Editor's Note: The 60th American Society of Clinical Oncology (ASCO) Annual Meeting was held from May 31 to June 4, 2024, in Chicago, USA. During the meeting, Professor Binghe Xu from the Chinese Academy of Medical Sciences Cancer Hospital presented groundbreaking results from the phase III OptiTROP-Breast01 study of China's first original TROP2 ADC, LuKangsa-Tropozumab (SKB264). This study, led by Professor Xu, primarily targeted advanced triple-negative breast cancer (TNBC) in China and showed that LuKangsa-Tropozumab 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 current TROP2 ADC with the best mPFS for TNBC. In this edition of "ASCO Voice of China," Professor Ying Fan shares insights into this pioneering achievement.Oncology Frontier: At the ASCO meeting, Professor Binghe Xu disclosed the data from the phase III OptiTROP-Breast01 study of China’s first original TROP2 ADC, LuKangsa-Tropozumab (SKB264), for the treatment of locally recurrent or metastatic TNBC. Could you introduce this study and its main results?
Professor Ying Fan: LuKangsa-Tropozumab is the first domestic TROP2 ADC drug developed by Sichuan Kelun Botai. As early as 2022 and 2023, it showed impressive early clinical research data at international conferences, demonstrating an ORR of 42.4%, a median PFS of 5.7 months, and a median OS of 16.8 months for advanced TNBC, which was very encouraging.
At this ASCO meeting, we reported the results of the OptiTROP-Breast01 study, a domestic, multicenter, randomized, controlled phase III study led by Professor Binghe Xu. This study targeted patients with advanced TNBC who had received at least two lines of standard chemotherapy and failed taxane treatment. A total of 263 patients were enrolled and randomized 1:1 to receive LuKangsa-Tropozumab or the physician’s choice of chemotherapy (TPC). The primary endpoint was PFS assessed by the Independent Review Committee (IRC), and secondary endpoints included OS, ORR, and investigator-assessed PFS.
This study yielded positive results for the first time. The primary endpoint showed that the median PFS assessed by IRC extended from 2.5 months in the TPC group to 6.7 months in the LuKangsa-Tropozumab group, reducing the risk of disease progression or death by 68% (HR=0.32, 95%CI 0.22-0.44, P<0.00001), a statistically significant difference. Although OS was immature, the LuKangsa-Tropozumab group showed significant statistical and clinical improvements (HR=0.53, 95%CI=0.36-0.78, P=0.0005). The ORR also significantly improved to 45.4% vs 12.0%, reaffirming the ORR from earlier clinical studies. Subgroup analysis showed greater PFS benefit for patients with high TROP2 expression (TROP2 H score >200). All current data of LuKangsa-Tropozumab demonstrated its significant clinical benefit compared to the chemotherapy control group, and it is expected to be approved in China soon.
Oncology Frontier: As you mentioned, LuKangsa-Tropozumab has shown ideal efficacy for advanced TNBC. Based on your clinical experience, how is its safety profile?
Professor Ying Fan: In the phase III OptiTROP-Breast01 study, involving 263 patients, LuKangsa-Tropozumab demonstrated safety consistent with phase I and II studies, with no new safety events and overall mild adverse events. The main grade 3 and above adverse reactions included leukopenia (25%), neutropenia (32%), and anemia (28%) as manifestations of bone marrow suppression, and oral ulcers (less than 10%), which were overall manageable.
In my center’s clinical research experience, the incidence of grade 3 and above bone marrow suppression is not high, and most patients do not require measures such as the use of G-CSF. If there are occasional cases of clear bone marrow suppression, preventive G-CSF treatment can allow patients to complete the entire treatment safely and smoothly. Most oral ulcers are grade 1-2 and can be well tolerated with preventive use of mouthwash for oral care.
Oncology Frontier: TROP2 ADC is reshaping the treatment landscape for advanced TNBC. In your view, what is the significance of the OptiTROP-Breast01 study for Chinese patients? How does LuKangsa-Tropozumab differ from other TROP2 ADCs?
