Merck's subcutaneous formulation of pembrolizumab, co-administered with berahyaluronidase alfa, has demonstrated noninferior pharmacokinetics when combined with chemotherapy, compared to the intravenous formulation of pembrolizumab plus chemotherapy in patients with previously untreated metastatic non-small cell lung cancer (NSCLC). These topline results come from the phase 3 MK-3475A-D77 trial.
The randomized, open-label trial (NCT05722015) compared subcutaneous pembrolizumab plus chemotherapy against intravenous pembrolizumab and chemotherapy as a first-line treatment for metastatic NSCLC. The study enrolled approximately 378 patients, randomized in a 2:1 ratio.
Primary Endpoint Achievement
The primary pharmacokinetic (PK) findings revealed that the subcutaneous formulation, when combined with chemotherapy, achieved noninferiority in the area under the curve (AUC) exposure of pembrolizumab during the first dosing cycle. It also demonstrated noninferiority in trough concentration (Ctrough) at steady state.
Secondary Endpoints and Safety
Secondary endpoints focused on efficacy and safety. Data indicated that subcutaneous pembrolizumab plus chemotherapy showed generally consistent results compared to intravenous pembrolizumab plus chemotherapy. Further details from the MK-3475A-D77 trial, along with other ongoing analyses, will be presented at an upcoming medical meeting and shared with global regulatory authorities.
Expert Commentary
Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, stated, "[Pembrolizumab] has helped transform the way we treat some of the deadliest forms of cancer, yet we continue to pursue additional innovations that may benefit patients. 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 to 3 minutes and has the potential to improve the patient experience as well as increase access for patients and health care providers compared [with] intravenous administration."
Trial Design and Patient Population
The MK-3475A-D77 trial included patients aged 18 years or older with histologically or cytologically confirmed squamous or nonsquamous NSCLC and a life expectancy of at least 3 months. Patients were excluded if they had received prior systemic anticancer therapy for metastatic NSCLC or any systemic anticancer therapy—including investigational agents—within 4 weeks of randomization. The two primary endpoints of the trial were AUC of pembrolizumab exposure during the first dosing cycle and the Ctrough of pembrolizumab at steady state. Secondary endpoints included additional PK parameters, efficacy outcomes (objective response rate, duration of response, progression-free survival, and overall survival), and safety.
Further Studies
Merck's subcutaneous pembrolizumab clinical development program also includes the phase 3 MK-3475A-F84 trial (NCT04956692), which is investigating subcutaneous pembrolizumab alone compared with IV pembrolizumab alone in the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (tumor proportion score ≥ 50%). The phase 2 MK-3475A-F65 trial (NCT06504394) is evaluating subcutaneous pembrolizumab alone in relapsed/refractory classical Hodgkin lymphoma and relapsed/refractory primary mediastinal large B-cell lymphoma. The phase 2 MK-3475A-F11 trial (NCT06099782) will evaluate patient-reported preferences for subcutaneous pembrolizumab vs IV pembrolizumab across multiple tumor types.
