ASCO Voice of China丨Professor Fan Ying: Completely breaking the ceiling of mTNBC 2L+ treatment, the first Chinese original TROP2 ADC, recanzatumumab, leads to longer PFS benefits
Editor's note: The 60th Annual Meeting of the American Society of Clinical Oncology (ASCO) was held in Chicago, USA, from May 31 to June 4, 2024. During the meeting, Academician Xu Binghe from the Cancer Hospital of the Chinese Academy of Medical Sciences gave an oral report on the amazing results of the OptiTROP-Breast01 clinical trial of Lukang sartuzumab (SKB264), the first TROP2 ADC in China. The study, led by Academician Xu Binghe, focused on the post-line treatment of advanced triple-negative breast cancer (TNBC) in China, and showed that Lukang satuzumab achieved a median progression-free survival (PFS) of 6.7 months, an objective response rate (ORR) of 45.4%, and a significant improvement in overall survival (OS), making it the TROP2 ADC with the best mPFS in the current post-line treatment of TNBC. In this issue of "ASCO Voice of China", Professor Fan Ying will take you to appreciate China's original style.
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Tumor Outlook: At this ASCO conference, Academician Xu Binghe disclosed the data of the first Chinese original TROP2 ADC, Lukang satuzumab (SKB264), in the treatment of locally recurrent or metastatic TNBC Phase III clinical trial OptiTROP-Breast01.
Prof. Ying Fan: Lukang satuzumab is the first TROP2 ADC drug developed by Sichuan Kelunbotai in China. As early as 2022 and 2023, it has presented impressive data from early clinical studies at international conferences, showing that for advanced TNBC, the single-agent objective response rate (ORR) is 42.4%, the median progression-free survival (PFS) is 5.7 months, and the median overall survival (OS) reaches 16.8 months, which is very exciting.
The OptiTROP-Breast01 study we reported at ASCO is a domestic multicenter, randomized, controlled phase III study led by Academician Xu Binghe. The study targeted patients with advanced TNBC after multiple lines of therapy and required patients to have received at least two prior lines of standard chemotherapy regimens and failed both taxane therapy. A total of 263 patients were enrolled and randomly assigned 1:1 to sartuzumab and physician-selected chemotherapy regimen (TPC). The primary endpoint was PFS as assessed by the Independent Review Committee (BICR), and the secondary endpoints included overall survival, objective response rate, investigator-assessed PFS, etc.
△OptiTROP-Breast01研究设计
This is the first report of the results of the study, and the preliminary positive results have been obtained. The primary endpoint showed a statistically significant difference in the risk of disease progression or death with a 68% reduction in the risk of disease progression or death (HR=0.32, 95% CI 0.22-0.44, P<0.00001) in mPFS as assessed by BICR from 2.5 months in the TPC arm to 6.7 months in the rukang satuzumab arm. Although OS was still immature, the sartozumab group also showed statistically significant and clinically meaningful improvements (HR=0.53, 95%CI=0.36-0.78, P=0.0005). The ORR was also significantly improved at 45.4% vs 12.0%, reaffirming the ORR of the previous clinical study. In addition, subgroup analyses showed a greater mPFS benefit from sartuzumab rucon in patients with high TROP2 expression (TROP2 H score >200).
△OptiTROP-Breast01研究的BICR PFS分析
△OptiTROP-Breast01研究的BICR ORR分析
At this stage, all the data obtained by Lukang satuzumab confirm its significant clinical benefit compared with the chemotherapy control group, and it is expected to be approved for marketing in China soon.
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Tumor Outlook: As you said, the efficacy of rekang satuzumab in advanced TNBC is very ideal, please talk about its safety based on clinical experience?
Prof. Ying Fan: After treatment, the 263 patients included in the phase III OptiTROP-Breast01 study showed that the safety profile of rekang satuzumab was consistent with that of the phase I and phase II studies, with no new safety events occurring, and the overall adverse events were relatively mild. The main adverse reactions of grade 3 and above were bone marrow suppression manifested by leukopenia (25%), neutropenia (32%) and anemia (28%), as well as oral ulcers (<10%), which were generally safe and controllable.
Based on the experience of clinical research carried out by our center, the bone marrow suppression of grade 3 and above is not high, and the absolute majority of patients do not need to use coping measures such as whitening needles. In the rare case of definite myelosuppression, the patient can be treated smoothly and safely with prophylactic whitening. In terms of mouth ulcers, most of them are grade 1 to 2 and are well tolerated by oral care with prophylactic use of mouthwash.
03
Oncology Outlook: TROP2 ADCs are reshaping the treatment landscape for advanced TNBC. In your opinion, what is the significance of the announcement of the OptiTROP-Breast01 study in Chinese patients? How is sartolizumab different from other TROP2 ADCs?
