Merck has announced promising results from its pivotal 3475A-D77 Phase 3 trial evaluating a novel subcutaneous formulation of pembrolizumab (KEYTRUDA) combined with berahyaluronidase alfa. The data, presented at the European Lung Cancer Congress (ELCC) 2025 and simultaneously published in Annals of Oncology, demonstrate that this new administration method could significantly improve the treatment experience for cancer patients while maintaining efficacy.
Comparable Efficacy with Improved Administration
The trial met its primary endpoints by demonstrating noninferior pharmacokinetics for subcutaneous pembrolizumab administered with chemotherapy compared to intravenous (IV) KEYTRUDA with chemotherapy for first-line treatment of metastatic non-small cell lung cancer (NSCLC). The subcutaneous formulation can be administered in approximately two minutes, compared to the standard IV infusion that typically takes much longer.
Secondary efficacy endpoints showed consistent results between the two administration methods:
- Objective response rate (ORR): 45.4% for subcutaneous versus 42.1% for IV administration
- Median duration of response (DOR): 9.1 months for subcutaneous versus 8.0 months for IV administration
- Median progression-free survival (PFS): 8.1 months for subcutaneous versus 7.8 months for IV administration
- Median overall survival (OS): Not reached in either arm
The safety profile was also comparable, with Grade ≥3 adverse events occurring in 47% of patients receiving subcutaneous pembrolizumab with chemotherapy versus 47.6% of patients receiving IV KEYTRUDA with chemotherapy. The incidence of local injection site reactions for subcutaneous administration was only 2.4%, all of which were low grade.
Significant Time Savings for Patients and Healthcare Providers
A prospective, observational time and motion study conducted alongside the clinical trial revealed substantial time savings with the subcutaneous formulation:
- Patient chair time during treatment was reduced by 49.7% (59.0 versus 117.2 minutes)
- Patient time in the treatment room decreased by 47.4% (66.7 versus 126.9 minutes)
- Total active healthcare professional time was reduced by 45.7% (14.0 versus 25.8 minutes)
"These study findings demonstrate subcutaneous pembrolizumab reduces time demands for both the patient and the healthcare provider, all while providing a consistent efficacy and safety profile with IV pembrolizumab," said Dr. Enriqueta Felip, head of Thoracic Tumors Group, Vall d'Hebron Institute of Oncology. "As a physician, I am thrilled to see these data for subcutaneous pembrolizumab, which, if approved, have the potential to give patients valuable time back in their treatment day with results that are consistent with IV pembrolizumab."
Regulatory Status and Future Applications
Based on these results, the U.S. Food and Drug Administration (FDA) has accepted for review a Biologics License Application (BLA) seeking approval of subcutaneous pembrolizumab across all previously approved solid tumor indications for KEYTRUDA. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of September 23, 2025.
Additionally, the European Medicines Agency (EMA) has validated an extension application to introduce this new pharmaceutical form and route of administration for KEYTRUDA.
Dr. Marjorie Green, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, emphasized the potential impact: "If approved, we are excited about the potential of subcutaneous pembrolizumab to become a new meaningful treatment option that may increase access and save time needed for administration compared to IV KEYTRUDA. We look forward to working with global regulatory authorities to bring the first subcutaneous checkpoint inhibitor that can be administered in approximately two minutes to patients and providers."
Broader Clinical Development Program
Merck's subcutaneous pembrolizumab clinical development program extends beyond this pivotal trial to include:
- The 3475A-F84 Phase 3 trial evaluating subcutaneous pembrolizumab alone compared to IV KEYTRUDA alone for first-line treatment of metastatic NSCLC with high PD-L1 expression
- The 3475A-F65 Phase 2 trial evaluating subcutaneous pembrolizumab in relapsed or refractory classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma
- A patient preference Phase 2 study (3475A-F11) evaluating participant-reported preference between subcutaneous and IV administration
Study Design and Methodology
The 3475A-D77 trial was a randomized, open-label Phase 3 study that enrolled 377 patients with metastatic NSCLC, regardless of PD-L1 tumor proportion score expression. Patients were randomized 2:1 to receive either subcutaneous pembrolizumab with chemotherapy or IV KEYTRUDA with chemotherapy.
The time and motion study was conducted at 17 sites across eight countries, with trained observers using stopwatches to measure various time points. Time associated with chemotherapy administration was removed from patient in-chair and treatment room duration measurements to isolate the impact of the pembrolizumab administration method.
Implications for Cancer Care
If approved, subcutaneous pembrolizumab could represent a significant advancement in cancer care delivery. The substantial time savings for both patients and healthcare providers could improve clinic efficiency, potentially allowing more patients to be treated and reducing the burden of lengthy treatment sessions on patients already dealing with cancer.
KEYTRUDA has become a cornerstone of immunotherapy treatment across multiple cancer types, with more than 1,600 clinical trials studying its effects in various cancers and treatment settings. The development of a subcutaneous formulation that maintains efficacy while improving administration efficiency demonstrates Merck's continued commitment to enhancing cancer care beyond just developing new therapies.
The potential approval of subcutaneous pembrolizumab would make it the first subcutaneous checkpoint inhibitor available, potentially setting a new standard for immunotherapy administration in oncology.
