TROP2 overexpression frequently occurs in HR+/HER2- metastatic breast cancer and is correlated with unfavorable patient prognosis. SKB264 (MK-2870), originating from Kelun-Biotech and jointly developed in collaboration with Merck, is an ingeniously designed ADC targeting TROP2, which is composed of a humanized anti-TROP2 monoclonal antibody securely attached to a small molecule toxin T030 (a novel topoisomerase I inhibitor) via an optimized CL2A linker (employing methylsulfonyl pyrimidine for irreversible conjugation between the linker and antibody). It has gained Breakthrough Designations (BTDs) from China's National Medical Products Administration (NMPA) for treating locally advanced or metastatic HR+/HER2– breast cancer after second-line systemic therapy. In the first half of 2023, SKB264's clinical development showed significant progress. Its remarkable preclinical outcomes have paved the way for its inclusion in clinical trials, raising expectations for potential clinical advantages in patients grappling with gastric carcinoma, lung cancer, and breast cancer. SKB264 has also shown promise even in patients with triple-negative breast cancer (TNBC) who have failed second-line or subsequent standard treatment options, successfully meeting its primary goal. This breakthrough underscores its significance in the medical advancements.

The notable therapeutic effectiveness exhibited by SKB264 (MK-2870), coupled with its potential significance for clinical applications and future research, were the primary factors for its selection as an oral presentation at the ESMO conference. The Phase I/II single-arm, basket 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. The median follow-up duration was 8.2 months.

In the context of efficacy, post-treatment with SKB264 (MK-2870) demonstrated impressive results, including a 36.8% objective response rate (ORR), an 89.5% disease control rate (DCR), and a 6-month duration of response (DoR) rate of 80%. In terms of survival data, the median progression-free survival (PFS) duration reached 11.1 months. This contrasts sharply with the current standard approach of chemotherapy, which typically yields a meager 15% objective response rate (ORR) and a limited progression-free survival (PFS) of approximately 4 to 5 months. Therefore, the Phase II study clearly establishes that SKB264 (MK-2870) significantly outperforms chemotherapy, offering substantial survival advantages for patients. Furthermore, these benefits extended across various patient subgroups, including those with low or null HER2 expression, individuals with primary and secondary resistance to endocrine drugs, and those previously treated with CDK4/6 inhibitors. As the study's follow-up period continues, further positive outcomes in survival data are anticipated.

In terms of safety, the primary adverse reactions predominantly involved hematological toxicities. The most frequently observed Grade 3 or higher Treatment-Related Adverse Events (TRAEs) included decreased neutrophil count (36.6%), reduced white blood cell count (22%), anemia (14.6%), and diminished platelet count (9.8%). The majority of these hematological toxicities manifested within the initial two months of treatment and were resolved without the need for transfusion, following administration of G-CSF or erythropoietin. The dosage was reduced in 17.1% (7/41) of patients due to TRAEs, with no instances of medication discontinuation or death resulting from TRAEs. The occurrence of gastrointestinal TRAEs was minimal, and there were no observed instances of drug-associated neuropathy or interstitial lung disease/pneumonia.

SKB264, administered at 5 mg/kg, demonstrates a manageable safety profile and promising antitumor activity in patients with pre-treated HR+/HER2- mBC. In addition, two Phase III studies are currently planned in HR+/HER2- mBC, one in China for patients after at least one chemo for mBC and a second global for patients previously untreated with chemo for mBC, both comparing SKB264 vs investigator selected chemo.

KOL insights

“The results look promising and merit further exploration in clinical studies, however, given the considerable technological efforts that have been made to generate this agent, it is quite disappointing to see higher levels of hematological toxicity than might have been expected. We will have to wait for results on tolerability and efficacy from ongoing trials, to more accurately assess the therapeutic potential of SKB264.”− Medical oncologist, France

Conclusion: 

According to the data from the International Agency for Research on Cancer (IARC) in 2020, breast cancer has become the most prevalent cancer globally, surpassing lung cancer in terms of new cases. Among breast cancer subtypes, HR+/HER2- breast cancer accounts for approximately 70% of cases, making it the most common subtype. Treatment for HR+/HER2- breast cancer typically involves endocrine therapy, with the addition of CDK4/6 inhibitors significantly improving survival rates for metastatic patients. However, for those who have failed these therapies, treatment options are limited. 

In recent years, innovative ADC therapeutics like TROP2-ADCs, specifically exemplified by Sacituzumab govitecan (SG), have provided new alternatives for HR+/HER2- breast cancer patients who have undergone prior treatments. Sacituzumab govitecan has received FDA approval for use in patients who have previously received endocrine therapy and at least two lines of systemic treatment for metastatic disease. Additionally, promising results from a Phase III study on Dato-DXd, another TROP2-targeted ADC, were presented at the ESMO conference this year. It's worth noting that, as of now, no TROP2-ADC has been approved for use in HR+/HER2- breast cancer patients in China, highlighting an urgent unmet medical need in the country.

In the landscape of medical advancements, the dynamic SKB264 has emerged as an Antibody-Drug Conjugate (ADC), setting its sights on the TROP2 protein. What sets it apart is its shared monoclonal antibody (mAb) with IMMU-132. Unlike its predecessor, IMMU-132, SKB264 boasts an extended half-life that wields a powerful targeting effect and an impressive anti-tumor prowess. 

Based on recent data presented at 2023 ESMO, SKB264 shows promising prospects for the treatment of patients with HR+/HER2- metastatic breast cancer who have undergone multiple prior lines of therapy, and its clinical development in other solid tumors is also advancing steadily.  As of the data cut-off on April 12, 2023, results from a Phase I/II basket study in HR+/HER2– patients demonstrated a 36.8% ORR, 89.5% DCR, 7.4 months median DoR, 80% 6-month DoR rate, and 11.1 months median PFS. SKB264 exhibits a well-tolerated safety profile with no instances of treatment discontinuation or death attributed to TRAEs. 

SKB264 (MK-2870) showcases a unique structural design that balances potent antitumor activity with safety. The promising data suggests that the drug carries the torch of hope, offering superior therapeutic potential for tackling TROP2-positive tumors. 

For more insight into the patient’s burden/epidemiology, treatment, and changing market landscape-related advancements, refer to these reports:

• HER2-Negative Breast Cancer Market Insight and Market Forecast
• Metastatic HR+/HER2− Breast Cancer Market Insights and Market Forecast
• Triple Negative Breast Cancer (TNBC) Market Insights and Market Forecast