LBA-5 ANCHOR CRC: a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer

Background BRAFV600E mutations are identified in 8-15% of metastatic colorectal cancer (mCRC) patients and confer a poor prognosis. In patients with BRAFV600E-mutant mCRC, the combination of encorafenib (ENCO) + cetuximab (CETUX) ± binimetinib (BINI) in second- and third-line therapy has demonstrated improved outcomes compared to standard therapies (BEACON CRC study). The ANCHOR CRC study was designed to investigate the triplet combination (ENCO + BINI + CETUX) in the first line setting of this population. Methods ANCHOR CRC is an open-label, single arm, two-stage design, phase 2 study in patients with BRAFV600E-mutant mCRC who did not receive any prior systemic therapy for metastatic disease. Patients received ENCO 300 mg orally QD + BINI 45 mg orally BID and CETUX IV weekly (250mg/m2 after a first dose of 400mg/m2) for the first 28 weeks and then once every two weeks (500mg/m2). The primary endpoint was confirmed Objective Response Rate (cORR) based on local review; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Analysis for Stage 1 was performed after the first 40 evaluable patients with a centrally confirmed BRAFV600E mutation had completed four post-baseline tumor assessments or discontinued. At least 12 responses in Stage 1 were needed to initiate Stage 2 and to enroll 50 additional patients to complete the recruitment with a total of 90 patients in the study. Stage 1 analysis results are presented here. Results Forty-one BRAFV600E-mutant mCRC patients with a median age of 67 years old (61% of the patients were ≥ 65 years old) were enrolled in Stage 1 and received the triplet combination as first line metastatic treatment. At study entry, 56% of patients presented with ECOG PS 1, 78% had metastases to at least 2 organs and 51% had peritoneal metastasis. Forty patients were evaluable for efficacy (BRAFV600E mutation was not centrally confirmed for one patient). The investigator assessed cORR was 50% (95% confidence interval [CI], 33.8-66.2) with 85% of patients having a decrease in tumor size. The investigator measured median PFS was 4.9 months (95% CI, 4.4-8.1). Adverse events were consistent with those observed in prior studies with this triplet combination. Grade 3 or higher adverse events were seen in 68% of patients, the most common being: diarrhea (15%), acute kidney injury (12%) and anemia (12%). Conclusion The ANCHOR CRC study is the first prospective study using a BRAF inhibitor-based therapy in first line BRAFV600E-mutant mCRC. Despite the high risk features of the population enrolled in Stage 1, including high proportion of patients ≥ 65 years old and advanced stage at diagnosis (multiple metastatic sites with frequent peritoneal carcinomatosis), most patients had tumor regression. The safety profile was acceptable and toxicities remained manageable. The Stage 1 analysis exceeded the minimal number of confirmed responses and proceeded to enroll 54 additional patients in Stage 2 to complete the study recruitment.