T-DXd plus osimertinib for HER2-overexpressing NSCLC after osimertinib resistance: a multicenter real-world study

HER2 overexpression is a key resistance mechanism to osimertinib in EGFR-mutant non-small cell lung cancer (NSCLC). However, real-world evidence remains limited. This first real-world study included 3,589 EGFR-mutant NSCLC patients from six PLAGH medical centers, and 50 patients with HER2 overexpression (immunohistochemistry (IHC) 2+/3+) met the inclusion criteria. HER2 overexpression was either present at diagnosis ( n = 33, Cohort P) or acquired under osimertinib therapy ( n = 17, Cohort A). Clinicopathological data, objective response rate (ORR), progression-free survival (PFS), and adverse events were analyzed. The most common EGFR mutation was exon 21 L858R ( n = 29), and TP53 ( n = 24) was the most common co-mutation. In Cohort P, 3 patients received trastuzumab deruxtecan (T-DXd) plus osimertinib achieved PFS exceeding 14.0 months (individual PFS: 14.0, 15.8, and 29.0 months), with the ORR of 66.7%. The mPFS in Cohort P patients who did not receive T-DXd plus osimertinib ( n = 30) was 6.7 months (95% CI, 3.7–9.7). In Cohort A, 7 patients received T-DXd plus osimertinib, with an ORR of 14.3% and an mPFS of 13.2 months (95% CI, 7.0-19.4), compared with 3.8 months (95% CI, 2.9–4.7) in those not receiving T-DXd plus osimertinib ( n = 10). Treatment-related adverse events occurred in 100.0% of patients receiving T-DXd plus osimertinib (mostly grade 1–2), with hematologic AEs as the most common type. In summary, T-DXd plus EGFR-TKI may offer clinical benefit for patients with HER2 overexpression after osimertinib resistance. However, the potential role of this combination must be tested in prospective trials. Not Applicable.