Prof. Yongmei Yin at 2023 ESMO: SKB264 (MK-2870), an innovativeTROP2-ADC originating from Chinese biotech, achieves remarkable success in overcoming the therapeutic impasse in HR+/HER2- metastatic breast cancer

CHENGDU, China, Oct. 26, 2023 /PRNewswire/ -- The European Society for Medical Oncology (ESMO) convened its annual meeting in Madrid, Spain, from October 20th to 24th, 2023. As the preeminent academic gathering in the field ofoncology, it brought together global experts in oncology to share the latest research findings and exchange experiences in clinical diagnosis and treatment across various tumor types. In the realm of breast cancer research, Professor Yongmei Yin from Jiangsu Province Hospital, representing the research team, delivered an oral presentation on the study data of SKB264 (MK-2870) (MK-2870) used in the treatment of HR+/HER2- metastatic breast cancer patients who have previously undergone chemotherapy. The principal investigators of this study included Professor  Quchang Ouyang from Hunan Cancer Hospital, Professor Yongmei Yin from Jiangsu Province Hospital, Professor Lihua Song from Shandong Cancer Hospital, Professor Min Yan from Henan Cancer Hospital, ProfessorXinhong Wu from Hubei Cancer Hospital, Professor Zhongsheng Tong from Tianjin Medical University Cancer Institute & Hospital, Professor Yunpeng Liu from The First Hospital of China Medical University, and Professor Xian Wang from Sir Run Run Shaw Hospital Affiliated with Zhejiang University School of Medicine. Oncology News invited Professor Yongmei Yin to discuss the initial intent behind the study design, dissect the key data findings, and explore the potential applications of SKB264 (MK-2870).

 An innovativeTROP2-ADC originating from Chinese biotech has ascended to challenge the therapeutic impasse of previously treated HR+/HER2- metastatic breast cancer.

According to the data from the International Agency for Research on Cancer (IARC) in 2020, the incidence of new breast cancer cases has exceeded that of lung cancer, making it the most prevalent cancer globally. Breast cancer of the HR+/HER2- subtype constitutes approximately 70%, making it the most prevalent subtype of breast cancer. Endocrine therapy serves as the foundation for the treatment of HR+/HER2- breast cancer, while the use of CDK4/6 inhibitors significantly extends the survival period for patients with HR+/HER2- metastatic breast cancer. However, for patients with HR+/HER2- metastatic breast cancer who have experienced treatment failure with endocrine and CDK4/6 inhibitor therapies, the efficacy of currently available treatment options is limited. There is an urgent need for more effective therapeutic drugs to improve clinical prognosis.

In recent years, innovative ADC therapeutics, exemplified by TROP2-ADCs, have introduced new treatment alternatives for patients diagnosed with HR+/HER2- breast cancer. Sacituzumab govitecan (SG) has received FDA approval for use in HR+/HER2- breast cancer patients who have previously undergone endocrine therapy and at least two lines of systemic treatment for metastatic disease. Furthermore, the results of a Phase III study on Dato-DXd, another TROP2-targeted ADC, have been disclosed at the ESMO conference this year. At present, no TROP2-ADC has received approval for use in HR+/HER2- breast cancer patients within China, which constitutes an immediate unmet medical need.

SKB264 (MK-2870), an innovative TROP2-ADC  originating from Kelun-Biotech and jointly developed in collaboration with Merck, was presented at the 2023 ESMO conference. The study preliminarily explored the therapeutic efficacy and safety of SKB264 (MK-2870) in patients with HR+/HER2- metastatic breast cancer who had previously undergone at least one line of chemotherapy. The promising therapeutic efficacy data demonstrated by SKB264 (MK-2870), along with its potential value for clinical treatment and future research, were the primary factors for its selection as an oral presentation at the ESMO conference. SKB264 (MK-2870) has been awarded  breakthrough therapy designation by the Center for Drug Evaluation (CDE) of the National Medical Products Administration. This designation is for the treatment of patients with locally advanced or HR+/HER2- metastatic breast cancer who have previously undergone at least two lines of systemic chemotherapy.

In the realm of breast cancer, beyond HR+/HER2- breast cancer, SKB264 (MK-2870) has also been awarded breakthrough therapy designation by the CDE for the treatment of locally advanced or metastatic TNBC. The Phase III registrational study of SKB264 (MK-2870) for the treatment of locally advanced or metastatic TNBC has achieved its primary endpoint. The plan is to submit for marketing approval by the end of the year, with the potential to become the first approved TROP2-ADC on the Chinese market.

The efficacy data for SKB264 (MK-2870) is promising, positioning it as a potential new therapeutic option for the treatment of HR+/HER2- metastatic breast cancer.

The Phase II study presented at ESMO aimed to assess the therapeutic efficacy and safety of SKB264 (MK-2870) in patients with HR+/HER2- metastatic breast cancer who had previously undergone at least one line of chemotherapy. Patients enrolled in the study received SKB264 (MK-2870) treatment at a dosage of 5 mg/kg every two weeks (Q2W), continuing until either disease progression or the emergence of intolerable toxicity. At a median follow-up duration of 8.2 months, therapeutic efficacy was evaluable in 38 patients. Among these, 47% exhibited primary endocrine drug resistance, 79% had undergone at least two lines of chemotherapy, and 65.8% had previously been treated with CDK4/6 inhibitors.

