The first phase 3 trial to demonstrate that an ADC plus pembrolizumab significantly outperforms pembrolizumab alone in first-line PD-L1–positive NSCLC without targetable alterations.
For over a decade, pembrolizumab monotherapy has been the standard of care for patients with PD-L1–positive advanced non-small cell lung cancer (NSCLC) without targetable genomic alterations. Yet a substantial proportion of these patients fail to achieve durable responses. Efforts to build upon immunotherapy — adding chemotherapy, anti-angiogenic agents, or other targeted therapies — have repeatedly failed to meaningfully improve outcomes.
That paradigm may have shifted. At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, investigators reported the interim analysis of OptiTROP-Lung05 (Abstract 8506), a randomized, open-label, phase 3 trial demonstrating that the addition of the TROP2-directed antibody-drug conjugate sacituzumab tirumotecan (sac-TMT; SKB264/MK-2870) to pembrolizumab reduced the risk of disease progression or death by 65% compared with pembrolizumab alone in first-line PD-L1–positive advanced NSCLC.
The findings were published simultaneously in The Lancet (Volume 407, Issue 10548, 27 June–3 July 2026, Pages 2607-2619).
Sacituzumab Tirumotecan (Sac-TMT): A China-Developed First-in-Class TROP2 ADC
Sacituzumab tirumotecan (sac-TMT, also known as SKB264/MK-2870, brand name 佳泰莱® in China) is a novel TROP2-directed antibody-drug conjugate independently developed by China-based Kelun-Biotech (Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.). It represents a new generation of ADC technology and is one of the first TROP2-directed ADCs to emerge from China's homegrown innovation ecosystem.
Mechanism of Action:
- A humanized monoclonal antibody that specifically targets TROP2 — a transmembrane glycoprotein overexpressed in many epithelial cancers, including up to 89% of lung cancers.
- A novel enzymatically cleavable linker (optimized CL2A linker) that provides dual stabilization in circulation: the antibody end uses a methyl sulfonyl pyrimidine linker for irreversible conjugation, while the toxin end contains a methyl sulfone structure that enhances linker binding stability.
- A belotecan-derived topoisomerase I inhibitor payload (tirumotecan/KL610023) with a drug-to-antibody ratio (DAR) of 7.4.
Once the ADC binds to TROP2 on the tumor cell surface, it is internalized and undergoes lysosomal degradation, releasing the cytotoxic payload to induce DNA damage. The linker also enables dual-release mechanisms within the tumor microenvironment: pH-sensitive release in the acidic tumor microenvironment and enzymatic cleavage after internalization — enhancing killing of heterogeneous tumor cells while sparing healthy tissue.
China-Developed, Globally Licensed:
Sac-TMT was wholly independently developed by Kelun-Biotech with full independent intellectual property rights. In May 2022, Kelun-Biotech licensed exclusive rights to Merck & Co. (known as MSD outside the U.S. and Canada) to develop and commercialize sac-TMT outside Greater China — a landmark out-licensing deal that underscores the global recognition of China's ADC innovation capabilities.
The drug has already received multiple approvals in China, including for triple-negative breast cancer (November 2024) and NSCLC (March 2025), and has been included in the National Reimbursement Drug List (NRDL). As of 2026, Kelun-Biotech has initiated 9 registrational clinical studies for sac-TMT in China alone.
Study Design
OptiTROP-Lung05 (NCT06448312) is a multicenter, randomized, open-label phase 3 trial conducted across 68 hospitals in China. Between June 7, 2024, and March 27, 2025, 741 patients were screened, and 413 eligible patients were randomly assigned 1:1 to receive either:
- Sac-TMT 4 mg/kg every 2 weeks plus pembrolizumab 400 mg every 6 weeks (n = 208), or
- Pembrolizumab 400 mg alone every 6 weeks (n = 205)
Eligible patients had treatment-naïve, locally advanced (stage IIIB/IIIC) or metastatic (stage IV) NSCLC without sensitizing EGFR or ALK alterations, and PD-L1 tumor proportion score (TPS) ≥1% by central 22C3 immunohistochemistry testing. Randomization was stratified by histology (squamous vs nonsquamous), PD-L1 TPS (1–49% vs ≥50%), and ECOG performance status (0 vs 1).
