Triplet Gets Breakthrough Therapy Designation in Colorectal Cancer

The FDA has granted a breakthrough therapy designation to the combination of the BRAF inhibitor Braftovi (encorafenib), the MEK inhibitor Mektovi (binimetinib), and the EGFR inhibitor Erbitux (cetuximab) for the treatment of patients with BRAF V600E—mutant metastatic colorectal cancer (mCRC) following one or two prior lines of treatment in the metastatic setting.

The designation, which will expedite the development and review of the novel triplet in this setting, is based on data from the safety lead-in phase of the ongoing randomized phase 3 BEACON CRC trial (NCT02928224). Study findings presented in June 2018 at the 20th ESMO World Congress on Gastrointestinal (GI) Cancer showed a confirmed overall response rate (ORR) of 48 percent and a one-year overall survival (OS) rate of 62 percent 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, M.D., chief medical officer, Array BioPharma, the manufacturer of binimetinib and encorafenib, said in a statement.

"As there are no regimens approved specifically for BRAFV600E—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," added Sandor.

The safety lead-in phase of the open-label, global phase 3 BEACON CRC trial included 30 patients with mCRC who had disease progression following one or two prior regimens. All except one patient had a BRAF V600E mutation, and there was one patient with microsatellite instability-high disease. Patients received Braftovi at 300 mg daily, Mektovi at 45 mg twice daily, and Erbitux per label.

At 12.6 months’ follow-up, the median OS had not yet been reached. The median progression-free survival was eight months and was consistent regardless of whether patients had received one or two prior treatment lines. Among patients who had received only one prior line of therapy, the ORR was 62 percent.

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

In a statement released at the time of presentation of the safety lead-in data at the World GI Congress, Axel Grothey, M.D., 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 eight months is a meaningful improvement compared to the benchmark of about two months, and the overall survival of 62 percent at 12 months is very promising given that with current approved standards of care, half of patients will succumb to their disease within four to six 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 3 study, patients are randomized to Braftovi / Mektovi plus Erbitux; Braftovi / Erbitux; or investigator's choice of either irinotecan/ Erbitux or FOLFIRI/ Erbitux.

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