Merck & Co/MSD has initiated a pivotal Phase 3 trials for of its investigational antibody-drug conjugates (ADC) candidate MK-2870/SKB264, an innovative TROP2-targeting ADC being developed in collaboration with Kelun-Biotech. The global Phase 3 studies have been initiated and are actively enrolling for the following investigational candidates.

MK-2870 is an investigational ADC that consists of an antibody targeting human trophoblast cell-surface antigen 2 (TROP2-) linked to a belotecan-derived payload.

TROP2 is highly expressed in a variety of epithelial-derived tumors and can promote tumor cell proliferation, invasion and metastasis. TROP2 ADCs specifically target TROP2-expressing tumor cells to deliver cytotoxic effects and have shown encouraging anti-tumor activity in clinical studies.[1][2][3]

Merck & Co has initiated three pivotal Phase 3 clinical trials evaluating MK-2870 in which patients are now enrolling: MK-2870-004 (NCT06074588), MK-2870-007 (NCT06170788) and MK-2870-005 (NCT06132958).

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MK-2870-004 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study evaluating MK-2870 compared to chemotherapy (docetaxel or pemetrexed) for the treatment of previously treated advanced or metastatic NSCLC with EGFR mutations or other genomic alterations. The trial is slated to enroll approximately 556 patients around the world. The primary endpoints of the study are PFS and OS, and key secondary endpoints include ORR and DOR.

MK-2870-007 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study evaluating MK-2870 in combination with KEYTRUDA® (pembrolizumab) compared to pembrolizumab (Keytruda®; Merck & Co/MSD) alone in patients with metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. The trial is slated to enroll approximately 614 patients around the world. The primary endpoint of the study is OS, and key secondary endpoints include PFS, DOR and objective response (OR).

MK-2870-005 is a Phase 3, global, randomized, open-label, active-comparator-controlled clinical study evaluating MK-2870 compared to a treatment of physicians’ choice in patients with endometrial carcinoma who have received prior platinum-based chemotherapy and immunotherapy.

The trial is slated to enroll approximately 710 patients around the world. The primary endpoints of the study are PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by BICR and OS. Key secondary endpoints include ORR per RECIST 1.1 as assessed by BICR and DOR per RECIST 1.1 as assessed by BICR.

Collaboration
MK-2870 was developed by Kelun-Biotech, a subsidiary of Kelun Pharmaceutical which focuses on the R&D, manufacturing, commercialization and global collaboration of innovative biological drugs and small molecule drugs.

Under a collaboration agreement, Kelun-Biotech has granted Merck & Co the exclusive rights to develop, manufacture, and commercialize MK-2870 in all territories outside of Greater China.

In addition to MK-2870-004, MK-2870-007 and MK-2870-005, Merck intends to rapidly advance the global clinical development program evaluating MK-2870 as a monotherapy and in combination with pembrolizumab in various solid tumors.

Chinese domestically developed ADC
In December 2023 investigators and research experts from about 60 research centers in China met to discuss the MK-2870/SKB264 product design features, pre-clinical research data, phase II research against the background of the current status of HR+/HER2- breast cancer treatment and unmet clinical needs.

This study (NCT06081959/CTR20232807) evaluates single agent SKB264 versus the investigator’s choice regimen for the treatment of unresectable locally advanced, recurrent, or metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative patients who have failed at least one prior line of chemotherapy. A randomized, open-label, multicenter phase III clinical trial in patients with (HER2-) breast cancer. It is planned to enroll approximately 376 subjects in the Cancer Hospital of the Chinese Academy of Medical Sciences.

“HR+/HER2- breast cancer accounts for about 60% to 70% of the total breast cancer population. For patients with resistance after endocrine and CDK4/6 inhibitor treatment, single-agent chemotherapy is still the preferred option, however, the response rate and survival benefit of the currently available chemotherapy options are limited, and more effective clinical treatments are urgently needed,” saide Xu Binghe, MD chairman of OptiTROP Breast02 investigators conference.

“This meeting marks the launch of the Phase 3 registration clinical study for HR+/HER2- breast cancer of SKB264, which expected to become the first domestic innovation approved for marketing in China,” Binghe concluded.

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Clinical trials
MK-2870 Versus Chemotherapy in Previously Treated Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With EGFR Mutations or Other Genomic Alterations (MK-2870-004) – NCT06074588
MK-2870 in Combination With Pembrolizumab Versus Pembrolizumab Alone in Metastatic Non-small Cell Lung Cancer (NSCLC) With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥ 50% (MK-2870-007) – NCT06170788
MK-2870 in Post Platinum and Post Immunotherapy Endometrial Cancer (MK-2870-005) – NCT06132958
A Phase III Study of SKB264 for Locally Advanced, Recurrent or Metastatic HR+/​HER2- Breast Cancer – NCT06081959

Highlights of Prescribing Information
Pembrolizumab (Keytruda®; Merck & Co/MSD) [Prescribing Information]

References
[1] Liu X, Deng J, Yuan Y, Chen W, Sun W, Wang Y, Huang H, Liang B, Ming T, Wen J, Huang B, Xing D. Advances in Trop2-targeted therapy: Novel agents and opportunities beyond breast cancer. Pharmacol Ther. 2022 Nov;239:108296. doi: 10.1016/j.pharmthera.2022.108296. Epub 2022 Oct 5. Erratum in: Pharmacol Ther. 2023 Mar;243:108336. PMID: 36208791.
[2] Wen Y, Ouyang D, Zou Q, Chen Q, Luo N, He H, Anwar M, Yi W. A literature review of the promising future of TROP2: a potential drug therapy target. Ann Transl Med. 2022 Dec;10(24):1403. doi: 10.21037/atm-22-5976. PMID: 36660684; PMCID: PMC9843409.
[3] Cheng Y, Yuan X, Tian Q, Huang X, Chen Y, Pu Y, Long H, Xu M, Ji Y, Xie J, Tan Y, Zhao X, Song H. Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132. Front Oncol. 2022 Dec 23;12:951589. doi: 10.3389/fonc.2022.951589. Erratum in: Front Oncol. 2023 Dec 07;13:1334938. PMID: 36620535; PMCID: PMC9817100.

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