Real-world survival comparison of second-line treatment strategies for patients with RAS/RAF wild-type, right-sided metastatic colorectal cancer.

73 Background: For patients with RAS/RAF wild type metastatic colorectal cancer (mCRC), systemic therapy usually includes fluoropyrimidine-based chemo + anti-VEGF or anti-EGFR targeted therapy. The PARADIGM trial established tumor sidedness as an important predictive biomarker for patients with RAS/RAF wild-type disease; in right-sided tumors, there was no survival difference between first-line chemo + anti-EGFR vs. chemo + anti-VEGF. However, there is no comparative data to guide second-line treatment decisions in this population. We aim to compare the effectiveness of second-line chemo + anti-EGFR versus chemo + anti-VEGF therapy for patients with RAS/RAF wild-type, right-sided mCRC who received first-line chemo + anti-VEGF. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data obtained from ~280 cancer clinics and curated via technology-enabled abstraction. Patients ≥18 years old with RAS/RAF wild-type, right-sided mCRC who received first-line therapy consisting of chemotherapy ((FOLFIRI or FOLFOX or CAPEOX) + anti-VEGF and initiated second-line chemotherapy with either anti-EGFR or anti-VEGF targeted therapy between January 2013-May 2024 were included. Multiple imputation with chained equations imputed missing values for sidedness, RAS/RAF status, and propensity score covariates (age, gender, year of diagnosis, synchronous/metachronous disease, MMR/MSI status, ECOG score, CEA level, and first-line therapy duration). Cox proportional hazards modeling with stabilized inverse probability of treatment weighting (IPTW) assessed the association of anti-EGFR vs anti-VEGF treatment with overall survival. Results: 4,444 patients received appropriate first-line treatment and received chemo + anti-EGFR or chemo + anti-VEGF in the second line. Across 25 imputations, an average of 444 patients met inclusion criteria: 175 patients received chemo + anti-EGFR and 269 patients received chemo + anti-VEGF. Following IPTW, baseline characteristics were balanced between treatment groups. Patients who received chemotherapy + anti-EGFR had a 24% increased hazard of death when compared with patients who received chemotherapy + anti-VEGF, though this was not statistically significant (HR 1.24, 95% CI 0.96 – 1.61, p=0.097). Conclusions: Among patients with RAS/RAF wild-type, right-sided mCRC who received first-line chemotherapy + anti-VEGF, there is some evidence to support continuing anti-VEGF therapy vs. switching to anti-EGFR therapy in the second line, though the result was not statistically significant. Future studies should explore predictive biomarkers for EGFR vs VEGF-directed treatment for this population to determine the patients most likely to benefit from anti-EGFR therapy during their disease course.