In the context of efficacy, post-SKB264 (MK-2870) treatment demonstrated an objective response rate (ORR) of 36.8%, a disease control rate (DCR) of 89.5%, and a 6-month duration of response (DoR) rate of 80%. In terms of survival data, the median progression-free survival (PFS) duration was 11.1 months. In comparison, the prevailing guidelines currently recommend chemotherapy as the principal treatment strategy for this patient demographic. However, the objective response rate (ORR) for chemotherapy stand at a mere 15%, with progression-free survival (PFS) limited to approximately 4 to 5 months. Therefore, the findings from this Phase II study clearly indicate that the therapeutic efficacy of SKB264 (MK-2870) significantly surpassed that of chemotherapy and couldoffer enhanced survival benefits to patients. As the follow-up period continues to be extended, it is anticipated that the survival data from this study will yield further encouraging outcomes. Notably, all subpopulations derived benefits from  SKB264 (MK-2870) treatment, including patients with low and null HER2 expression, those with primary and secondary endocrine drug resistance, and those who have previously been treated with CDK4/6 inhibitors.

In terms of safety, the study demonstrated a low occurrence rate of Grade 3 or higher treatment-related adverse events (TRAEs), with merely 17.1% of patients experiencing dose reductions as a result of TRAEs. Importantly, no instances of treatment discontinuation or death were attributed to TRAEs. The primary adverse events observed were clinically prevalent hematological toxicities, with no incidence of interstitial lung disease (ILD).

SKB264 (MK-2870) showcases a unique structural design that balances potent antitumor activity with safety.

The favorable antitumor activity and safety profile exhibited by SKB264 (MK-2870) can be attributed to the design of its ADC pharmaceutical formulation. SKB264 (MK-2870) is a construct of a humanized anti-TROP2 monoclonal antibody, exhibiting strong affinity and specificity. It is conjugated to a proprietary small molecule toxin T030 (novel topoisomerase I inhibitor) via a stability-optimized CL2A linker, whose antibody end is irreversibly coupled with the antibody using methanesulfonylpyrimidine, resulting in a high average drug-to-antibody ratio (DAR) of up to 7.4. T030, with antitumor activity equivalent to DXd, incorporates a methyl sulfone structure, enabling stable binding to the toxin end of the linker and minimizing detachment. SKB264 (MK-2870) exhibits high stability within the bloodstream and possesses an extended half-life, enabling a greater quantity of the drug to reach TROP2-expressing cancer cells and thereby exerting its antitumor activity.

SKB264 (MK-2870) exhibits tripartite antineoplastic action. Initially, it reaches cancer cells via an antibody that targets TROP2. Subsequently, pH-sensitive linkers undergo lysis in the acidic tumor microenvironment, liberating toxin molecules that eradicate the surrounding cancer cells. Secondly, once SKB264 (MK-2870) is internalized into cancer cells that express the TROP2 antigen, the attached toxin segment of the linker can also be cleaved by intracellular lysosomes, thereby providing additional release of  toxin molecules that induce the death of the  affected cancer cells. Thirdly, the toxin molecule itself  has the ability to permeate cell membranes, demonstrating a "bystander effect" and persistently eliminating surrounding cancercells.

The pharmaceutical design of SKB264 (MK-2870) effectively balances safety while maintaining potent antitumor activity.

In the strategic development of HR+/HER2- metastatic breast cancer, SKB264 (MK-2870) is anticipated to yield further significant results.

In addition to the Phase II study highlighted at ESMO, several other clinical studies involving SKB264 (MK-2870) in the field of HR+/HER2- breast cancer are ongoing or planned to be initiated. The multicenter Phase III registrational clinical study in China, utilizing SKB264 (MK-2870) for the treatment of HR+/HER2- metastatic breast cancer in patients who have undergone at least one round of chemotherapy, has received CDE approval to commence. A global, multicenter Phase III registrational clinical study is set to commence, targeting patients with HR+/HER2- metastatic breast cancer who have experienced treatment failure with prior endocrine therapy, but have not yet undergone chemotherapy. A Phase II study is currently underway, investigating the use of SKB264 (MK-2870), either alone or in combination with KL-A167 (anti-PD-L1 monoclonal antibody), as a first-line treatment for patients with HER2-negative breast cancer, including those with HR+/HER2- and TNBC subtypes. It is anticipated that these studies will further substantiate the therapeutic efficacy of SKB264 (MK-2870) in patients with HR+/HER2- metastatic breast cancer, thereby expanding the range of treatment options available for these patients.

Beyond its application in breast cancer, SKB264 (MK-2870) has also demonstrated promising therapeutic potential in non-small cell lung cancer (NSCLC). The exploration of its use in other solid tumors, including as monotherapy and in combination with immunotherapeutic agents, is ongoing. It is highly anticipated that  SKB264 (MK-2870) will benefit an increasing number of patients and in the process serve as a beacon of the rapidly growing innovation strength of Chinese biotech.

The research and development prowess for innovative pharmaceuticals in China is continually advancing, with the anticipation of benefiting a broader patient population in the future.

In recent years, China's progress in the development of innovative pharmaceuticals has been growing rapidly, particularly in the realm of anticancer drug research. This advancement has not only elevated the standards of clinical research within the country but has also amplified China's presence and influence on the global stage. The research, development, and subsequent market approval of novel anticancer agents have ushered in more accessible treatment alternatives for many cancer patients in China. Looking ahead, it is anticipated that innovative pharmaceutical firms, exemplified by Kelun-Biotech, will consistently achieve breakthroughs in the realm of anticancer drug research and development, thereby benefiting cancer patients in China and around the world.

Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. has been granted authorization by Oncology News to repost the news article: https://mp.weixin.qq.com/s/xWllrIxEZsjhYTJFrsGojA (Original link)

SOURCE Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.