Interim phase 3: Sacituzumab tirumotecan plus pembrolizumab improves PFS in PD-L1–positive advanced NSCLC

An interim phase 3 analysis published in The Lancet found that adding sacituzumab tirumotecan to pembrolizumab significantly prolonged progression-free survival, or the time before a patient’s cancer worsens, compared with pembrolizumab alone as first-line treatment for PD-L1-positive advanced non-small-cell lung cancer. The result is immediately notable because pembrolizumab by itself is already a standard first-line option for some patients in this setting, though the new data are still interim, overall survival is not yet mature and toxicity was higher with the combination.

The study, called OptiTROP-Lung05, is a randomized, open-label, multicenter phase 3 trial of sacituzumab tirumotecan, or sac-TMT, plus pembrolizumab versus pembrolizumab alone. It enrolled 413 patients with previously untreated, locally advanced or metastatic non-small-cell lung cancer whose tumors had a PD-L1 tumor proportion score of at least 1% and no targetable driver alterations, with trial materials specifically noting exclusion of EGFR and ALK alterations. Both squamous and non-squamous disease were included. Patients were randomly assigned 1:1 to receive sac-TMT at 4 mg/kg every two weeks plus pembrolizumab 400 mg every six weeks, or pembrolizumab 400 mg every six weeks alone.

At the pre-specified interim analysis, the trial met its primary endpoint of progression-free survival as assessed by blinded independent central review. Reported results showed a hazard ratio of about 0.35, implying roughly a 65% reduction in the risk of progression or death with the combination. Median progression-free survival was not reached in the sac-TMT plus pembrolizumab arm, compared with 5.7 months for pembrolizumab alone. With a median follow-up of about 10.5 months, the objective response rate was about 70% with the combination versus about 42% with pembrolizumab alone.

The key caution is that the overall survival analysis was still immature at the time of the interim readout. Sponsor materials described only a positive trend, not a confirmed survival benefit. Safety was also worse with the two-drug regimen. Conference summaries reported grade 3 or higher treatment-emergent adverse events in roughly 55.3% of patients on sac-TMT plus pembrolizumab, compared with 31.4% on pembrolizumab alone. Neutropenia, a potentially serious drop in white blood cells that can raise infection risk, was highlighted as an important severe side effect.

That balance of stronger disease control and greater toxicity is why the result is likely to draw close attention from oncologists. Pembrolizumab monotherapy is an established first-line treatment for some patients with PD-L1-positive advanced non-small-cell lung cancer that lacks targetable mutations, so outperforming it in a phase 3 trial is clinically meaningful. At the same time, clinicians and regulators will want to see whether the progression-free survival advantage translates into an overall survival benefit and whether the safety profile remains manageable with longer follow-up. The data were also presented Friday as an oral abstract at the 2026 American Society of Clinical Oncology annual meeting, Abstract No. 8506.

Sac-TMT is a TROP2-directed antibody-drug conjugate developed by Sichuan Kelun-Biotech in China. Merck, known as MSD outside the United States and Canada, holds development and commercial rights to the drug outside Greater China. China’s National Medical Products Administration, the country’s drug regulator, accepted for review on May 8 a supplemental application for sac-TMT plus pembrolizumab in this first-line PD-L1-positive non-small-cell lung cancer setting. For now, the OptiTROP-Lung05 readout looks promising and potentially important, but it remains an interim result that will require mature overall survival data, longer safety follow-up and confirmation that the findings generalize broadly.