The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Overall survival (OS) was a key secondary endpoint.
Baseline Characteristics
| Characteristic | Sac-TMT + Pembro (n=208) | Pembro Alone (n=205) |
|---|---|---|
| Median age | 64 years | 65 years |
| ECOG PS 1 | ~84.6% | ~84.4% |
| Squamous histology | 40.9% | 39.0% |
| PD-L1 TPS 1–49% | 60.1% | 60.0% |
| PD-L1 TPS ≥50% | 39.9% | 40.0% |
Efficacy Results
At the prespecified interim analysis, conducted after a median follow-up of 10.5 months (IQR 8.7–12.5), the combination demonstrated a dramatic and statistically significant PFS benefit.
Primary Endpoint: Progression-Free Survival (BICR)
| Endpoint | Sac-TMT + Pembro | Pembro Alone | HR (95% CI) | P-value |
|---|---|---|---|---|
| Median PFS | Not reached | 5.7 months | 0.35 (0.26–0.47) | <0.0001 |
| 12-month PFS rate | 62.4% | 29.0% | — | — |
The 65% reduction in the risk of disease progression or death represents, in the words of one analyst, "a magnitude that forces a direct comparison with every benchmark currently defining first-line NSCLC care".
Subgroup Analyses: Consistent Benefit Across Key Populations
| Subgroup | HR for PFS (95% CI) |
|---|---|
| PD-L1 TPS 1–49% | 0.28 (0.19–0.41) |
| PD-L1 TPS ≥50% | 0.47 (0.29–0.77) |
| Non-squamous histology | 0.28 (0.18–0.43) |
| Squamous histology | 0.44 (0.29–0.66) |
The 0.28 HR observed in the TPS 1–49% subgroup is particularly noteworthy — and, paradoxically, more favorable than the 0.47 seen in the TPS ≥50% group. This suggests the combination may be especially impactful in patients with lower PD-L1 expression, where pembrolizumab monotherapy has historically been less effective.
Objective Response Rate
| Sac-TMT + Pembro | Pembro Alone | |
|---|---|---|
| ORR | 70.2% | 42.0% |
| Disease control rate | ~94% | ~72% |
The 28-percentage-point absolute increase in ORR suggests the combination is converting non-responders, not simply deepening responses in patients already benefiting from PD-1 blockade.
Overall Survival: Early Favorable Trend
| Endpoint | HR (95% CI) |
|---|---|
| Overall Survival | 0.55 (0.36–0.85) |
This 45% reduction in the risk of death, while based on immature data, provides early signal of a potential survival benefit that will be confirmed at the final analysis.
Safety Profile
Grade ≥3 treatment-emergent adverse events (TEAEs) were more common in the combination arm — 55.3% versus 31.4% with pembrolizumab alone. This was driven predominantly by hematologic toxicity, expected given sac-TMT's drug-to-antibody ratio of 7.4 and its belotecan-derivative payload.
| Adverse Event | Sac-TMT + Pembro | Pembro Alone |
|---|---|---|
| Neutrophil count decreased | 17.3% | <1% |
| Anemia | 9.1% | ~1% |
| Stomatitis | 5.3% | 0% |
| Pneumonia | ~8% | ~5% |
Importantly, TEAEs led to discontinuation of sac-TMT in only 3.8% of patients and pembrolizumab in 5.3% of patients in the combination arm, compared with 4.9% in the pembrolizumab-alone arm. The similar discontinuation rates suggest that ADC-related toxicity did not meaningfully compromise immunotherapy tolerability — a real concern in combination regimens.
Clinical Implications
"This is the first phase 3 study to demonstrate that an ADC plus pembrolizumab significantly improves clinical outcomes versus pembrolizumab alone for PD-L1–positive wild-type NSCLC," said Study Investigator Caicun Zhou, MD, PhD, of Shanghai East Hospital, Tongji University School of Medicine. "[The findings support] sac-TMT plus pembrolizumab as a potential new treatment option in this setting."
