Anti-PD-(L)1 therapy is a standard first-line treatment option for PD-L1-positive non-small cell lung cancer (NSCLC), either as monotherapy or in combination with chemotherapy. However, a substantial number of patients derive only limited benefit from chemo-immunotherapy.
TROP2 is broadly expressed in NSCLC, and higher TROP2 expression may be associated with an immunosuppressive tumor microenvironment. This suggests that TROP2-directed antibody-drug conjugates (ADCs) may complement PD-(L)1 blockade through cytotoxicity, immunogenic cell death, antigen release, and T-cell priming.
In previous phase II studies, sacituzumab tirumotecan (sac-TMT) plus pembrolizumab demonstrated promising results in patients with PD-L1-positive advanced NSCLC. These findings provided the rationale for the Opti-TROP-Lung 05 trial.
The randomized study is the first phase III trial to demonstrate a significant progression-free survival (PFS) benefit of an ADC plus pembrolizumab over pembrolizumab monotherapy as first-line treatment in this population. The data also indicate a favorable overall survival (OS) trend, improved response rates, and a manageable safety profile.
Caicun Zhou, MD, PhD, ABFT, presented the findings at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
Study Design
A total of 413 patients were randomly assigned in a 1:1 ratio to receive either sac-TMT plus pembrolizumab (n = 208) or pembrolizumab monotherapy (n = 205) until disease progression or unacceptable toxicity. Sac-TMT was administered intravenously every two weeks at a dose of 4 mg/kg in the combination cohort, while all patients received pembrolizumab 400 mg every six weeks.
Patients were stratified based on histology, PD-L1 expression, and performance status. Eligibility criteria included:
- Locally advanced or metastatic NSCLC
- No prior systemic antitumor therapy
- No sensitizing EGFR or ALK alterations
- PD-L1-positive tumors
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
The primary endpoint was PFS assessed by blinded independent central review (BICR), while the secondary endpoints included OS, investigator-assessed PFS, overall response rate (ORR), duration of response (DoR), and safety. Baseline characteristics were generally balanced between the two treatment groups.
The majority of patients were male, had an ECOG performance status of 1, had previously or currently smoked, and had stage IV disease. In both cohorts, about 40% of patients exhibited PD-L1 expression of 50% or higher—39.9% in the sac-TMT plus pembrolizumab group and 40% in the pembrolizumab-only cohort—while nearly 60% of patients in both groups had adenocarcinoma histology.
At the data cutoff (September 29, 2025), there were 194 observed PFS events. Additionally, more patients remained on treatment in the sac-TMT plus pembrolizumab group compared with the pembrolizumab monotherapy cohort (63.5% vs. 33.2%).
Results
Dr. Zhou cited a consistent PFS benefit in the sac-TMT plus pembrolizumab group compared with pembrolizumab monotherapy. The median PFS was not reached in the sac-TMT plus pembrolizumab group compared with 5.7 months for pembrolizumab monotherapy, and the 1-year PFS rate was significantly higher for patients who received combination treatment (62.4% with sac-TMT plus pembrolizumab vs. 29% with pembrolizumab alone).
“The PFS curves separated early, favoring sac-TMT plus pembrolizumab,” Dr. Zhou said.
The investigator-assessed PFS rate was comparable to the BICR-assessed PFS results (57.3% vs. 27.4%), and this benefit was consistent across several subgroups, including those with high PD-L1 expression (12-month PFS rate: 65.6% vs. 39%), low PD-L1 expression (12-month PFS rate: 60.1% vs. 21.6%), non-squamous histology (12-month PFS rate: 71.3% vs. 33%), and squamous histology (12-month PFS rate: 51.3% vs. 24.6%).
“As you can see, patients in almost all subgroups derived a PFS benefit, except for the subgroup with liver metastases, likely due to the small sample size,” Dr. Zhou said.
Although OS data were not yet mature, the trend favored sac-TMT plus pembrolizumab compared with pembrolizumab monotherapy (12-month OS rate: 80.4% with sac-TMT plus pembrolizumab vs. 68.9% with pembrolizumab alone).
The combination regimen was associated with a significant improvement in ORR compared with monotherapy (70.2% with sac-TMT plus pembrolizumab vs. 42% with monotherapy). Additionally, sac-TMT plus pembrolizumab yielded a superior deep response rate than pembrolizumab monotherapy (49% vs. 25.9%) and a greater DoR (77.7% vs. 59.4%).
Dr. Zhou indicated that the safety profile of sac-TMT combined with pembrolizumab was manageable and consistent with the known profiles of the individual agents, with no new safety signals observed. There was a higher incidence of grade 3 or higher treatment-emergent adverse events (TEAEs) in the combination group compared with monotherapy (55.3% with sac-TMT plus pembrolizumab vs. 31.4% with pembrolizumab alone); however, these were primarily driven by hematologic toxicities associated with the combination regimen.
TEAEs leading to discontinuation of the sac-TMT plus pembrolizumab combination occurred in 3.8% to 5.3% of patients, compared with 4.9% of patients receiving pembrolizumab monotherapy. The most common grade 3 or higher TEAEs of special interest in patients treated with sac-TMT plus pembrolizumab were decreased neutrophil counts (17.3%), anemia (9.1%), and stomatitis (5.3%), Dr. Zhou said.
“These results from the Opti-TROP-Lung 05 study support sac-TMT plus pembrolizumab as a potential new treatment option for first-line PD-L1-positive advanced NSCLC without EGFR or ALK alterations,” he said.
