Survival outcomes of human epidermal growth factor receptor 2 (HER2)–amplified and HER2-mutated left-sided colorectal cancer (CRC) patients treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs).

3543 Background: Current guidelines support the use of anti-EGFR mAbs in left-sided CRCs without mutations in KRAS , NRAS and BRAF . Recent reports indicated that HER2-amplified CRCs might respond worse to anti-EGFR mAbs, whereas HER2-mutated CRCs and their response to anti-EGFR mAbs remained relatively unexplored. In this study, we assembled the largest collection of HER2-altered (amplified or mutated) CRCs to date from a real-world database with the goal of describing the impact of these alterations on anti-EGFR mAb therapy. Methods: Patients profiled by Caris Life Sciences with microsatellite stable, left-sided CRC without mutations in KRAS / NRAS / BRAF who received anti-EGFR mAbs (cetuximab or panitumumab) were included in this study. Microsatellite stability, amplifications (copies ≥6), and pathogenic or likely pathogenic mutations were identified by NGS. Patient outcomes were obtained from insurance claims data. Overall survival (OS) was calculated from start of anti-EGFR mAbs to time of last clinical contact. Time on treatment (ToT) was calculated from start to end of anti-EGFR mAbs. Hazard ratios and p-values were calculated using the Cox proportional hazards model and log-rank test. Results: A total of 3217 patients were included for analysis. Patients were stratified into 3 cohorts: HER2-amplified (N=114), HER2-mutated (N=46), and HER2-normal (N=3057). The HER2-mutated group was older than the HER2-amplified and the HER2-normal groups (median: 64.5 vs 56 and 58 years, p=0.006); no other significant differences were found in patient demographics. The HER2-mutated group had worse OS and ToT than the HER2-normal group (median OS 12.4 vs 25.9 months, HR 1.57, p=0.013; median ToT 4.3 vs 6.7 months, HR 1.40, p=0.036). The HER2-amplified group showed no significant differences in OS but worse ToT compared to the HER2-normal group (median OS 26.1 vs 25.9 months, HR 0.98, p=0.856; median ToT 5.8 vs 6.7 months, HR 1.25, p=0.035). In multivariate Cox regressions accounting for age, gender, and receipt of HER2-targeted therapy, the HER2-mutated group had worse OS and ToT compared to HER2-normal group (OS HR 1.66, p=0.007; ToT HR 1.55, p=0.007), while the HER2-amplified group showed no significant differences in OS and ToT compared to HER2-normal group (OS HR 1.14, p=0.398; ToT HR 1.26, p=0.073). Conclusions: In this large, real-world cohort of KRAS / NRAS / BRAF wild-type, left-sided CRCs receiving anti-EGFR mAbs, HER2-mutated patients had worse ToT and OS than HER2-normal patients, whereas HER2-amplified patients showed no difference in OS compared to HER2-normal patients. These findings suggest that alternative treatment studies should be explored in HER2-mutated left-sided CRCs, underscoring the importance of additional biomarker-directed studies in this patient cohort.