Several aspects of these findings warrant particular attention:
1. A New Mechanism of Action
The combination leverages complementary mechanisms: sac-TMT, a TROP2-directed ADC, induces immunogenic cell death, exposing tumor antigens and activating dendritic cells and T cells — converting immunologically "cold" tumors into "hot" tumors susceptible to immune clearance. Simultaneously, tumor cell killing upregulates PD-L1 expression, creating a positive feedback loop with PD-1 inhibition. This rationale distinguishes the ADC–immunotherapy combination from prior failed attempts to improve upon pembrolizumab monotherapy.
2. Broad Applicability Across PD-L1 Strata
The consistent benefit across both PD-L1 TPS 1–49% and ≥50% subgroups is clinically consequential. First-line pembrolizumab monotherapy is currently reserved for TPS ≥50% patients in many guidelines; expanding the efficacy argument to the TPS 1–49% stratum opens a substantially larger eligible population.
3. Histology-Independent Benefit
The benefit was observed in both squamous (HR 0.44) and non-squamous (HR 0.28) histologies — the latter being particularly noteworthy given that TROP2-targeted strategies have been less convincingly validated in squamous disease.
4. A Milestone for China-Developed Oncology Innovation
The OptiTROP-Lung05 results represent more than a clinical victory — they are a testament to China's emergence as a global force in ADC development. Sac-TMT, independently developed by Kelun-Biotech with full intellectual property rights, has become the first China-developed ADC to demonstrate a statistically significant and clinically meaningful PFS benefit over pembrolizumab in a head-to-head phase 3 registration trial. The fact that Merck & Co. licensed global rights to this China-origin asset — and is now advancing it toward global registration — underscores the quality of Chinese ADC innovation and its potential to reshape global treatment standards.
Remaining Questions and Future Directions
- Mature OS data will be critical. The current interim HR of 0.55 is directionally strong, but a first-line approval in the United States or Europe on PFS alone — absent a defined biomarker or unmet need argument — faces a higher bar.
- Toxicity management in community oncology settings remains an open question. Pembrolizumab monotherapy is currently administered with minimal monitoring burden; whether the higher Grade ≥3 adverse event rates (55% vs 31%) are acceptable in outpatient settings will require real-world experience.
- Comparison with platinum-doublet chemotherapy plus pembrolizumab — the current standard for many patients with PD-L1–positive NSCLC — has not yet been evaluated. As the ASCO Daily News noted, "a comparison of sac-TMT plus pembrolizumab and platinum doublet plus pembrolizumab is needed".
- The OptiTROP-Lung06 trial is already addressing a related question: in July 2026, Kelun-Biotech announced that the phase 3 OptiTROP-Lung06 study of sac-TMT plus pembrolizumab in PD-L1–negative, non-squamous NSCLC met its primary PFS endpoint at a prespecified interim analysis. This represents the first phase 3 study of an ADC plus immunotherapy to meet its primary endpoint in PD-L1–negative NSCLC.
Conclusion
The OptiTROP-Lung05 interim analysis represents a landmark achievement: the first phase 3 trial to demonstrate that an ADC plus pembrolizumab significantly improves outcomes versus pembrolizumab alone in first-line PD-L1–positive advanced NSCLC without targetable alterations. The 65% reduction in disease progression risk, the near-doubling of objective response rates, and the consistent benefit across PD-L1 strata and histologic subtypes position this combination as a potential new standard of care.
Equally significant is what this trial represents for China's biopharmaceutical innovation. Sacituzumab tirumotecan — a China-developed, independently developed ADC with full intellectual property — has now delivered the first positive phase 3 readout of its kind, validated by a global partnership with Merck. As Zhou and colleagues noted in The Lancet, the PFS benefit was "broadly consistent across subgroups". With mature OS data expected and the companion OptiTROP-Lung06 trial already showing promise in PD-L1–negative disease, the ADC–immunotherapy combination paradigm — powered by Chinese innovation — is rapidly reshaping the first-line treatment landscape for NSCLC.
"From follower to competitor, and now to leader" — the OptiTROP-Lung05 results exemplify China's emergence as a global force in oncology drug development.