Background
Randomized, open-label, phase 3 trial (68 hospitals, China). N=413 with previously untreated locally advanced/metastatic NSCLC without targetable (EGFR/ALK) alterations and PD-L1 TPS ≥1%. Sacituzumab tirumotecan (sac-TMT) is a TROP2-directed antibody–drug conjugate with a topoisomerase-I-inhibitor payload. The trial tested adding sac-TMT to pembrolizumab vs pembrolizumab alone as first-line therapy.
Results
Interventions and follow up: Arm A: Sacituzumab tirumotecan (sac-TMT) 4 mg/kg IV days 1, 15, 29 + pembrolizumab 400 mg IV day 1, every 6 weeks
Arm B: Pembrolizumab 400 mg IV every 6 weeks
Primary endpoint: PFS by blinded independent central review (ITT)
mFollow up: 10.5 months (prespecified interim analysis)
Results: PFS (primary): median NR vs 5.7 months, HR 0.35, 95% CI 0.26–0.47, P<.0001
PFS, PD-L1 TPS 1–49%: HR 0.28, 95% CI 0.19–0.41
PFS, PD-L1 TPS ≥50%: HR 0.47, 95% CI 0.29–0.77
OS: NR (immature; final analysis pending)
Arm B: Pembrolizumab 400 mg IV every 6 weeks
Primary endpoint: PFS by blinded independent central review (ITT)
mFollow up: 10.5 months (prespecified interim analysis)
Results: PFS (primary): median NR vs 5.7 months, HR 0.35, 95% CI 0.26–0.47, P<.0001
PFS, PD-L1 TPS 1–49%: HR 0.28, 95% CI 0.19–0.41
PFS, PD-L1 TPS ≥50%: HR 0.47, 95% CI 0.29–0.77
OS: NR (immature; final analysis pending)
Adverse events
Grade ≥3 TEAE (any): 55% vs 31%
Profile: reflects the sac-TMT class (hematologic, stomatitis/mucosal) plus pembrolizumab immune-related events; term-level grade ≥3 rates not detailed in the interim publication (NR)
Profile: reflects the sac-TMT class (hematologic, stomatitis/mucosal) plus pembrolizumab immune-related events; term-level grade ≥3 rates not detailed in the interim publication (NR)
Conclusions
sac-TMT + pembrolizumab markedly improved PFS vs pembrolizumab alone (HR 0.35) as first-line therapy for PD-L1+ advanced NSCLC without driver alterations — the first phase 3 to show an ADC–IO combination beating IO monotherapy in this setting. Benefit was consistent across PD-L1 strata. OS is immature and toxicity was substantially higher with the combination.
Key Limitations
Interim analysis at short median follow-up (10.5 months); OS immature/NR. Single-country (China), open-label design limits generalizability (PFS was BICR-assessed, mitigating endpoint bias). Comparator was pembrolizumab monotherapy — not chemo–IO or platinum-doublet + pembrolizumab used for much of the PD-L1-low population. Nearly double the grade ≥3 toxicity. Mature OS and global confirmatory data needed.
Clinical Context
Standard 1L for PD-L1+ driver-negative advanced NSCLC is pembrolizumab ± platinum chemotherapy (PD-L1-dependent). OptiTROP-Lung05 introduces a chemo-free ADC–IO doublet with a large PFS signal that could redefine 1L if OS confirms. sac-TMT is investigational for NSCLC, not FDA-approved in this setting; data derive from a China-based trial. Not yet in NCCN/ESMO 1L NSCLC guidance pending mature OS and regulatory review.