On April 10, 2025, a research team led by Professor Li Zhang and Professor Wenfeng Fang from Sun Yat-sen University Cancer Center published a significant study in the world-renowned journal Nature Medicine.This marks the second time in just one month that Professor Zhang’s team has been featured in Nature Medicine. Their previous publication, released on March 13, presented the results of the first-in-human Phase I clinical trial of YL201, a novel antibody-drug conjugate (ADC) targeting B7-H3 for advanced solid tumors.
In this latest study, the team focused on Sacituzumab Tirumotecan for the treatment of advanced non-small cell lung cancer (NSCLC), achieving noteworthy progress.
The research was led by Sun Yat-sen University Cancer Center and carried out in collaboration with multiple global research institutions. It serves as a compelling example of the “China-led, globally coordinated” research model and highlights China’s growing impact and innovation in the field of international oncology research.
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% to 85% of all lung cancer cases.
The majority of patients are diagnosed at an advanced stage, where prognosis tends to be poor. Although current treatment strategies—including platinum-based chemotherapy, immune checkpoint inhibitors, and targeted therapies for specific gene mutations—can provide disease control for a period of time, most patients eventually develop resistance, leading to disease progression. Therefore, there is an urgent need to develop novel and effective treatment options for patients with advanced NSCLC.
Sacituzumab Tirumotecan Breaks Through the TROP2-ADC Bottleneck in NSCLC
TROP2, a transmembrane glycoprotein overexpressed in many solid tumors including lung cancer, has emerged as a promising target for ADC development. However, two Phase III trials involving existing TROP2-ADCs—SG and Dato-DXd—failed in previously treated, unselected NSCLC populations.
Sacituzumab Tirumotecan is a next-generation TROP2-targeting ADC that incorporates proprietary conjugation technology, a novel cytotoxic payload, and a high drug-to-antibody ratio (DAR). This design enhances the drug’s stability and antitumor activity while minimizing off-tumor toxicity.
Under the leadership of Professor Li Zhang’s team, results from a Phase II study provided the foundation for two multicenter, randomized controlled registration trials focused on patients with EGFR-mutant NSCLC who had developed resistance to prior therapies.
On March 4, 2025, Sacituzumab Tirumotecan was granted a new indication for the treatment of adult patients with locally advanced or metastatic EGFR mutation-positive non-squamous NSCLC who had progressed following EGFR-TKI and platinum-based chemotherapy. This approval marks the first time a TROP2 ADC has been authorized for use in lung cancer, establishing Sacituzumab Tirumotecan as a leader in this therapeutic space.
Dual Studies Demonstrate a Synergistic Model of Exploration and Validation
The Nature Medicine publication comprises two key clinical studies: Cohort 3A of the KL264-01 trial and Part 1 of the SKB264-II-08 trial.
The KL264-01 trial is a global, multicenter, open-label Phase I/II study evaluating the safety and efficacy of Sacituzumab Tirumotecan across multiple advanced solid tumors. Cohort 3A included 43 patients with advanced NSCLC, encompassing both EGFR wild-type and EGFR-mutant subgroups.
The SKB264-II-08 trial is a Phase II study designed to further validate the efficacy of Sacituzumab Tirumotecan in advanced NSCLC. Part 1 of this trial enrolled 64 patients with EGFR-mutant NSCLC, divided into two groups:
- Cohort 1 included patients who were resistant to EGFR tyrosine kinase inhibitors (TKIs) and had received prior platinum-based chemotherapy
- Cohort 2 included patients who were resistant to TKIs but had not received chemotherapy.
Both studies were conducted globally, involving patients from Asia, Europe, and North America, thereby accounting for regional differences and providing a broader understanding of the drug’s therapeutic potential. This international, multicenter approach not only accelerated the clinical development timeline but also laid a solid foundation for global drug registration and commercialization.
Efficacy Data Lead the Field, With Greater Benefit Observed in EGFR-Mutant NSCLC Patients
Across the full analysis sets (FAS) from KL264-01 (n=43) and SKB264-II-08 (n=64), Sacituzumab Tirumotecan demonstrated robust antitumor activity.
