Impact of anti-EGFR and anti-VEGF antibodies on survival in BRAF ^V600E mutated metastatic colorectal cancer: A pooled analysis of eight clinical trials performed in the first-line treatment of mCRC (German AIO Study Group).

3543 Background: BRAF V600E mutation in metastatic colorectal cancer (mCRC) is associated with poor prognosis. Registrational approval of anti-EGFR antibodies does not exclude their use in BRAF V600E mutated (mut) mCRC, while current guidelines explicitly advise against the use of anti-EGFR-directed therapy and recommend the use of chemotherapy plus anti-VEGF antibodies. The present analysis of single-patient data evaluates the therapeutic benefit from anti-EGFR- vs. anti-VEGF-directed therapy in BRAF V600E mut mCRC. Methods: We conducted a pooled analysis of eight first-line AIO-studies (FIRE-1, FIRE-3, FIRE-4, FIRE-4.5, CIOX, XELAVIRI, PANAMA, VOLFI) including 251 evaluable pts with BRAF V600E mut and RAS wild-type mCRC. Right-sided primary tumors (RSPT) included tumors from the caecum to the colon transversum, while left-sided tumors (LSPT) included the splenic flexure to the rectum. Results: Of 251 BRAF V600E mut pts, exact primary tumor location was available in 230 pts. In this cohort, 117 were male (50.9%) and 113 female (49.1%). LSPT was observed in 106 (46.1%) pts compared to 124 (53.9%) with RSPT. In the entire cohort, median OS (mOS) of LSPT vs. RSPT did not differ significantly (15.2 months vs. 13.4 months; HR 0.96; 95% CI, 0.70–1.29; P=0.77). Pts with LSPT showed a numerical survival benefit with anti-EGFR therapy compared to anti-VEGF therapy (17.8 months vs. 11.8 months; HR 0.71; 95% CI, 0.45–1.14; P=0.16). This effect was observed independent of sex. In contrast, pts with RSPT showed a trend towards inferior outcome with anti-EGFR vs. anti-VEGF therapy (11.6 months vs. 17.1 months; HR 1.31; 95% CI, 0.84–2.05; P=0.23). This effect was primarily driven by females, who experienced a significant survival disadvantage with anti-EGFR therapy (10.2 months vs. 17.1 months; HR 1.85; 95% CI, 1.05–3.25; P=0.031). For males, however, both anti-VEGF and anti-EGFR antibodies were associated with comparable outcome. Conclusions: The present analysis performed in the first-line treatment of BRAF V600E mut mCRC suggests a survival benefit from anti-EGFR antibodies in pts with LSPT, independent of gender. Male pts with RSPT appear to derive comparable benefit from anti-EGFR and anti-VEGF antibodies, while female pts exhibit a survival disadvantage from anti-EGFR antibodies. Clinical trial information: NCT00433927 (FIRE-3), NCT02934529 (FIRE-4), NCT04034459 (FIRE-4.5), NCT01249638 (ML22011), NCT00254137 (CIOX), NCT01991873 (PANAMA), NCT01328171 (VOLFI). [clinicaltrials.gov].