Based on recent data presented at 2023 ESMO, the innovative TROP2 ADC SKB264 (MK-2870) 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

CHENGDU, China, Oct. 24, 2023 /PRNewswire/ -- Human trophoblastic cell surface antigen 2 (TROP2) exhibits high expression in numerous solid tumors, making it a prominent target in recent oncology studies. The progress in the development of Antibody-Drug Conjugates (ADCs) against  this target has garnered significant interest in recent years. At this year's European Society for Medical Oncology (ESMO) Congress held in Madrid, Spain from October 20-24, the innovative TROP2-ADC (SKB264, MK-2870) for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic Breast Cancer (mBC) was jointly presented by Kelun-Biotech and MSD. The results of a Phase I/II single-arm, basket study (Abstract No. 380MO) were delivered orally, confirming the manageable safety profile and potent antitumor activity of SKB264 (MK-2870) in patients with HR+/HER2- metastatic breast cancer. Professor Yongmei Yin represented the study team in delivering a plenary report on this promising  study and its primary outcomes.

Study Background

TROP2  overexpression frequently occurs in HR+/HER2- metastatic breast cancer and is correlated with unfavorable patient prognosis. SKB264 (MK-2870) is an ingeniously designed ADC targeting TROP2, which is composed of a humanized anti-TROP2 monoclonal antibodysecurely attached to a small molecule toxin T030 (a novel topoisomerase I inhibitor) via an optimized CL2A linker (employing methanesulfonylpyrimidine for irreversible conjugation between the linker and antibody). The Drug-to-Antibody Ratio (DAR) averages as high as 7.4. Importantly, this is the inaugural public reporting of SKB264 (MK-2870)   being used in a Phase II cohort study for patients with HR+/HER2- metastatic Breast Cancer.

Study Methods

Patients with HR+/HER2- metastatic breast cancer (inclusive of low and null HER2 expression) were administered  SKB264 at a dosage of 5 mg/kg biweekly, continuing until the emergence of either disease progression or intolerable toxicity. The study incorporated patients who had previously experienced treatment failure with endocrine therapy and had undergone at least one round of chemotherapy. Tumor evaluations were conducted by the investigator every 8 weeks in accordance with RECIST v1.1.

Study Results

As of April 12, 2023, the study has enrolled a total of 41 patients, with a median age of 50 years. Among these patients, 61% have an ECOG PS score of 1. The study's median follow-up duration was 8.2 months.

The primary adverse reactions predominantly involved hematological toxicities. The most frequently observed ≥ Grade 3 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.

Among the 38 patients evaluable for efficacy, 71% demonstrated low HER2 expression, 47% demonstrated primary endocrine drug resistance, and 79% had previously undergone ≥2 lines of chemotherapy for metastatic breast cancer. All patients had been treated with taxane-based chemotherapydrugs, and 65.8% had previously received CDK4/6 inhibitor treatment. The observed Objective Response Rate (ORR) stood at 36.8%, with the Disease Control Rate (DCR) registering at 89.5%. The rate of duration of  response (DoR) over a 6-month period was 80%, and the median Progression-Free Survival (PFS) spanned 11.1 months. Most notably, all subgroups experienced benefits, encompassing patients with low and null HER2 expression, primary and secondary endocrine drug resistance, and those with or without prior use of CDK4/6 inhibitors.

Study Conclusion

SKB264 (MK-2870) has demonstrated manageable safety profiles and promising antitumor activity in patients with HR+/HER2- metastatic breast cancer. Two Phase III clinical studies are presently being planned for patients with HR+/HER2- metastatic breast cancer: one domestic study will focus on on patients who have undergone at least one line of chemotherapy in the metastatic setting, and the other is planned to be a global  study involving patients who have not previously been treated with chemotherapy in the metastatic setting.

Summary
Previously, SKB264 (MK-2870) demonstrated promising efficacy and manageable safety profiles in patients with metastatic Triple-Negative Breast Cancer (TNBC) and Non-Small Cell Lung Cancer (NSCLC) who had undergone multiple prior lines of treatment. At this year's ESMO conference, it has now also demonstrated significant therapeutic potential in patients with HR+/HER2- metastatic breast cancer, undoubtedly bolstering confidence for the initiation of further series of studies in related fields.

During the 2022 SABCS Annual Conference, SKB264 (MK-2870) released  data from a Phase II extension study conducted on patients suffering from locally advanced or metastatic TNBC. Among the 55 patients eligible for efficacy evaluation, the ORR was 43.6%, and the DCR was 80%. Notably, in patients exhibiting high TROP2 expression, the ORR was 55.2%. The median Duration of Response (mDoR) was 11.5 months, the median Progression-Free Survival (PFS) was 5.7 months, the median Overall Survival (mOS) was 14.6 months, and the overall survival rate at 12 months was 66.4%.

During the 2023 ASCO Annual Conference, SKB264 (MK-2870) released  data from a Phase II extension study conducted on patients with previously treated locally advanced or metastatic NSCLC. The therapeutic efficacy was evaluable in 39 patients, exhibiting an ORR of 43.6%, a DCR of 94.9%, a mDoR of 9.3 months, a 6-month DoR of 77%, and a 12-month Overall Survival (OS) rate of 70.6%. In the subgroup analysis of patients  with EGFR mutations, the ORR was 60%, the DCR reached 100%, the mDoR was 9.3 months, the mPFS was 11.1 months, and the 12-month Overall Survival (OS) rate stood at 80.7%.

Based on the currently published study data,  SKB264 (MK-2870)stands out as one of the most promising TROP-ADCs  for the treatment of advanced triple-negative breast cancer, advanced HR+HER2- breast cancer, and non-small cell lung cancer  with EGFR mutations unresponsive to TKI treatment.

Based on compelling study data in breast and lung cancer, SKB264 (MK-2870) has been granted three breakthrough therapy designations by the CDE. These include its use as a monotherapy for locally advanced or metastatic TNBC, for locally advanced or metastatic EGFR-mutated Non-Small Cell Lung Cancer (EGFRm NSCLC) unresponsive to EGFR-TKI treatment, and for locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative (HER2-) breast cancer in patients who have previously undergone at least two lines of systemic chemotherapy.

In the field of breast cancer, the Phase III registrational study of SKB264 (MK-2870) as a standalone treatment for patients with locally advanced or metastatic triple-negative breast cancer, who have previously undergone two or more lines of systemic treatment, has achieved its primary study endpoint. Based on the study results, an application for market approval in China is expected to be submitted to CDE by the end of this year. A Phase III registrational study for the use of SKB264 (MK-2870) as a monotherapy in patients with locally advanced or metastatic HR+HER2- breast cancer, who have previously experienced at least one unsuccessful round of chemotherapy, has also received CDE approval to proceed. A Phase II study investigating the use of SKB264 (MK-2870) in conjunction with KL-A167 (an anti-PD-L1 monoclonal antibody) as a first-line treatment for patients with HER2-negative breast cancer is also currently underway. Additionally, several registrational studies in NSCLC are advancing rapidly, including  active exploration in  combination therapy regimens  and the applications in other solid tumors. There is undoubtedly much anticipation for the release of further clinical study findings, which may further demonstrate  the potential of SKB264 (MK-2870) to be a beacon of hope for cancer patients worldwide!

SOURCE Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.