Sac-TMT Combo Improves PFS in First-Line PD-L1–Negative Nonsquamous NSCLC

First-line sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (Keytruda) significantly prolonged progression-free survival (PFS) compared with chemotherapy plus pembrolizumab in patients with PD-L1–negative advanced nonsquamous non–small cell lung cancer (NSCLC) without targetable genomic alterations, according to results from the phase 3 OptiTROP-Lung06 trial (NCT06711900) presented at the 2026 European Society for Medical Oncology (ESMO) Congress and simultaneously published in The New England Journal of Medicine.^1,2

What were the PFS outcomes?

At a median follow-up of 9.7 months in this prespecified interim analysis, the median PFS by blinded independent central review (BICR) was 15.0 months (95% CI, 9.9-not estimable [NE]) with sac-TMT plus pembrolizumab vs 5.7 months (95% CI, 5.5-7.4) with chemotherapy plus pembrolizumab (HR, 0.49; 95% CI, 0.36-0.65; P <.001). The sac-TMT combination reduced the risk of disease progression or death by 51% vs chemotherapy plus pembrolizumab. The estimated 12-month PFS rate was 51.1% (95% CI, 41.5%-59.9%) with sac-TMT plus pembrolizumab vs 22.8% (95% CI, 15.3%-31.3%) with chemotherapy plus pembrolizumab.

A generally consistent PFS benefit was observed across prespecified subgroups, although confidence intervals were wide. In a prespecified biomarker analysis, the PFS benefit was consistent regardless of TROP2 expression level, with an HR of 0.59 (95% CI, 0.37-0.92) among patients with high expression and 0.49 (95% CI, 0.30-0.80) among those with low expression.

What did the response and survival data show?

The objective response rate was similar between the arms, at 50.2% (95% CI, 43.6%-56.9%) with sac-TMT plus pembrolizumab vs 47.3% (95% CI, 40.7%-54.1%) with chemotherapy plus pembrolizumab, but responses were deeper and more durable with the sac-TMT combination. A deep response, defined as at least 50% tumor shrinkage, occurred in 28.8% vs 17.3% of patients, and the median duration of response (DOR) was 13.6 months (95% CI, 9.7- not evaluable [NE]) vs 6.8 months (95% CI, 4.2-10.6; HR, 0.47; 95% CI, 0.29-0.77), with 12-month DOR rates of 61.7% (95% CI, 47.5%-73.1%) vs 27.2% (95% CI, 11.2%-46.0%).

Overall survival (OS) data were immature at the interim analysis and were not formally tested. Death occurred in 36 patients (15.7%) vs 55 patients (24.3%); the median was not reached in either arm, and the HR for death was 0.58 (95% CI, 0.38-0.88), with 12-month OS rates of 77.6% vs 66.4%.

What was the safety profile?

Grade 3 or higher treatment-emergent adverse events (TEAEs) were less frequent with sac-TMT plus pembrolizumab than with chemotherapy plus pembrolizumab (47.6% vs 60.6%), driven largely by fewer hematologic events; grade 3 or higher anemia occurred in 6.1% vs 20.4% of patients, and grade 3 or higher decreased neutrophil counts in 19.7% vs 28.8%. TEAEs led to dose reduction in 4.8% vs 19.9% of patients, to treatment discontinuation in 5.7% vs 14.2%, and to death in 2.2% vs 6.2%; treatment-related deaths occurred in 0.4% (1 patient, due to respiratory failure) vs 1.3%.

Among AEs of special interest for sac-TMT, stomatitis occurred in 51.1% of patients but was predominantly grade 1 or 2, with grade 3 or higher events in 2.2% that all resolved with supportive care or dose modification. Ocular-surface toxic effects (13.5%) and infusion-related reactions (4.4%) were all grade 1 or 2, and no excess of interstitial lung disease or pneumonitis was observed with the sac-TMT combination (10.5% vs 13.7%).

“Results from OptiTROP-Lung06 study support sac-TMT [plus pembrolizumab] as a potential new first-line treatment option for PD-L1–negative advanced nonsquamous NSCLC without EGFR or ALK alteration,” Caicun Zhou, MD, PhD, from Shanghai East Hospital, Tongji University, Shanghai, China, concluded with coinvestigators.

What is the trial design and clinical context?

OptiTROP-Lung06 is a randomized, open-label phase 3 trial conducted at 81 centers in China that enrolled 455 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, a PD-L1 tumor proportion score of less than 1% by central testing, and no EGFR or ALK alterations or other targetable genomic alterations. Patients were randomly assigned 1:1 to sac-TMT at 4 mg/kg plus pembrolizumab or to pemetrexed and platinum-based chemotherapy plus pembrolizumab, with PFS by BICR as the primary end point.

Sac-TMT is a TROP2-directed antibody-drug conjugate that links an anti-TROP2 monoclonal antibody to a belotecan-derived topoisomerase I inhibitor payload through a cleavable bifunctional linker. Pembrolizumab plus platinum-based chemotherapy is a widely used first-line standard in this setting, but outcomes remain suboptimal, with a historical median PFS of approximately 6 months. The investigators concluded that the results support sac-TMT plus pembrolizumab as an active first-line regimen for PD-L1–negative advanced nonsquamous NSCLC without targetable genomic alterations, noting that OS data were immature.

References

1. Zhou C, Zhou F, Meng X, et al. Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab versus chemotherapy plus pembrolizumab as first-line treatment for PD-L1–negative advanced nonsquamous NSCLC: randomized phase 3 OptiTROP-Lung06 study. Presented at: European Society for Medical Oncology (ESMO) Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA66.
2. Zhou F, Meng X, Ding Q, et al. Sacituzumab tirumotecan plus pembrolizumab in PD-L1–negative advanced NSCLC. N Engl J Med. Published online October 25, 2026. doi:10.1056/NEJMoa2611280