Compiled by: Oncology NewsSource: Oncology News
In the field of lung cancer treatment, patients with EGFR-mutated non-small cell lung cancer (NSCLC) have long faced a “treatment desert” after developing resistance to TKI therapy, with traditional chemotherapy offering limited efficacy and significant side effects. The Chinese innovative drug, sacituzumab tirapazamine, developed by Professor Zhang Li’s team, is the world’s first TROP2 ADC approved for lung cancer treatment. Its related research results have not only been published in top international journals such as BMJ, but have also broken the deadlock in the treatment of EGFR-mutated lung cancer patients in later lines of therapy. Oncology News invited Professor Zhang to provide an in-depth interpretation of the clinical value, research design wisdom, and future potential to reshape the treatment landscape for lung cancer, showcasing the significant contributions of Chinese innovative drugs in the global lung cancer treatment arena.
Professor Zhang LiDirector of the Department of Medical Oncology, Sun Yat-sen University Cancer Center, PhD Supervisor, Professor, Chief Expert in Lung Cancer
Honorary Chairman of the Cancer Rehabilitation and Palliative Care Committee of the Chinese Anti-Cancer Association (CACA)Incoming Chairman of the Clinical Research Committee of the Chinese Anti-Cancer Association (CACA)Vice Chairman of the Small Cell Lung Cancer Committee of the Chinese Anti-Cancer Association (CACA)Executive Director of the Chinese Society of Clinical Oncology (CSCO)Chairman of the Immunotherapy Expert Committee of the Chinese Society of Clinical Oncology (CSCO)Vice Chairman of the Non-Small Cell Lung Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO)Vice Chairman of the Supportive Care and Rehabilitation Committee of the Chinese Society of Clinical Oncology (CSCO)Chairman of the Clinical Research Branch of the Guangdong Medical AssociationChairman of the Precision Medicine Committee of the Guangdong Clinical Medicine AssociationLeading talent in Guangdong Province, Outstanding Talent of the “Special Support Plan” (Nanyue Hundred Talents)
Addressing Clinical Pain Points: Breaking the Dilemma of Treatment for EGFR-Mutated Lung Cancer
EGFR mutations are a common type of driver gene mutation in non-small cell lung cancer, with a mutation rate as high as 40%-50% among patients in China, particularly significant in the Asian patient population. The advent of EGFR-TKIs has greatly improved treatment outcomes for these patients, but the issue of resistance is unavoidable. After patients undergo first-line and second-line TKI treatments, and even fail subsequent platinum-based chemotherapy, clinical treatment options become extremely limited, with docetaxel becoming the standard treatment in this phase. However, the treatment efficacy of docetaxel falls far short of clinical expectations. Its objective response rate is only about 10%-15%, with a short duration of response, and the median progression-free survival (PFS) for patients is only 2.8 months. Additionally, docetaxel can cause a series of side effects such as bone marrow suppression and fatigue, severely impacting patients’ quality of life. For patients with EGFR-mutated lung cancer, the dilemma of “poor efficacy and high toxicity” in later-line treatment urgently needs to be overcome. The emergence of sacituzumab tirapazamine has brought a turning point to break this deadlock. In earlier phase I/II clinical trials, the research team found that the efficacy of this drug was particularly prominent in EGFR mutation-positive patients, with an objective response rate exceeding 50%. Based on this positive result, the team further conducted the OptiTROP-Lung03 randomized controlled study1. This study focused on EGFR mutation-positive non-small cell lung cancer patients who had failed EGFR-TKI and platinum-based chemotherapy, comparing the efficacy and safety of sacituzumab tirapazamine with docetaxel. The final study results showed that sacituzumab tirapazamine exhibited significant advantages: the objective response rate in the experimental group reached 45%, nearly three times that of the docetaxel control group (16%); the median PFS was extended from 2.8 months in the control group to 6.9 months; more importantly, the overall survival (OS) of patients showed significant improvement, with a 51% reduction in the risk of death. This achievement not only confirmed the outstanding efficacy of sacituzumab tirapazamine in later-line treatment of EGFR-mutated lung cancer but also provided strong evidence for ending the “chemotherapy era” and replacing docetaxel with sacituzumab tirapazamine as an important treatment option in this field.
