Abstract Background: HER2-positive (HER2-amplified, IHC3+) microsatellite-stable (MSS), metastatic colorectal cancer (mCRC) represents a small but clinically meaningful subgroup with aggressive biology and limited responsiveness to standard chemotherapy. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate, has shown encouraging activity in DESTINY-CRC01 and DESTINY-CRC02. However, real-world effectiveness of T-DXd remains unclear due to variability in comorbidities, performance status, treatment sequencing, and prior therapy exposure. This study evaluated real-world overall survival (OS) with T-DXd versus standard chemotherapy in patients with MSS, HER2-amplified mCRC to assess effectiveness outside trial settings. Methods: De-identified TriNetX data (2010-2025) were used to identify adults (18 years) with HER2-amplified mCRC treated with either second-line chemotherapy (FOLFOX, FOLFIRI, or CAPOX ± bevacizumab) or T-DXd as second-line of treatment. Because anti-EGFR therapy is ineffective in HER2-amplified disease, cetuximab- or panitumumab-treated patients were excluded. Patients were assigned to cohorts based on the line in which T-DXd or standard chemotherapy was initiated. Propensity score matching (1:1) balanced age, sex, comorbidities, metastatic burden, and prior therapies. OS was evaluated using Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards models. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported; significance was defined as two-sided P ≤ 0.05. Results: Two cohorts were identified: standard chemotherapy (n = 9,135) and T-DXd (n = 1,977). Before matching, the T-DXd cohort was slightly older (67.4 ± 13.1 vs 66.5 ± 12.8 years; p = 0.006) and had more females (71% vs 49%; p = 0.0001). Both groups had received one prior line of systemic therapy. After 1:1 propensity score matching (n = 1,870 each), demographics, clinical characteristics, and prior treatments were well balanced. In the matched population, 1-year OS was only slightly different (83.0% vs 84.8%; p = 0.03). However, 5-year OS favored T-DXd (66.6% vs 62.1%; p = 0.0046). Multivariable Cox regression demonstrated a significantly higher mortality risk with standard chemotherapy compared with T-DXd (HR 1.14; 95% CI, 1.05-1.24; p = 0.0024). Conclusion: Although DESTINY-CRC01 evaluated T-DXd in the third-line or later setting, where patients had received a median of four prior therapies, this real-world analysis demonstrates that T-DXd is associated with improved long-term survival even when used in the second line setting, with fewer treatment-related adverse events. In patients with HER2-amplified mCRC, T-DXd showed a meaningful 5-year overall survival advantage compared with standard chemotherapy. Citation Format: Sumbal Aziz, Zunairah Shah, Mariam H. Ahmad, Jayasree Krishnan, Sohaib Asghar, Woojoo Lee, Sheheryar Kabraji, Kannan Thanikachalam. Real-world overall survival with trastuzumab deruxtecan versus standard chemotherapy in HER2-amplified MSS metastatic colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1303.
Aziz et al. (Fri,) studied this question.