363P Prevalence of acquired (acq) genomic alterations (GAs) after progression on anti-EGFR mAb (EGFRi) based therapy in metastatic colorectal cancer (mCRC): A systematic review and meta-analysis

Abstract

While several studies have explored the evolving clonal profile of mCRC under stress of EGFRi using circulating tumor DNA (ctDNA), the heterogeneity and small samples limit our understanding of true prevalence of acq-GAs associated with EGFR resistance, and potential for concurrent chemotherapy to alter resistance patterns. A systematic literature search (PubMed + Google Scholar) was performed for studies assessing acq-GAs in ctDNA post progression on EGFRi based therapy (± chemotherapy) in mCRC. Data was extracted from 13 identified studies, categorized by their use of EGFRi in either first-line (1L) (N = 2) or second-line and beyond (2L+) (N = 11). The primary objective was to assess prevalence of acq-GAs of interest, expressly, those established as resistance mechanisms to EGFRi: KRAS, NRAS, BRAF, EGFR ectodomain mutations and ERBB2 and MET amplification. The pooled prevalence was calculated using a fixed effect model (heterogeneity assessed by I2 statistic). Across 13 examined studies, the net sample size was 825 (range 4 - 331) [1L (138) and 2L+ (687)] and 325 patients acq GAs at progression on EGFRi with a pooled prevalence of 39% (95%CI 36 – 41). This varied substantially by line of therapy with prevalence of 8% (95%CI 3 – 12) in 1L studies (I2 0%) significantly lower than 55% (95%CI 52 – 58) seen in 2L+ setting (I2 95%) (OR 0.07, 95%CI 0.04 – 0.13, P < 0.0001). Prevalence of specific acq-GAs was also lower in 1L compared to 2L+ studies (Table).Table: 363PGenomic AlterationPooled Prevalence1Comparison21L (%)2L+ (%)OR, 95%CIPMutationsAll RAS5400.08, 0.03-0.17<0.0001KRAS2290.05, 0.02-0.15<0.0001NRAS160.12, 0.01-0.660.0083BRAF190.08, 0.00-0.420.0002EGFR-ectodomain (ECD)2200.09, 0.03-0.26<0.0001AmplificationsERBB2270.23, 0.02-2.100.25MET0170.00, 0.00-0.310.00081. Pooled prevalence and its corresponding 95% confidence intervals (95%CI) were calculated by meta-analysis of extracted proportions of key GAs with Jamovi software. 2. Odds ratio (OR) and 95%CI were calculated using Fisher-exact test for comparison of prevalence between groups. Open table in a new tab Our analysis demonstrates that acquisition of key GAs associated with resistance to EGFRi in mCRC is rare with upfront use of anti-EGFR mAbs compared to later lines, indicating differing resistance mechanisms. This has implications for prospective trials examining EGFRi rechallenge strategies and its clinical use guided by acq-GAs and highlights need to address alternate resistance mechanisms.