FDA Grants Breakthrough Designation to Triplet Regimen for Metastatic CRC

The FDA has granted breakthrough therapy designation to a triplet combination regimen, which would expedite the development and review of the first treatment for BRAFV600E–mutant metastatic colorectal cancer (mCRC).

The FDA has granted breakthrough therapy designation to a triplet combination regimen, which would expedite the development and review of the first treatment for BRAFV600E—mutant metastatic colorectal cancer (mCRC).

The designation includes the combination use of the BRAF inhibitor encorafenib (Braftovi), the MEK inhibitor binimetinib (Mektovi), and the EGFR inhibitor cetuximab (Erbitux) to treat patients with BRAF V600E—mutant mCRC following 1 or 2 prior lines of therapy in the metastatic setting.

The designation is based on data from the safety lead-in phase of the ongoing randomized phase III BEACON CRC trial (NCT02928224). Study findings—which were presented at the 20th ESMO World Congress on Gastrointestinal (GI) Cancer—showed a confirmed overall response rate (ORR) of 48% and a 1-year overall survival (OS) rate of 62% with the regimen.

"We are delighted that the FDA has recognized the potential of this combination for patients with BRAF V600E—mutant metastatic colorectal cancer," Victor Sandor, MD, chief medical officer, Array BioPharma, the manufacturer of binimetinib and encorafenib, said in a statement.

"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," added Sandor.

The safety lead-in phase of the open-label, global phase III BEACON CRC trial included 30 patients with mCRC who had disease progression following 1 or 2 prior regimens. All except 1 patient had a BRAF V600E mutation, and there was 1 patient with microsatellite instability-high disease. Patients received encorafenib at 300 mg daily, binimetinib at 45 mg twice daily, and cetuximab per label.

At 12.6 months’ follow-up, the median OS had not yet been reached. The median progression-free survival was 8 months (95% CI, 5.6-9.3) and was 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 ORR was 62%.

Grade 3/4 adverse events (AEs) occurring in at least 10% of patients included fatigue (13%), anemia (10%), increased blood creatine kinase (10%,) and increased AST (10%).

In a statement released at the time of presentation of the safety lead-in data at the World GI Congress, Axel Grothey, MD, Division of Hematology/Oncology, Mayo Clinic, said, "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."

"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," added Grothey.

Based on the positive results from the safety lead-in phase, enrollment in the randomized portion of BEACON CRC is ongoing. In this part of the phase III study, patients are randomized to encorafenib/binimetinib plus cetuximab; encorafenib/cetuximab; or investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.

In June 2018, the FDA approved encorafenib/binimetinib for the treatment of patients with BRAF-mutant unresectable or metastatic melanoma, as detected by an FDA-approved test.


Array Biopharma Receives FDA Breakthrough Therapy Designation for Braftovi™ in Combination With Mektovi® and Cetuximab For BRAFV600E-Mutant Metastatic Colorectal Cancer. Array BioPharma Inc. investor.arraybiopharma.com/news-releases/news-release-details/array-biopharma-receives-fda-breakthrough-therapy-designation. Posted August 7, 2018. Accessed August 7, 2018.