Encorafenib and cetuximab with/without binimetinib therapies for patients with <i>BRAF</i> -mutated metastatic colorectal cancer with prognostic factors: The BEETS trial (JACCRO CC-18).

164 Background: BRAF inhibitor combination therapies, triplet (encorafenib, binimetinib and cetuximab) and doublet (encorafenib and cetuximab), have been approved for BRAF -mutated metastatic colorectal cancer (mCRC) in Japan. The treatment with triplet is recommended for patients (pts) with clinical prognostic factors according to the sub-group analysis of the BEACON CRC trial. However, it is unclear whether the treatment strategy is useful. We therefore conducted a study on the use of combination therapy with triplet or doublet based on observational study that accumulated real world data. Methods: The BEETS trial was a multicenter observational study to prospectively evaluate the efficacy and safety of BRAF inhibitor combination therapy as a 2nd- or 3rd-line treatment in pts with BRAF -mutated mCRC in clinical practice [UMIN000045530]. Two hundred pts were assigned to either triplet or doublet therapy based on the physician’s choice. The primary endpoint was overall survival (OS). The secondary endpoints included overall response rate (ORR), disease control rate, progression-free survival (PFS), and safety. The exploratory analysis was performed to evaluate the efficacy of triplet and doublet therapies in all pts and pts with clinical prognostic factors (PS1, 3 or more metastatic sites, elevated CRP value, or primary tumor present) using inverse probability weighting (IPW) analysis based on propensity scores to account for potential cofounding factors. Results: Among 203 pts enrolled from Oct 2021 to Nov 2023, 195 pts were evaluable (median age 67 years old, 52% male, ECOG PS 0/1/2 55%/39%/6%, no. of prior regimens 1/2 85%/15%, right-sided primary 61%, MSI-high 7%, triplet regimen 57%). Median OS was 13.2 months (95%CI 11.4-17.4) with 1y-survival rate of 53%, and median PFS was 4.9 months. Comparing the triplet and doublet using IPW, the median OS and PFS were comparable between the two treatments (triplet vs. doublet; 16.0 months vs. 13.6 months [HR 0.88, 95%CI 0.53-1.48] and 5.7 months vs. 4.8 months [HR 0.87, 95%CI 0.59-1.28]). In 139 pts with any prognostic factors, median OS and 1y-survival rate were 13.2 months vs. 9.6 months [HR 0.80, 95%CI 0.45-1.43] and 54% vs. 42%, median PFS and ORR were 5.3 months vs. 4.2 months [HR 0.75, 95%CI 0.48-1.19] and 34% vs. 42%, in the triplet vs. doublet therapy, respectively. Conclusions: Our study demonstrated that BRAF inhibitor doublet therapy is a reasonable treatment for BRAF -mutated mCRC. However, triplet therapy may be a clinically useful for pts with clinical prognostic factors. Clinical trial information: UMIN000045530 .