Datopotamab Deruxtecan (TROP2-ADC) + Pembrolizumab Delivers 55–56% ORR and 20-Month DoR in First-Line Advanced NSCLC

Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody–drug conjugate, was paired with the PD-1 inhibitor pembrolizumab ± platinum chemotherapy in the Phase 1b/2 TROPION-Lung02 trial (NCT04526691). Among 96 untreated stage IV NSCLC patients, the chemo-light doublet (Dato-DXd 4/6 mg kg⁻¹ Q3W + pembro; n = 42) produced a confirmed ORR of 55% (1 CR, 22 PR) and median PFS of 11.2 months, with durable responses lasting 20.1 months. Adding platinum (triplet; n = 54) increased ORR to 56% but shortened DoR to 13.7 months and PFS to 6.8 months. Disease control rates were similar across squamous and non-squamous histologies (doublet: 88-89%; triplet: 83-91%). Stomatitis (doublet, 57%; triplet, 33%) and nausea (doublet, 42%; triplet, 48%) were mostly grade 1–2. Serious treatment-related AEs occurred in 12% (doublet) and 22% (triplet) with no drug-related deaths reported. In comparison, standard For context, pembrolizumab + chemo (KEYNOTE-189/407) yields ORR 48–58% and median PFS 8–9 months, with DoR ≈11 mo.—figures These results demonstrate that the Dato-DXd doublet matches or beats the standard while sparing full-dose platinum for many patients.