Efficacy and safety of T-DXd versus Other HER2-targeted therapies in second-line and later settings for HER2-positive metastatic breast cancer: A Bayesian network meta-analysis

Background HER2-positive advanced breast cancer remains challenging after trastuzumab-based therapy because available regimens differ in survival, response, and toxicity. We compared therapies used in second-line and later settings. Methods This PRISMA-NMA-compliant review was registered with PROSPERO (CRD420251244047). PubMed, Embase, Web of Science, and CENTRAL were searched through July 24, 2026. Phase II or III randomized controlled trials after trastuzumab-based therapy were eligible. Bayesian network meta-analysis summarized PFS and OS as hazard ratios and confirmed ORR and safety outcomes as odds ratios. Random-effects models were used where heterogeneity was estimable; fixed-effect Bayesian models were used for the sparse SAE and ILD/pneumonitis networks. DoR was analyzed exploratorily using a fixed-effect Bayesian normal model after prespecified conversion of arm-level summary statistics; TTP was not quantitatively synthesized when the required summary measures were unavailable or clinically non-equivalent. Results Sixteen reports representing seven independent randomized trial families and 3,339 unique randomized participants were included. Relative to T-DXd, T-DM1 had less favorable PFS (HR 3.30, 95% CrI 2.06–5.28) and OS (HR 1.52, 1.19–2.01). However, T-DXd was not represented in the second-line-only OS network or the Asia-dominant PFS/OS networks; therefore, its survival ranking reflects evidence primarily from mixed-line, non-Asia-dominant trials. T-DXd produced higher confirmed ORR than Lap-Cap (OR 7.43, 3.80–13.16), PTN-Cap (OR 3.35, 1.24–8.19), and T-DM1 (OR 6.31, 3.98–10.32). DoR showed no clear between-treatment difference in the EMILIA/NALA network, and TTP could not be quantitatively synthesized. Any-grade AE estimates did not indicate a safety advantage for T-DXd. SAE comparisons were also inconclusive: T-DM1 vs Lap-Cap OR 0.90 (0.67–1.21) and T-DXd vs T-DM1 OR 1.30 (0.87–1.93). T-DXd had higher ILD/pneumonitis odds than T-DM1 (OR 5.55, 2.79–12.16); LVD differences were unclear. Conclusion Within the connected overall networks, T-DXd showed a favorable survival profile and the highest confirmed ORR, although its survival ranking was not estimable in the second-line-only OS or Asia-dominant survival networks. Its increased ILD/pneumonitis risk relative to T-DM1 is clinically important. Indirect survival comparisons and sparse safety networks require cautious interpretation.