Survival outcomes of first-line anti-EGFR antibody versus anti-VEGF therapy stratified by DNA methylation status in right-sided metastatic colorectal cancer: A propensity score weighting analysis.

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156 Background: The clinical benefit of anti-EGFR antibodies (anti-EGFR ab) is generally limited in right-sided metastatic colorectal cancer (mCRC). Recent evidence suggests genome-wide DNA methylation may influence anti-EGFR efficacy (Cancer Sci, 2022). We evaluated whether DNA methylation could identify patients deriving comparable benefit from anti-EGFR ab and anti-VEGF therapy. Methods: We retrospectively analyzed unresectable right-sided RAS wild-type mCRC patients treated first-line with anti-EGFR ab or anti-VEGF therapy. DNA methylation was assessed using OncoGuide EpiLight and classified as high (HM) or low (LM). Endpoints were response rate (RR), depth of response (DpR), PFS, and OS, analyzed by methylation status and molecular subtype. Propensity score weighting (PSW) balanced baseline characteristics. Results: Among 198 patients, 85 and 59 RAS/BRAF wild-type received anti-EGFR (Group E) and anti-VEGF (Group V), respectively. LM proportion was 78.8% (67/85) in Group E and 59.3% (35/59) in Group V. After PSW, RR, DpR, PFS and OS by DNA methylation and molecular subtype are shown in the Table. LM patients in Group E tended to have higher RR and markedly better DpR than those in Group V, while PFS and OS were comparable. Conclusions: Low methylation may identify a subset of right-sided mCRC patients who benefit similarly from anti-EGFR and anti-VEGF therapy. These findings support prospective validation of DNA methylation as a predictive biomarker. DNA methylation status Group RAS wild RAS/BRAF wild RAS/BRF wild/MSS/HER2 (-) RR (event/N;%) All E 69/125=55.2% 48/85=56.5% 47/76=61.8% V 33/73=45.2% 29/59=49.2% 26/54=48.1% P value 0.19 0.40 0.15 LM E 50/75=66.7% 43/67=64.2% 43/61=70.5% V 21/36=58.3% 20/35=57.1% 19/34=55.9% P value 0.41 0.53 0.18 DpR (N;median (range)) All E 115, 26.0(-85.2 - 100) 80, 39.5(-74 - 100) 71, 42.1(-51.4 – 100) V 62, 17.4(43 – 61.6) 51, 21(-43 – 61.6) 46, 21(-43 – 61.6) P value 0.0041 0.012 0.0030 LM E 72, 44.5(-44 – 100) 64, 44(-44 – 100) 58, 45.5(-44 – 100) V 32, 30.5(-41 – 61.6) 31, 30(41 – 61.6) 30, 29(-41 – 61.6) P value 0.0086 0.014 0.0025 PFSmedian months (95% CI) All E 9.95(8.64 -12.0 ) 11.5(9.17 - 16.3) 11.5(9.17 - 18.6) V 11.7(10.6 - 17.8) 12.7(10.9 - 18.2) 12.7 (10.6 - 18.0) HR (95% CI) 0.83 (0.61-1.13) 0.96 (0.67-1.38) 1.03 (0.71-1.5)

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