Phase 3: first-line sac-TMT plus pembrolizumab prolonged PFS vs pembrolizumab alone in PD-L1-positive advanced NSCLC without targetable alterations.

Evidence before this study

We searched PubMed for studies published from database inception to April 21, 2026, using the terms “PD-1”, “PD-L1”, “TROP2” or “trophoblast cell-surface antigen 2”, “advanced” or “metastatic”, “first-line” or “previously untreated”, and “non-small-cell lung cancer”, with the clinical trial filter applied. This search yielded 196 results. We identified several randomised phase 3 trials investigating combinations of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors and chemotherapy in advanced non-small-cell lung cancer (NSCLC), including KEYNOTE-189, KEYNOTE-407, CameL, CameL-sq, ORIENT-11, ORIENT-12, CHOICE-01, GEMSTONE-302, RATIONALE-304, RATIONALE-307, ASTRUM-002, ASTRUM-004, IMpower131, IMpower132, and EMPOWER-Lung 3. In studies evaluating agents with alternative mechanisms of action in patients with advanced NSCLC without targetable genomic alterations, the addition of antiangiogenic agents to PD-1 and PD-L1 inhibitors (eg, in the CAMPASS and LEAP-007 trials) improved progression-free survival, with hazard ratios ranging from 0·70 to 0·78; however, an overall survival benefit was not shown or remained uncertain. In the HARMONi-2 study, ivonescimab, a PD-1 and vascular endothelial growth factor bispecific antibody, showed clinical benefit in PD-L1-positive advanced NSCLC, with a median progression-free survival of 11·1 months and a hazard ratio of 0·51 versus pembrolizumab, although overall survival data were not formally reported.

Added value of this study

OptiTROP-Lung05 provides the first phase 3 evidence supporting sac-TMT plus pembrolizumab as a first-line antibody-drug conjugate (ADC)-immunotherapy strategy for PD-L1-positive advanced NSCLC without targetable genomic alterations. By integrating a trophoblast cell-surface antigen 2-targeting-directed ADC with a differentiated linker-payload platform and PD-1 blockade, the study establishes a therapeutic concept beyond conventional immunotherapy alone or chemoimmunotherapy. The benefit observed across PD-L1-defined populations, including patients with PD-L1 tumour proportion (TPS) of 1–49% and those with PD-L1 TPS of 50% or greater, and histological subtypes, including both non-squamous and squamous disease, supports the biologic and clinical rationale for sac-TMT plus pembrolizumab and provides a foundation for further defining ADC-immunotherapy strategies in advanced NSCLC.

Implications of all the available evidence

This study provides evidence that first-line treatment with sac-TMT plus pembrolizumab significantly prolonged progression-free survival as compared with pembrolizumab alone among patients with PD-L1-positive advanced NSCLC without targetable genomic alterations. The magnitude of benefit observed in this study suggests the potential to redefine first-line treatment for a broad population of patients with PD-L1-positive NSCLC without targetable genomic alterations. Together with the biologic rationale, previous phase 2 data, and the established phase 3 activity of sac-TMT in NSCLC, these findings strengthen the evidence base for combining sac-TMT, a TROP2-directed ADC with a differentiated linker-payload platform, with pembrolizumab in PD-L1-positive advanced NSCLC.

Source: The Lancet