Precision Design Shows Wisdom: Breakthroughs from Mechanistic Research to Clinical Translation
In the development process of sacituzumab tirapazamine, the precise selection of target populations was key to the success of the research. Previously, two TROP2 ADCs had been studied in the field of non-small cell lung cancer, but due to the use of an “all-comer” enrollment strategy, which included both EGFR mutation-positive and negative patients as well as different pathological types (such as adenocarcinoma and squamous cell carcinoma), both large phase III clinical trials ultimately ended with negative results. This experience highlighted to the research team the importance of precisely selecting beneficiary populations for drugs like TROP2 ADCs. Based on this insight, the research team focused on identifying advantageous populations in the phase I/II clinical trials of sacituzumab tirapazamine, discovering that the treatment effect in EGFR mutation-positive patients was significantly better than in wild-type patients. To explore the underlying mechanisms, the team conducted translational research, and relevant results were published in Nature Medicine this April. The study found that EGFR mutation-positive patients not only had higher TROP2 expression levels but, more importantly, the endocytic activity of TROP2 was significantly enhanced2. The mechanism of action of ADC drugs is to target and bind to tumor cell surface antigens, which are then internalized by the cells and release cytotoxic agents under lysosomal action, thereby killing tumor cells. Therefore, merely having high antigen expression does not guarantee good drug efficacy; an efficient endocytic process is also crucial. Translational research further confirmed that after introducing EGFR gene mutations into lung cancer cell lines, the endocytic effect of sacituzumab tirapazamine was significantly enhanced, which also explains why EGFR mutation-positive patients can derive more significant benefits from this drug treatment. It is precisely based on a profound understanding of the drug’s mechanism of action and the positive results of earlier clinical trials that the research team designed the OptiTROP-Lung03 study, precisely focusing on patients who had failed EGFR-TKI and chemotherapy. This “from Bench to Bedside” translational medicine thinking, along with a population enrichment strategy based on biological principles, not only maximized the efficacy advantages of sacituzumab tirapazamine but also avoided diluting efficacy in insensitive populations, providing a valuable example for the global development of TROP2 ADCs in lung cancer, showcasing the wisdom and strength of Chinese innovative drug development.
Expanding Treatment Boundaries: Leading New Changes in the Lung Cancer Treatment Ecosystem
The approval of sacituzumab tirapazamine for the treatment of NSCLC after failure of EGFR-TKI and platinum-based chemotherapy is just the starting point for reshaping the lung cancer treatment ecosystem. To allow more patients to benefit earlier and more fully, the research team has initiated multiple follow-up studies to continuously expand the treatment boundaries of this drug. Among them, the OptiTROP-Lung04 phase III randomized controlled study will move the treatment line forward, targeting patients who have developed resistance to EGFR-TKI but have not yet received chemotherapy, comparing the efficacy of sacituzumab tirapazamine with pemetrexed plus carboplatin regimen. This study has already achieved positive results, and detailed data will be presented at this year’s ESMO conference, with current data still under confidentiality. If the results of this study are successfully translated into clinical applications, it will enable EGFR mutation lung cancer patients to use this highly effective and low-toxicity drug in the second-line treatment phase, further extending patient survival and improving quality of life. On this basis, the research team has not stopped but has challenged first-line treatment, designing the OptiTROP-Lung07 study. This study uses a combination of osimertinib and sacituzumab tirapazamine, directly comparing the efficacy of the combination regimen with osimertinib monotherapy in first-line treatment of EGFR mutation lung cancer. Currently, the OptiTROP-Lung07 study has completed enrollment and is in the follow-up phase. Considering that the median PFS of osimertinib monotherapy has reached 16-18 months, the follow-up period for this study is expected to take 1.5-2 years. If successful, this study will provide a new combination treatment strategy for first-line treatment of EGFR mutation lung cancer, further enhancing treatment outcomes for patients.
Conclusion
The development and application of sacituzumab tirapazamine not only brings good news to Chinese patients with EGFR-mutated lung cancer but also sets a benchmark for Chinese innovative drugs in the global lung cancer treatment field. Currently, foreign studies of similar TROP2 ADCs are often inspired by the research design ideas of this drug, and Chinese innovative drugs have transitioned from “catching up and running” to “leading”. As highlighted in the editorial of the New England Journal of Medicine, how to enable global patients (including those in the United States) to benefit from the research achievements of Chinese new drug development has become an important issue in the international pharmaceutical field. In the future, with the emergence of more clinical research results, sacituzumab tirapazamine is expected to play a greater role in lung cancer treatment, driving the global lung cancer treatment ecosystem towards more precise and efficient transformations.
References
[1]. Fang W, Li X, Wang Q, et al. Sacituzumab tirapazamine versus docetaxel for previously treated EGFR-mutated advanced non-small cell lung cancer: multicentre, open label, randomised controlled trial. *BMJ*. 2025;389:e085680. doi:10.1136/bmj-2025-085680.[2]. Zhao S, Cheng Y, Wang Q, et al. Sacituzumab tirapazamine in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials. *Nat Med*. 2025. doi:10.1038/s41591-025-03638-2.
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