Sac-TMT Combo Improves PFS vs Pembrolizumab in NSCLC

Progression-free survival (PFS) significantly improved when combining first-line sacituzumab tirumotecan (sac-TMT) with pembrolizumab (Keytruda) vs pembrolizumab alone among those with advanced PD-L1–positive non–small cell lung cancer (NSCLC), according to a presentation on data from the phase 3 OptiTROP-Lung05 trial (NCT06448312) at the 2026 American Society of Clinical Oncology Annual Meeting (ASCO).^1,2

Specifically, the trial demonstrated a 65% reduction in the risk of disease progression or death in the intention-to-treat (ITT) population (HR, 0.35; 95% CI, 0.26-0.47; P < .0001).

Trial Design and Patient Population

OptiTROP-Lung05 was a randomized, multicenter, open-label phase 3 study conducted to evaluate the efficacy of the trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate (ADC) sac-TMT in combination with pembrolizumab. The study enrolled 413 patients with locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC who had received no prior systemic antitumor therapy. Eligible participants were required to have a PD-L1 tumor proportion score (TPS) of ≥1%, an ECOG performance status of 0 or 1, and no sensitizing EGFR or ALK alterations.

Patients were randomized 1:1 to receive either sac-TMT at 4 mg/kg every 2 weeks plus pembrolizumab at 400 mg every 6 weeks (n = 208) or pembrolizumab monotherapy at 400 mg every 6 weeks (n = 205). Stratification factors included histology (squamous vs non-squamous), PD-L1 TPS (1-49% vs ≥50%), and ECOG score (0 vs 1). The primary endpoint was PFS as assessed by a blinded independent central review (BICR).

Key Efficacy and Survival Outcomes

At the data cut-off of September 29, 2025, with a median follow-up of 10.5 months, the median PFS for the pembrolizumab monotherapy group was 5.7 months (95% CI, 4.3-7.0), while the median PFS for the combination arm was not reached (95% CI, 13.6-NE). Subgroup analyses confirmed a consistent PFS benefit across clinical subsets, including histology and PD-L1 expression levels.

In patients with a PD-L1 TPS ≥50%, the combination reduced the risk of progression or death by 53% (HR, 0.47; 95% CI, 0.29-0.77). For those with a TPS of 1-49%, the risk reduction was 72% (HR, 0.28; 95% CI, 0.19-0.41). When analyzed by histology, the hazard ratio was 0.28 (95% CI, 0.18-0.43) for non-squamous disease and 0.44 (95% CI, 0.29-0.66) for squamous cell carcinoma.

The objective response rate (ORR) was also significantly higher in the combination group at 70.2% compared with 42.0% in the monotherapy group. Furthermore, deep responses (defined as ≥50% reduction in the sum of lesion diameters) were achieved by 49.0% of patients receiving the combination versus 25.9% receiving pembrolizumab alone.

While overall survival (OS) data were immature at the time of the interim analysis, a descriptive trend favored the sac-TMT and pembrolizumab arm (HR, 0.55; 95% CI, 0.36-0.85). The 12-month OS rate was 80.4% for the combination group compared with 68.9% for the monotherapy group.

Safety and Adverse Event Profile

The safety profile of the combination was reported as manageable and consistent with the known profiles of the individual agents, with no new safety signals identified. However, the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was higher in the combination arm (55.3%) than in the monotherapy arm (31.4%).

The most frequent TEAEs associated with the sac-TMT combination were primarily hematologic:

• Anemia: 87.5% any grade; 9.1% grade ≥3.
• Neutrophil count decreased: 44.7% any grade; 17.3% grade ≥3.
• White blood cell count decreased: 46.2% any grade; 8.7% grade ≥3.

Other common any-grade events included alopecia (65.9%) and stomatitis (40.4%). Adverse events of special interest (AESI) for sac-TMT included ocular surface toxicity in 14.4% of patients and infusion-related reactions in 5.8%. Immune-related AESIs for pembrolizumab, such as hypothyroidism (13.5%) and pneumonitis (12.5%), were slightly more frequent in the combination arm than in the monotherapy group (11.3% and 7.4%, respectively).

Clinical Implications and Next Steps

Standard first-line therapy for PD-L1–positive advanced NSCLC has historically yielded suboptimal outcomes for many patients, with median PFS typically ranging between 5 and 8 months. The results from OptiTROP-Lung05 suggest that integrating TROP2-directed ADCs with immune checkpoint inhibitors may provide a more effective first-line strategy.

The investigators noted that the irreversible connection of the sac-TMT linker ensures minimal payload loss in circulation, while the membrane permeability of the payload elicits a bystander effect in nearby tumor cells, which may contribute to the efficacy observed across varying levels of TROP2 and PD-L1 expression.

Despite the positive PFS data, the study is limited by the immaturity of the OS findings and the open-label design. Long-term follow-up will be necessary to confirm the survival benefit and further characterize the duration of response.

References

1. Zhou C, Xiong A, Yao W, et al. Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab versus pembrolizumab as first-line treatment for PD-L1–positive advanced non-small cell lung cancer (NSCLC): results from the randomized phase 3 OptiTROP-Lung05 study. J Clin Oncol. 2026;44(suppl 16):8506. doi:10.1200/JCO.2026.44.16_suppl.8506
2. Xiong A, Yao W, Zheng W, et al. Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1-positive advanced non-small-cell lung cancer (OptiTROP-Lung05): interim analysis of a randomised, open-label, phase 3 trial. Lancet. May 29, 2026. doi:10.1016/S0140-6736(26)00968-2