1. BEACON CRC is a multicenter, randomized, phase 3 clinical trial evaluating the triplet combination of binimetinib (BINI, a MEK inhibitor) + encorafenib (ENCO, a BRAF inhibitor) + cetuximab (CETUX, an EGFR antibody) for the treatment of metastatic colorectal cancer.
2. Preliminary analysis of the Safety Lead-in Study for the BEACON CRC reveals that the triplet combination is generally well tolerated and has promising clinical activity with an overall response rate of 41%.
Evidence Rating Level: 2 (Good)
Study Rundown: BRAF oncogene mutations are detected in 10%-15% of metastatic colorectal cancer (mCRC) cases and are associated with a poor prognosis and incomplete response to therapy. The current standard-of-care treatment involves a combination of CETUX + irinotecan (a topoisomerase inhibitor). Among patients receiving this combination treatment, only 21% exhibit tumor shrinkage, and over half of patients experience more than two-fold increases in tumor volume.
In a prior phase 2 study, patients who were treated with a combination of CETUX and ENCO showed superior responses to CETUX + irinotecan. Several other studies have demonstrated that addition of a MEK inhibitor to a BRAF inhibitor results in improved safety and efficacy relative to BRAF inhibition alone. The BEACON CRC is a 3-arm phase 3 clinical trial whose purpose is to evaluate the efficacy of triplet therapy (BINI + ENCO + CETUX) relative to doublet therapy (ENCO + CETUX) and the current standard-of-care (a topoisomerase inhibitor + CETUX). As the triplet combination of BINI + ENCO + CETUX had not been previously studied, a safety lead-in (SLI) for the study was designed to evaluate the safety of this combination prior to the phase 3 portion of the study.
Of the twenty-nine BRAF mutation-positive patients in the SLI, 41% responded to the triple therapy, and an additional 31% had extended survival duration (≥6 months). A complete response was observed in 3/29 patients. Response to therapy was monitored based on radiologic imaging and by measuring levels of two mCRC tumor markers: carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Observed adverse events were consistent with known BRAF, MEK, and EGFR inhibitor toxicities, and the rate of severe skin toxicities was generally lower than that observed for CETUX alone or CETUX + standard chemotherapy. These results suggest that the triplet combination of BINI + ENCO + CETUX may have superior safety and efficacy compared to the current standard-of-care treatment and compared to the doublet therapy of ENCO + CETUX. These promising results from the SLI have led to the initiation of the phase 3 portion of the BEACON CRC trial, which is currently enrolling patients.
Relevant Reading: Emerging treatment options for BRAF-mutant colorectal cancer
In-Depth [clinical trial]: Thirty patients were treated in the SLI. Twenty-nine of these patients had tumors with the BRAF V600E mutation, while one patient was found to have a different mutation. All patients included in the study had histologically or cytologically confirmed mCRC with disease progression after 1 or 2 prior regimens in the metastatic setting. Thirteen patients had received prior treatment with irinotecan. None of the patients had prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab, or other anti-EGFR inhibitors. The median age of patients in the study was 59, with a range of 38-77. Twenty-two of the patients had more than one organ with metastases, with the greatest proportion of metastases occurring the liver, lymph nodes, peritoneum, and lung.
All patients were treated with a single starting dose of ENCO 300mg once daily + BINI 45mg twice daily + CETUX at the standard weekly dose (400 mg/m2), then 250mg/m2 administered in 28-day cycles. Safety data were periodically reviewed by an independent data monitoring committee. Efficacy was assessed based on radiologic imaging (e.g. CT, MRI, x-ray, whole-body bone scans) and tumor assessments were performed every 6 weeks after the first dose for the first 24 weeks, and then every 12 weeks. Changes in the tumor markers CEA and CA19-9 were assessed based on blood samples collected on cycle 1 day 1 and day 1 of subsequent cycles, and at the end of treatment.
Grade ¾ adverse events (AEs) reported in >10% of patients were fatigue (4 patients), urinary tract infection (3 patients), increased aspartate aminotransferase (AST; 3 patients), increased blood creatine phosphokinase (3 patients), and skin rash (1 patient).
The median time on study treatment was 7.9 months (range 1.0-11.9 months) and 10 patients remained on study treatment at the time of data cutoff. At least a partial response was observed in 14/29 patients, including a complete response in 3/29 patients. The objective response rate in patients with 1 previous line of therapy was 62% and in patients with 2 previous lines of therapy was 31%. The majority of responses were observed at first tumor assessment (6 weeks) and the median duration of response was 5.4 months (95% CI, 4.1-7.1 months). Preliminary estimate of median progression free survival (PFS) is 8.0 months (95% CI, 5.6-8.5 months), substantially improved over historical standards of care which have a median PFS of approximately 2 months. Among patients with elevated baseline values, CEA and CA19-9 decreased in all patients.
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