Background
Phase 2 single-arm basket trial (DESTINY-PanTumor02); N=267 HER2-expressing (IHC 2+/3+) advanced solid tumors previously treated, including a NSCLC cohort.
Interventions and follow up
Treatment: Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV q3w (no comparator arm)
Primary endpoint: objective response rate
mFollow up: ~12mo
Primary endpoint: objective response rate
mFollow up: ~12mo
Results
Overall ORR: 37.1%; mPFS 6.9mo; mOS 13.4mo
HER2 IHC 3+ ORR: 61.3%; mPFS 11.9mo; mOS 21.1mo
NSCLC cohort ORR: 49%; mPFS 5.5mo; mOS 11.3mo
HER2 IHC 3+ ORR: 61.3%; mPFS 11.9mo; mOS 21.1mo
NSCLC cohort ORR: 49%; mPFS 5.5mo; mOS 11.3mo
Adverse events
Pulmonary: grade ≥3 pneumonitis/ILD 10% (adjudicated drug-related ILD a key class toxicity)
Constitutional: grade ≥3 fatigue 5%
Constitutional: grade ≥3 fatigue 5%
Conclusions
T-DXd showed meaningful activity across HER2-expressing tumors including NSCLC, with response enriched in IHC 3+ disease, supporting HER2 expression as a tumor-agnostic target.
Key Limitations
Single-arm, no control; modest NSCLC cohort size; ILD risk requires monitoring; benefit concentrated in IHC 3+ subset.
Clinical Context
Supported FDA tumor-agnostic accelerated approval of T-DXd for IHC 3+ HER2-expressing solid tumors (April 2024). Distinct from HER2-mutant NSCLC indication (DESTINY-Lung). HER2 IHC testing now relevant for ADC selection.