Background
Phase 2 single-arm, multinational; advanced/metastatic NSCLC with actionable genomic alterations (EGFR, ALK, ROS1, NTRK, BRAF, MET ex14, RET) progressing after targeted therapy + platinum chemo. N=137; 71.5% had ≥3 prior lines; EGFR 56.9%, ALK 24.8%.
Results
Interventions and follow up: Treatment: datopotamab deruxtecan (Dato-DXd) 6 mg/kg IV q3w until PD/unacceptable toxicity.
Primary endpoint: confirmed ORR by blinded independent central review.
mFollow up: NR.
Results: ORR (overall): 35.8% (95% CI 27.8–44.4).
ORR (EGFR-mutant): 43.6% (95% CI 32.4–55.3).
ORR (ALK-rearranged): 23.5% (95% CI 10.7–41.2).
DCR: 78.8% overall.
mDOR: 7.0mo overall.
Primary endpoint: confirmed ORR by blinded independent central review.
mFollow up: NR.
Results: ORR (overall): 35.8% (95% CI 27.8–44.4).
ORR (EGFR-mutant): 43.6% (95% CI 32.4–55.3).
ORR (ALK-rearranged): 23.5% (95% CI 10.7–41.2).
DCR: 78.8% overall.
mDOR: 7.0mo overall.
Adverse events
Most common (any grade): stomatitis 56.2%, nausea 54.7%, alopecia 49.6%, decreased appetite 20.4%, fatigue 19.0%.
Grade ≥3: 28.5% overall; stomatitis 9.5% the most common.
Notable: treatment-related ILD/pneumonitis 3.6% (5 pts), including 1 grade 5 (0.7%); TRAE discontinuation 5.1%.
Grade ≥3: 28.5% overall; stomatitis 9.5% the most common.
Notable: treatment-related ILD/pneumonitis 3.6% (5 pts), including 1 grade 5 (0.7%); TRAE discontinuation 5.1%.
Conclusions
Dato-DXd showed encouraging, durable activity in heavily pretreated NSCLC with actionable alterations, greatest in the EGFR-mutant subgroup; safety consistent with prior reports, with stomatitis and ILD/pneumonitis notable.
Key Limitations
Single-arm, no OS comparison, ORR surrogate; pooled population spans distinct molecular subtypes with uneven representation, limiting subgroup precision; mDOR modest (~7mo); a fatal ILD event mandates pulmonary monitoring.
Clinical Context
With phase 3 TROPION-Lung01, informed a US priority review for Dato-DXd in previously treated advanced NSCLC; later granted breakthrough therapy designation for previously treated EGFR-mutant NSCLC. European NSCLC application voluntarily withdrawn; investigational in this setting at publication.