First-line treatment outcomes in HER2-altered advanced NSCLC: a real-world multi-center study comparing trastuzumab deruxtecan with conventional therapies and analysis by HER2/EGFR co-alteration status

Background First-line treatment options for HER2 -altered advanced non-small cell lung cancer (NSCLC) remain limited, especially in cases with HER2-EGFR co-alterations. While new agents like trastuzumab deruxtecan (T-DXd) have emerged, its real-world evidence in first line remains limited. Methods This study included patients with advanced NSCLC who had HER2 mutations or amplification and received first-line systemic therapy at six medical centers. Outcomes were evaluated following chemotherapy-based combinations, pan-HER tyrosine kinase inhibitors (TKIs), and T-DXd. Endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), one-year and two-year survival rates, and toxicity. Results A total of 69 patients were enrolled, comprising 45 with only HER2 alterations and 24 with HER2 - EGFR co-alterations. In patients with only HER2 -altered NSCLC, those receiving first-line T-DXd had an mPFS of 15.7 months (95% CI, 12.5–18.9), an ORR of 85.7%, and a DCR of 100.0%. The mPFS for patients receiving chemotherapy-based regimens, pan-HER TKIs, and chemotherapy plus pan-HER TKIs were 7.6 (95% CI, 6.6–8.5) months, 4.4 (95% CI, 4.0-4.9) months, and 7.0 (95% CI, 6.1–9.1) months, respectively. The ORR for the three groups above was 33.3%, 0, and 0, respectively. In subgroup analysis, patients with only HER2 alterations who did not harbor TP53 mutations had a longer PFS than those with TP53 co-mutations (8.7 m vs. 7.2 m; HR: 0.35; 95% CI: 0.11–0.99; P = 0.048). In patients with EGFR-HER2 co-alterations, first-line EGFR-TKI monotherapy yielded an mPFS of 9.7 (95% CI, 8.6–10.8) months, an ORR of 40.0%, and a DCR of 93.3%. Regarding safety, we did not observe Grade ≥ 3 TRAEs in first-line T-DXd treatment. Conclusions First-line T-DXd showed promising activity signals in only HER2 -altered NSCLC. In EGFR-HER2 co-altered patients, the EGFR-TKI monotherapy showed limited efficacy. The findings underscored the urgent need for prospective randomised trials.