In KL264-01 Cohort 3A, as of March 5, 2024, the median follow-up time was 26 months. The overall objective response rate (ORR) reached 40%, with a disease control rate (DCR) of 81%. Median duration of response (DoR) was 8.7 months, median progression-free survival (PFS) was 6.2 months, and median overall survival (OS) was 21.8 months.
Among EGFR wild-type patients, the ORR was 24% and median PFS was 5.3 months. In contrast, EGFR-mutant patients experienced significantly greater clinical benefit, with an ORR of 55% and median PFS of 11.1 months.
Further subgroup analysis confirmed that patients with EGFR mutations derived more benefit from Sacituzumab Tirumotecan monotherapy compared to those with wild-type EGFR, highlighting its potential as a promising therapeutic option in this high-need population.
Among the 64 patients enrolled in Part 1 of the SKB264-II-08 trial, as of April 19, 2024, the median follow-up duration was 12.7 months. The objective response rate (ORR) reached 34%, with a median duration of response (DoR) of 9.6 months. The median progression-free survival (PFS) was 9.3 months, and the median overall survival (OS) had not yet been reached at the time of data cut-off.
Unique Mechanism Drives Outstanding Efficacy: EGFR Mutations May Further Enhance Sacituzumab Tirumotecan’s Potential
Antibody-drug conjugates (ADCs) are composed of a monoclonal antibody linked to a cytotoxic payload via a specialized linker. An ideal ADC remains stable in systemic circulation, precisely targets tumor cells, and releases its cytotoxic payload only upon reaching the tumor microenvironment. Sacituzumab Tirumotecan was designed to meet these criteria, incorporating a high-affinity antibody, excellent stability, a high drug-to-antibody ratio (DAR), and three distinct antitumor mechanisms, all of which underpin its potent clinical activity.
First, Sacituzumab Tirumotecan is an innovative ADC targeting TROP2—a promising therapeutic target that is minimally expressed in normal tissues, thereby enhancing treatment precision and reducing off-target toxicity.
Second, it consists of a humanized anti-TROP2 monoclonal antibody with high affinity and selectivity. This antibody is conjugated via a next-generation, methanesulfonyl pyrimidine-based linker (CL2A) using a proprietary conjugation technology that ensures irreversible binding on the antibody side. On the payload side, it is linked to T030, a novel self-developed topoisomerase I inhibitor. This design results in a DAR as high as 7.4.
Furthermore, mechanistic studies have shown that activated EGFR mutations can significantly enhance the internalization of Sacituzumab Tirumotecan and its antitumor activity. These findings align with clinical observations, suggesting that patients with EGFR-mutant NSCLC may derive particularly strong benefit from Sacituzumab Tirumotecan monotherapy.
Favorable Safety Profile: Sacituzumab Tirumotecan Demonstrates Manageable Adverse Events in Clinical Use
In terms of safety, Sacituzumab Tirumotecan has shown good tolerability. Among 107 patients who received sac-TMT treatment, 98% experienced treatment-related adverse events (TRAEs) of any grade, while 71% reported grade 3 or higher TRAEs. The most common adverse events were hematologic toxicities; however, most patients recovered quickly with appropriate supportive care. These findings indicate that Sacituzumab Tirumotecan has an overall manageable safety profile, and its treatment-related toxicities can be effectively controlled with adequate medical support.
Future Outlook: Global Phase III Trials Underway
Thanks to the leadership of Chinese investigators in global multicenter trials, Sacituzumab Tirumotecan has successfully overcome the development challenges faced by other TROP2-targeting ADCs. Unlike similar international agents that failed to achieve efficacy in NSCLC, Chinese researchers made a pivotal discovery showing that EGFR mutations can enhance ADC internalization. This mechanistic insight, combined with the dual validation from the KL264-01 and SKB264-II-08 studies, supports a strategy of “precision enrichment and full-pathway coverage,” and has confirmed the efficacy of Sacituzumab Tirumotecan in lung cancer treatment.
Several Phase III clinical trials targeting EGFR-mutant NSCLC are currently ongoing. These include SKB264-III-09 (NCT05870319), which focuses on patients with EGFR-TKI resistance who have not received chemotherapy, and SKB264-III-15 (NCT06670196), a first-line treatment trial combining Sacituzumab Tirumotecan with osimertinib in previously untreated patients with EGFR mutations. These studies cover the entire disease course of advanced EGFR-mutant NSCLC and are expected to expand treatment options for this patient population.