Professor Ying Fan: The advent of TROP2 ADC drugs is a milestone for TNBC, significantly improving treatment efficacy. Currently, the only globally approved TROP2 ADC drug is Sacituzumab Govitecan (SG), which has just become available in China at a high cost. Therefore, we urgently need domestically developed TROP2 ADC drugs to fill this gap, and LuKangsa-Tropozumab has emerged in response.
Chemically, LuKangsa-Tropozumab differs from SG: it uses a different optimized CL2A linker, which irreversibly links to the antibody end and releases the toxin in the tumor microenvironment and tumor cells, enabling anti-tumor effects both inside and outside the cells. While both LuKangsa-Tropozumab and SG use topoisomerase I inhibitors, LuKangsa-Tropozumab employs a newly designed topoisomerase I inhibitor, T030, which contains a methylsulfonyl structure, enhancing linker stability and toxin permeability.
The OptiTROP-Breast01 study shows that LuKangsa-Tropozumab’s efficacy is not inferior to SG, with a longer numerical mPFS. Its bone marrow suppression is not prominent, and gastrointestinal toxicity is significantly reduced. Additionally, the study’s population was entirely Chinese, more closely reflecting real-world clinical practice and efficacy in Chinese breast cancer patients. Among the existing TROP2 ADC drugs, LuKangsa-Tropozumab stands out for its optimized efficacy and toxicity balance, which inspired us to name this study OptiTROP-Breast01.
Oncology Frontier: Besides TNBC, LuKangsa-Tropozumab has also shown good clinical performance in heavily pretreated advanced HR+/HER2- breast cancer patients. Could you discuss its specific achievements in this area?
Professor Ying Fan: For HR+/HER2- advanced breast cancer, last year’s European Society for Medical Oncology (ESMO) reported the initial results of LuKangsa-Tropozumab’s phase I/II basket study (KL264-01), showing outstanding efficacy. The study included HR+/HER2- advanced breast cancer patients requiring later-line treatment, with 66% having received CDK4/6 inhibitors, all receiving endocrine therapy and at least one line of chemotherapy after relapse and metastasis. In these patients, LuKangsa-Tropozumab achieved an ORR of over 36.8% and an mPFS of 11.1 months. Compared to other TROP2 ADC drugs like SG and Dato-DXd, LuKangsa-Tropozumab achieved the longest mPFS so far. Therefore, LuKangsa-Tropozumab holds great promise for achieving excellent results in HR+/HER2- advanced breast cancer.
We are also involved in another domestic, multicenter, randomized, controlled phase III study led by Professor Binghe Xu, primarily enrolling advanced breast cancer patients who have progressed after CDK46 inhibitor treatment and received at least 1-4 lines of chemotherapy. This study compares LuKangsa-Tropozumab head-to-head with physician’s choice treatment. The study is currently recruiting, and we will share the results once available.
Oncology Frontier: LuKangsa-Tropozumab has shown good performance in various breast cancer subtypes. How do you view its positioning in the breast cancer field, and what impact will it have on clinical practice and new drug development in China?
Professor Ying Fan: Internationally, LuKangsa-Tropozumab is jointly developed by Kelun Botai and Merck and has undergone multiple studies with impressive early data, gaining some international recognition. In breast cancer treatment, besides the reported TNBC data and ongoing HR+/HER2- advanced breast cancer studies, LuKangsa-Tropozumab is also being explored in first-line TNBC treatment compared head-to-head with chemotherapy, first-line combination with immunotherapy compared to standard treatment, and gradually moving towards the adjuvant treatment stage, seeking to provide better treatment outcomes for patients. Similarly, studies on LuKangsa-Tropozumab combined with other drugs in HR+/HER2- breast cancer are also underway and worth looking forward to.
In summary, TROP2 is a pan-cancer target, and ADCs developed based on it may have strong potential efficacy against various tumor types and different subtypes of tumors, bringing new treatment methods and optimizing overall treatment efficacy in the entire field of cancer treatment.
