Merck has announced positive topline results from the Phase 3 MK-3475A-D77 trial, evaluating a subcutaneous formulation of pembrolizumab, the company's anti-PD-1 therapy, for the first-line treatment of metastatic non-small cell lung cancer (NSCLC). The trial assessed the noninferiority of subcutaneous pembrolizumab, co-administered with berahyaluronidase alfa, versus intravenous (IV) KEYTRUDA, both in combination with chemotherapy.
Key Findings from the MK-3475A-D77 Trial
The Phase 3 trial met its dual primary pharmacokinetic (PK) endpoints. Subcutaneous pembrolizumab, administered every six weeks with chemotherapy, demonstrated noninferiority in Area Under the Curve (AUC) exposure during the first dosing cycle and trough concentration (Ctrough) at steady state, compared to IV KEYTRUDA administered every six weeks with chemotherapy. Secondary endpoints of efficacy and safety were generally consistent between the two administration routes.
Implications for Patient Care
Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, noted the potential benefits of the subcutaneous formulation. "It is very encouraging to see positive Phase 3 results evaluating this fixed-dose combination of subcutaneous pembrolizumab, which was administered, on average, in approximately 2-3 minutes and has the potential to improve the patient experience as well as increase access for patients and healthcare providers compared to intravenous administration."
Trial Design and Patient Population
The MK-3475A-D77 trial is a randomized, open-label Phase 3 study (ClinicalTrials.gov, NCT05722015 ) comparing subcutaneous pembrolizumab with berahyaluronidase alfa to IV KEYTRUDA, both administered every six weeks with chemotherapy, for the first-line treatment of adult patients with metastatic NSCLC. The trial enrolled an estimated 378 patients, randomized 2:1 to receive either subcutaneous pembrolizumab or IV KEYTRUDA in combination with chemotherapy. The primary endpoints were the AUC of pembrolizumab exposure during the first dosing cycle and the Ctrough of pembrolizumab at steady state. Secondary endpoints included additional PK parameters, efficacy (objective response rate, duration of response, progression-free survival, and overall survival), and safety.
Further Development of Subcutaneous Pembrolizumab
Merck's subcutaneous pembrolizumab clinical development program includes the Phase 3 MK-3475A-F84 trial, evaluating subcutaneous pembrolizumab alone versus IV KEYTRUDA alone for first-line treatment of metastatic NSCLC with high PD-L1 expression (TPS ≥50%). Additionally, the Phase 2 MK-3475A-F65 trial is assessing subcutaneous pembrolizumab alone in relapsed or refractory classical Hodgkin lymphoma and relapsed or refractory primary mediastinal large B-cell lymphoma. Merck is also conducting a Phase 2 patient preference study, MK-3475A-F11, comparing patient-reported preference for subcutaneous pembrolizumab versus IV KEYTRUDA.
About Pembrolizumab
KEYTRUDA (pembrolizumab) is an anti-programmed death receptor-1 (PD-1) therapy that enhances the immune system's ability to detect and fight tumor cells. It is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, activating T lymphocytes to target tumor cells.
