Sac-TMT Plus Pembrolizumab Beats Chemo-Immunotherapy in PD-L1–Negative NSCLC

A phase 3 trial combining an antibody-drug conjugate (ADC) with an immune checkpoint inhibitor has met its primary end point in previously untreated PD-L1–negative nonsquamous non–small cell lung cancer (NSCLC).¹

The OptiTROP-Lung06 (NCT06711900) found that sacituzumab tirumotecan (sac-TMT) combined with pembrolizumab (Keytruda) produced a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with pembrolizumab plus pemetrexed and platinum-based chemotherapy, the current first-line standard of care for this population. A positive trend in overall survival (OS) was also observed at the prespecified interim analysis. An independent data monitoring committee determined the study had met its primary end point.

Kelun-Biotech, the sponsor, characterized the finding as the first phase 3 result for an ADC combined with a checkpoint inhibitor to meet its primary end point in first-line treatment of driver gene-negative, PD-L1–negative nonsquamous NSCLC—a subgroup in which checkpoint monotherapy has limited activity because tumors express little to no PD-L1.

"For patients with driver gene‑negative and PD‑L1–negative NSCLC, immunotherapy combined with chemotherapy remains the current standard first-line treatment and has improved patient outcomes to some extent. However, long-term survival benefit remains limited. The achievement of positive results in the phase 3 OptiTROP-Lung06 study represents an important breakthrough in the first-line treatment of PD-L1–negative NSCLC. These results not only provide robust clinical evidence supporting the 'ADC plus immunotherapy' strategy of sac-TMT in combination with pembrolizumab, but also have the potential to offer these patients a new first-line treatment option beyond the current standard of care, with the promise of improved survival outcomes,” said Professor Caicun Zhou, national lead principal investigator from Shanghai East Hospital, Tongji University, in a news release.

Trial Design

OptiTROP-Lung06 is a randomized, open-label, multicenter phase 3 study enrolling patients with locally advanced or metastatic nonsquamous NSCLC and a PD-L1 tumor proportion score below 1%. Participants were assigned to receive sac-TMT plus pembrolizumab or pembrolizumab plus pemetrexed and platinum-based chemotherapy. The primary end point was PFS assessed by blinded independent central review; secondary end points included OS and safety.

According to the company, the safety profile of the combination was consistent with previously reported data on sac-TMT, and no new safety signals emerged.

Mechanism and Rationale

Sac-TMT is an ADC directed against TROP2, a protein expressed on the surface of most nonsquamous NSCLC tumor cells regardless of PD-L1 status. The drug uses a bifunctional linker to couple an anti-TROP2 monoclonal antibody to a belotecan-derived topoisomerase I inhibitor payload, with a drug-to-antibody ratio of 7.4. After the antibody binds TROP2 and the conjugate is internalized, the payload is released intracellularly, inducing DNA damage, cell-cycle arrest, and apoptosis; because the payload is membrane-permeable, it can also diffuse to and kill neighboring tumor cells independent of TROP2 expression, a mechanism known as bystander killing.

The rationale for combining sac-TMT with pembrolizumab rests on the premise that ADC-induced tumor cell death can generate immunogenic signals that prime the tumor microenvironment, potentially rendering tumors more responsive to PD-1 blockade even when baseline PD-L1 expression is low or absent.

Context Within the Development Program

OptiTROP-Lung06 follows OptiTROP-Lung05 (NCT06448312), a related phase 3 trial testing sac-TMT plus pembrolizumab against pembrolizumab monotherapy in patients with PD-L1–positive NSCLC. That trial also met its primary PFS end point; its results were presented at the 2026 American Society of Clinical Oncology Annual Meeting and published in The Lancet.^2,3 Kelun-Biotech has said it plans to discuss the OptiTROP-Lung06 results with China's Center for Drug Evaluation, part of the National Medical Products Administration, and that a related new-indication application for the PD-L1–positive setting is already under priority review.¹

Sac-TMT is currently approved in China for 4 indications, including previously treated triple-negative breast cancer and EGFR-mutant nonsquamous NSCLC following progression on EGFR tyrosine kinase inhibitor therapy.

REFERENCES

1. Kelun-Biotech Announces Phase III Study of Sacituzumab Tirumotecan (sac-TMT) in Combination with Pembrolizumab as First-Line Treatment for PD-L1-Negative Non-Squamous NSCLC Met Primary Endpoint. News release. Kelun-Biotech. July 15, 2026. Accessed July 15, 2026. https://tinyurl.com/mvmtems2

2. Zhou C, Xiong A, Yao W, et al. Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (P) versus pembrolizumab (P) 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. 44, 8506-8506(2026). doi:10.1200/JCO.2026.44.16_suppl.8506

3. 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. 2026 Jun 27;407(10548):2607-2619. doi: 10.1016/S0140-6736(26)00968-2. Epub 2026 May 29. PMID: 42214392.