Professor Li Zhang and Professor Wenfeng Fang from Sun Yat-sen University Cancer Center are the corresponding authors of the study. The co–first authors include Dr. Shen Zhao and Dr. Jun Liao from Sun Yat-sen University Cancer Center, Professor Ying Cheng from Jilin Cancer Hospital, Professor Qiming Wang from Henan Cancer Hospital, Professor Xingya Li from the First Affiliated Hospital of Zhengzhou University, Dr. Jordi Rodon Ahnert from MD Anderson Cancer Center, Professor Xiangjiao Meng from Shandong Cancer Hospital, and Professor Yongzhong Luo from Hunan Cancer Hospital.
Reference: Zhao, S., Cheng, Y., Wang, Q. et al. Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials. Nature Medicine (2025). https://doi.org/10.1038/s41591-025-03638-2
Corresponding Author
Professor Li Zhang Director of the Department of Medical Oncology, Sun Yat-sen University Cancer Center Doctoral Supervisor, Senior Professor (Tier 2), Chief Expert in Lung Cancer
- Chair, Committee on Cancer Rehabilitation and Palliative Care, Chinese Anti-Cancer Association (CACA)
- Chair-Elect, Committee on Clinical Oncology Drug Research, Chinese Anti-Cancer Association (CACA)
- Chair, Committee on Immunotherapy, Chinese Society of Clinical Oncology (CSCO)
- Vice Chair, Committee on Non-Small Cell Lung Cancer, Chinese Society of Clinical Oncology (CSCO)
- Vice Chair, Committee on Supportive and Rehabilitation Care in Oncology, Chinese Society of Clinical Oncology (CSCO)
- Chair, Clinical Research Branch, Guangdong Medical Association
- Chair, Precision Medicine Branch, Guangdong Society of Clinical Medicine
Corresponding Author
Professor Wenfeng Fang Chief Physician and Professor, Sun Yat-sen University Cancer Center Principal Investigator at the State Key Laboratory of Oncology in South China Doctoral Supervisor
- Selected Young Talent, National High-Level Talent Program
- Top Young Talent, Guangdong Provincial Special Support Program (“Hundred-Thousand-Ten Thousand Project”)
- Outstanding Young Medical Talent of Guangdong Province
- Pearl River Science and Technology Star, Guangzhou
- Member, Committee on Non-Small Cell Lung Cancer, Chinese Society of Clinical Oncology (CSCO)
- Member, Committee on Nasopharyngeal Carcinoma, Chinese Society of Clinical Oncology (CSCO)
- Standing Member, Lung Cancer Committee, Chinese Anti-Cancer Association
- Vice Chair, Youth Committee on Nasopharyngeal Carcinoma, Guangdong Anti-Cancer Association
- Vice Chair, Committee on Precision Medicine and Molecular Diagnostics, Guangdong Medical Association
- Vice Chair, Committee on Real-World Clinical Research, Guangdong Society of Clinical Medicine
First Author
Dr. Shen Zhao Associate Research Fellow, Associate Chief Physician, and Master’s Supervisor Sun Yat-sen University Cancer Center
- Graduate of the Eight-Year Clinical Medicine Program, Sun Yat-sen University
- Secretary, Committee on Precision Therapy and Clinical Research in Lung Cancer, Guangdong Society of Clinical Medicine
- Youth Committee Member, Chemotherapy Division, Guangdong Anti-Cancer Association
- Selected as one of CSCO’s “35 Most Promising Young Oncologists” in 2023
Research Focus: Targeted therapy and immunotherapy in lung cancer, including clinical and translational research
Principal Investigator of Projects Supported by: National Natural Science Foundation of China, China Postdoctoral Science Foundation, Outstanding Young Investigator Program at Sun Yat-sen University Cancer Center, Youth Talent Think Tank Program of the China Association for Science and Technology
Publications: The Lancet Oncology, Cancer Cell, Nature Communications, Journal of Thoracic Oncology, Journal of Hematology & Oncology
