Comparative safety and efficacy of trastuzumab deruxtecan (T-DXd) in HER2-positive and HER2-low gastrointestinal malignancies: A systematic review and meta-analysis.

e16337 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate approved for HER2-positive gastrointestinal (GI) cancers, with emerging evidence in HER2-low tumors. This systematic review and meta-analysis evaluated and compared T-DXd safety and efficacy in HER2-positive versus HER2-low GI malignancies. Methods: Following PRISMA guidelines, we searched Medline, Embase, Cochrane Central, and ClinicalTrials.gov. Of 7,060 studies, three met inclusion criteria (160 patients). HER2-positive was defined as IHC 3+ or IHC 2+/ISH-positive; HER2-low as IHC 1+ or IHC 2+/ISH-negative. NIH quality assessment was performed. Pooled analyses used the 'meta' package (R programming). Results: Median age was 58.5 years (range: 27–79); 68% male. Median follow-up: 4.2 months (range: 0.5–26.8). In HER2-positive patients, pooled ORR was 27.5% (95% CI: 19.6–36.1; I² = 0%), lower than pivotal trials (42-51%), likely reflecting more heavily pretreated populations. Median PFS and OS were 6.0 months (95% CI: 4.1–8.7) and 11.5 months (95% CI: 8.8–20.8), respectively, versus 5.6-6.9 and 12.5-14.7 months in DESTINY-Gastric trials. Median DoR was 7.0 months (95% CI: 5.8–9.5). In HER2-low patients, pooled ORR was 3.5% (95% CI: 0.0–24.5; I² = 91%), substantially lower than exploratory cohorts (9.5-26.3%). High heterogeneity (I² = 91-92%) limits interpretation. Despite low ORR, disease control rate was 76.3% (95% CI: 43.3–97.7), suggesting benefit through disease stabilization. Median PFS and OS were 3.25 months (95% CI: 1.4–7.1) and 7.55 months (95% CI: 3.0–NE). Median DoR was 7.6 months. Adverse events included myelosuppression, gastrointestinal toxicity, and interstitial lung disease (ILD)/pneumonitis. ILD/pneumonitis occurs in 10-14% of patients (predominantly grade 1-2), with grade ≥3 in 1.5-2.8% and rare fatalities (0.7-1.2%). No significant differences in adverse event incidence were observed between HER2 groups. Conclusions: T-DXd demonstrates efficacy in HER2-positive GI malignancies and is established as standard second-line therapy based on DESTINY-Gastric04. Although HER2-low response rates are limited, high disease control rates warrant further investigation. HER2-low remains investigational and not approved for T-DXd. High heterogeneity in HER2-low results and lack of standardized definitions in GI cancers are significant limitations. Larger prospective trials with standardized HER2-low definitions are needed. Rebiopsy to confirm HER2 status after prior anti-HER2 therapy is recommended.