Real-world brain metastasis outcomes with T-DXd versus tucatinib-based therapy in second-line HER2-positive metastatic breast cancer.

Abstract

1051 Background: Brain metastases (BM) remain a major cause of morbidity and mortality in HER2+ metastatic breast cancer (MBC). HER2CLIMB established tucatinib/trastuzumab/capecitabine (TTC) as a standard regimen with CNS activity, including improved outcomes in patients (pts) with active BM. DESTINY-Breast12 further demonstrated clinically meaningful intracranial outcomes with trastuzumab deruxtecan (T-DXd) in pts with stable and active BM. However, real-world (RW) comparative estimates of incident BM risk and timing between these two regimens among pts without baseline BM are limited, particularly in the second-line (2L) setting. Methods: We conducted a retrospective cohort study using TriNetX, a federated electronic health record network. Eligible pts had HER2+ MBC previously treated with first-line THP (taxane + trastuzumab + pertuzumab) and were BM-free at index. To approximate a 2L comparison, index was the first dose of T-DXd or TTC; cohorts were mutually exclusive and prior T-DM1 exposure was excluded. Pts with documented BM prior to index were excluded. To reduce misclassification from occult baseline BM, a landmark sensitivity analysis excluded BM events within 60 days post-index. Cohorts were balanced using 1:1 propensity score matching (PSM) for age, comorbidity burden, and lines of treatment. Incident BM was compared using risk-based measures (risk difference, risk ratio [RR]) and time-to-event analyses (Kaplan–Meier [KM]; Cox [HR]; log-rank). OS was assessed from index to death using KM and Cox regression. Results: In the PSM cohorts (n=540 per arm; mean age 57.8±12.4 vs 59.2±12.3 years), median follow-up was 13.4 months. Incident BM occurred in 12.6% (68/540) with T-DXd vs 20.9% (113/540) with TTC, corresponding to an absolute risk difference of −8.3% (95% CI −13.34% to −2.90%; p=0.0015) and RR 0.62 (95% CI 0.46–0.83). 1-year BM-free survival probability was 72.65% with T-DXd vs 67.89% with TTC (log-rank p=0.03), with an HR of 0.72 (95% CI 0.54–0.97). Among pts who developed BM, TTC was associated with higher BM-associated healthcare encounter burden compared with T-DXd (mean 9.64 vs 5.20; p=0.03). CNS morbidity events were less frequent with T-DXd vs TTC, including seizures (4.77% vs 13.06%; OR 0.33, 95% CI 0.23–0.49; p<0.0001) and cerebral edema (5.47% vs 14.22%; OR 0.35, 95% CI 0.24–0.51; p<0.0001). OS did not differ significantly between T-DXd and TTC (HR 0.89, 95% CI 0.76–1.04; p=0.16). Conclusions: In HER2+ MBC pts without baseline BM following first-line THP, T-DXd was associated with significantly lower incident BM, delayed onset, and reduced CNS morbidity compared with TTC. These findings warrant validation using standardized CNS surveillance and may help inform treatment selection in pts at high risk for BM. BM outcomes in HER2+ MBC. T-DXd TTC Incident BM 12.6% 20.9% RR 0.62 (0.46–0.83) 1-year BM-free 72.65% 67.89% HR 0.72 (0.54–0.97)