BEACON Triplet Therapy for BRAF Mutant Metastatic Colorectal Cancer Shows Promise Interview with:

Scott Kopetz, M.D., Ph.D., FACP Associate Professor Department of Gastrointestinal Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Dr. Kopetz

Scott Kopetz, M.D., Ph.D., FACP
Associate Professor Department of Gastrointestinal Medical Oncology
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX What is the background for this study? What are the main findings?

Response: The BRAF mutation carries a very poor prognosis for patients with advanced colo-rectal cancer (CRC), and is particularly unresponsive after first-line therapy, so additional treatment options for these patients are needed. While treatment with a BRAF inhibitor alone has not been effective in treating this disease, combination therapies have shown promise and lead to the initiation of the BEACON study. The safety lead-in phase of the BEACON CRC trial was designed to assess the safety and tolerability of encorafenib, binimetinib  and cetuximab triplet combination prior to the Phase 3 randomized portion of the study. Thirty patients were treated in the safety lead-in and received the triplet combination (encorafenib 300 mg daily, binimetinib 45 mg twice daily, and cetuximab per label). Out of the 30 patients, 29 had a BRAFV600E mutation. Microsatellite instability-high (MSI-H) (resulting from defective DNA mismatch repair) was detected in only 1 patient. The triplet demonstrated good tolerability, supporting initiation of the randomized portion of the study. In addition, promising initial clinical activity was observed.

In patients with the BRAFV600E mutation, the estimated median progression-free survival (mPFS) at the time of analysis was 8 months. The confirmed overall response rate (ORR) in patients with the BRAFV600E mutation was 48%, and 3 patients achieved complete responses (CR). Further, the ORR was 62% in the 16 patients (10/16) who received only one prior line of therapy.

Additionally, the triplet combination was generally well-tolerated. Two patients discontinued treatment due to AEs with only one of these considered related to treatment. The most common grade 3 or 4 AEs seen in at least 10% of patients were fatigue (4/30), urinary tract infection (3/30), increased aspartate aminotransferase (AST; 3/30) and increased blood creatine kinase (CK; 3/30). What should readers take away from your report?

Response: These data represent substantial improvements compared to several separate historical published standard of care benchmarks for this population. To put these data in context, the observed mPFS of 8 months exceeds historical benchmarks of 2 months for mPFS, and 4 to 6 months for mOS, with current standards of care in this patient population. These results are also substantially better than any prior experimental combinations that have been reported, where response rates have generally been in the range of 15-25% with mPFS of 4-5 months. What recommendations do you have for future research as a result of this work?

Response: The safety lead-in data are encouraging, as they support the randomized portion of the BEACON CRC trial, which is designed to assess the efficacy of encorafenib in combination with cetuximab with or without binimetinib compared to cetuximab and irinotecan-based therapy in patients with BRAF-mutant advanced CRC. This is the first and only Phase 3 trial designed to study a BRAF/MEK combo targeted therapy in BRAF-mutant advanced CRC, a difficult-to-treat subtype of CRC that impacts about 10% of CRC patients. 


2018 Gastrointestinal Cancers Symposium

ASCO presentation:

BEACON CRC Study Safety Lead-in (SLI) in Patients With BRAFV600E Metastatic Colorectal Cancer (mCRC): Efficacy and Tumor Markers
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