cetuximab; encorafenib/cetuximab; or investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
The breakthrough therapy designation will expedite the development and review process for this novel triplet combination, potentially bringing this treatment option to patients with BRAF V600E-mutant mCRC more rapidly. This regulatory recognition builds on the FDA's June 2018 approval of encorafenib/binimetinib for treating patients with BRAF-mutant unresectable or metastatic melanoma.
