Background
Blinded, multicenter, randomized phase 2 dose-comparison (DESTINY-Lung02). N=152 with previously treated (platinum-containing) HER2-mutant metastatic NSCLC (SNVs or exon 20 insertions). Designed primarily to characterize the lower 5.4 mg/kg dose.
Interventions and follow up
Arm A: Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV q3w (randomized 2:1).
Arm B: T-DXd 6.4 mg/kg IV q3w.
Primary endpoint: Confirmed ORR (RECIST v1.1) by BICR.
mFollow up: 11.5mo (5.4 mg/kg arm).
Arm B: T-DXd 6.4 mg/kg IV q3w.
Primary endpoint: Confirmed ORR (RECIST v1.1) by BICR.
mFollow up: 11.5mo (5.4 mg/kg arm).
Results
ORR (5.4 mg/kg): 49.0%, 95% CI 39.0–59.1
mDOR (5.4 mg/kg): 16.8mo
ORR (6.4 mg/kg): 56.0%, numerically higher but greater toxicity
mDOR (5.4 mg/kg): 16.8mo
ORR (6.4 mg/kg): 56.0%, numerically higher but greater toxicity
Adverse events
Overall: Grade ≥3 drug-related 38.6% (5.4 mg/kg) vs 58.0% (6.4 mg/kg).
Pulmonary — ILD/pneumonitis (adjudicated): 12.9% at 5.4 mg/kg, 28.0% at 6.4 mg/kg; grade ≥3 ILD 2.0% in each arm.
Gastrointestinal/constitutional: Nausea most common (67.3% at 5.4 mg/kg, 82.0% at 6.4 mg/kg); fatigue ~55%.
Hematologic: Decreased neutrophils (~65%) and other cytopenias common.
Pulmonary — ILD/pneumonitis (adjudicated): 12.9% at 5.4 mg/kg, 28.0% at 6.4 mg/kg; grade ≥3 ILD 2.0% in each arm.
Gastrointestinal/constitutional: Nausea most common (67.3% at 5.4 mg/kg, 82.0% at 6.4 mg/kg); fatigue ~55%.
Hematologic: Decreased neutrophils (~65%) and other cytopenias common.
Conclusions
T-DXd produced durable responses in previously treated HER2-mutant NSCLC at both doses; 5.4 mg/kg offered the more favorable benefit-risk balance (particularly for ILD) and is the recommended dose.
Key Limitations
Non-comparative ORR-based design with no OS comparison; short follow-up at primary analysis; limited active-CNS enrollment leaves intracranial activity undefined; ILD is serious and potentially fatal.
Clinical Context
Supported FDA accelerated approval of T-DXd (Aug 2022), the first therapy approved specifically for HER2-mutant NSCLC after prior systemic therapy; ESMO-MCBS v1.1 grade 3. Positions T-DXd as a preferred later-line option in HER2-mutant NSCLC with mandatory ILD monitoring.