Prof. Ying Fan: The emergence of TROP2 ADC is a milestone for TNBC and has greatly improved the therapeutic effect. At present, the only approved TROP2 ADC drug in the world is gosatuzumab (SG), which is just now available in mainland China and is expensive. Therefore, we urgently need to develop the original TROP2 ADC drug in China to fill the gap in this field, and recançum sartuzumab came into being.
Lukang satuzumab is different from SG in terms of chemical structure: in terms of linker, it uses an optimized CL2A linker that is different from SG, which can be irreversibly coupled to the antibody end to release toxins in the tumor microenvironment and tumor cell cleavage, so that it can exert anti-tumor effects in both intracellular and extracellular. In terms of drug loading, although Lukang satuzumab and SG are both topoisomerase I inhibitors, Lukang satuzumab is a newly designed topoisomerase I inhibitor T030, which contains a methyl sulfone structure, which improves the stability of the linker and the membrane permeability of the toxin.
△芦康沙妥珠单抗(Sacituzumab Tirumotecan)的药物结构
From the OptiTROP-Breast01 study reported this time, we can see that the efficacy of sartuzumab is not inferior to that of SG, and even the mPFS is longer in value; In terms of safety, bone marrow suppression is not prominent, and gastrointestinal toxicity is significantly reduced; In addition, the enrollment population of the study is all Chinese patients, which is closer to the clinical practice and efficacy of Chinese breast cancer patients in the real world. Therefore, from the perspective of existing TROP2 ADC drugs, sartuzumab is a drug with more optimized efficacy and toxicity and more balance. That's why we named the study OptiTROP-Breast01.
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Tumor Outlook: In addition to TNBC, rekang satuzumab also has good clinical manifestations in patients with advanced HR+/HER2- breast cancer who have undergone multiple lines of chemotherapy.
Prof. Ying Fan: In terms of HR+/HER2- advanced breast cancer, the results of the preliminary Phase I/II basket study of sartuzumab (KL264-01 study) were reported at the European Oncology Congress (ESMO) last year, and the efficacy is very outstanding. The patients included in the study were all HR+/HER2- advanced breast cancer requiring post-line therapy, of which 66% had been treated with CDK4/6 inhibitors, and all of them had received endocrine therapy and at least first-line chemotherapy after recurrence and metastasis, and belonged to the drug-resistant population. After treatment with rucon satuzumab in these patients, an ORR of more than 36.8% was achieved with an mPFS of 11.1 months. Compared with other TROP2 ADC drugs such as SG and Dato-DXd, sartozumab achieved longer mPFS with rucan. Therefore, sartuzumab is very promising for achieving very good results in HR+/HER2- advanced breast cancer.
At present, we are also participating in another domestic, multicenter, randomized, controlled phase III study led by Academician Xu Binghe, mainly including patients with advanced breast cancer who have progressed after prior treatment with CDK46 inhibitors and have had at least 1-4 lines of chemotherapy, and are randomized to compare recançum satuzumab with the doctor's choice of treatment regimen head-to-head. The study is now in the process of enrollment, and we will share the results as soon as they are available.
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Tumor Outlook: Recanzazumab performs well in various subtypes of breast cancer, how do you see its layout in the field of breast cancer? What impact will it have on the clinical practice and new drug development of breast cancer in mainland China?
Prof. Ying Fan: Lukang satuzumab was jointly developed by Columbus and Merck in the world, and a number of studies have been carried out, and the preliminary data performance is amazing, and it has been recognized internationally. In terms of breast cancer treatment, in addition to the reported TNBC data and ongoing research on HR+/HER2- advanced breast cancer, recanzalizumab is also exploring head-to-head comparisons between first-line and chemotherapy and head-to-head comparisons between first-line combined immunotherapy and standard therapy in the field of TNBC, and gradually moving to the adjuvant treatment stage to seek the possibility of bringing better treatment outcomes to patients. Similarly, in HR+/HER2- breast cancer, future studies of rekang satuzumab in combination with other drugs are also underway, which is worth looking forward to.
All in all, TROP2 is a pan-tumor target, and ADCs developed based on it may have the potential to have powerful efficacy on multiple tumor types or multiple different types of tumors, thereby bringing new therapeutic approaches to the entire tumor treatment field and optimizing the overall treatment effect.
Prof. Ying Fan
Director of the Breast Disease Ward of the Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences
Chief physician, master's supervisor, eight-year doctor of Peking Union Medical College
2008-2009 Royal Marsden Hospital/ICR Scholar
Vice Chairman and Secretary-General of the Clinical Research Innovation and Development Committee of the China Medical Education Association
Vice Chairman of the Youth Committee of the Beijing Society for the Prevention and Treatment of Breast Diseases
Vice Chairman of the Youth Committee of Beijing Cancer Prevention and Treatment Research Association
He is a member of the Clinical Research Committee of Oncology Drugs of the Chinese Anti-Cancer Association
He is a member of the Cancer Chemotherapy Committee of the Chinese Anti-Cancer Association
Member of the CSCO Youth Professional Committee