SC Pembrolizumab Shows Noninferior PK in Metastatic NSCLC
Subcutaneous pembrolizumab demonstrated comparable efficacy vs intravenous administration in non–small cell lung cancer, with a significantly shorter injection time.
Lung cancer: © Crystal Light - stock.adobe.com
The subcutaneous (SC) administration of pembrolizumab (Keytruda) combined with berahyaluronidase alfa (MK-3475A; SC pembrolizumab) led to noninferior pharmacokinetics (PK) when given with chemotherapy with a median injection time of 2 minutes, vs intravenous (IV) pembrolizumab and chemotherapy for the first-line treatment of adult patients with metastatic non–small cell lung cancer (NSCLC), meeting the primary end points of the pivotal phase 3 3475A-D77 trial.1
Findings from the phase 3 3475A-D77 trial, a randomized, open-label study involving 377 patients with metastatic NSCLC, irrespective of PD-L1 TPS expression,2 were presented at the European Lung Cancer Congress (ELCC) 2025 and simultaneously published in Annals of Oncology.1
SC pembrolizumab given every 6 weeks with a median injection time of 2 minutes (4.8 mL) plus chemotherapy showed noninferiority of area under the curve (AUC) exposure of pembrolizumab during the first dosing cycle, with a geometric mean ratio of 1.14 (96% CI, 1.06-1.22; P <.0001). For trough concentration (Ctrough), the geometric mean ratio was 1.67 (94% CI, 1.52-1.84; P <.0001) at steady state, compared with IV pembrolizumab administered every 6 weeks with chemotherapy.
“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 Enriqueta Felip, MD, PhD, 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.”
For the study’s secondary end points, the objective response rate (ORR) was 45.4% (95% CI, 39.1%-51.8%) with SC pembrolizumab vs 42.1% (95% CI, 33.3%-51.2%) for IV pembrolizumab (95% CI, 0.85-1.37). The median duration of response (DOR) was 9.1 months (95% CI, 6.9-not reached) with SC pembrolizumab vs 8.0 months (95% CI, 7.4-not reached) with IV pembrolizumab, the median progression-free survival (PFS) was 8.1 months (95% CI, 6.3-8.3) vs 7.8 months (95% CI, 6.2-9.7; HR, 1.05; 95% CI, 0.78-1.43), and the median overall survival (OS) was not reached in either arm (HR, 0.81; 95% CI, 0.53-1.22).
Safety profiles were also consistent, with similar rates of grade 3 or greater adverse events (AEs) observed in both arms (47% for SC vs 47.6% for IV). Local injection site reactions for SC pembrolizumab were generally low grade and were seen in 2.4% of patients. The incidence of local injection site reactions for SC pembrolizumab with chemotherapy was 2.4%, and all were low grade.
In the SC pembrolizumab with chemotherapy arm, treatment-related adverse events (TRAEs) led to treatment discontinuation of SC pembrolizumab in 8.4% of patients vs 8.7% of patients in the IV pembrolizumab with chemotherapy arm. TRAEs led to discontinuation of chemotherapy in 15.1% of patients in the SC pembrolizumab with chemotherapy arm and 11.9% of patients in the IV pembrolizumab with chemotherapy arm.
Further, the rate of treatment-related deaths was slightly higher in the subcutaneous pembrolizumab group (3.6%) compared with the IV pembrolizumab group (2.4%).
“[Pembrolizumab] has helped transform the treatment of certain cancers, and we continue to pursue innovations that build on this breakthrough medicine to give patients and those who treat them better experiences,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “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 [pembrolizumab]. We look forward to working with global regulatory authorities to bring the first subcutaneous checkpoint inhibitor that can be administered in approximately 2 minutes to patients and providers.”
The FDA has now accepted for review a biologics license application (BLA) seeking approval of subcutaneous pembrolizumab across all previously approved solid tumor indications for pembrolizumab, and a Prescription Drug User Fee Act target action date of September 23, 2025, has been set. The European Medicines Agency has also validated an extension application to introduce a new pharmaceutical form and new route of administration for pembrolizumab.
References:
Merck’s investigational subcutaneous pembrolizumab with berahyaluronidase alfa demonstrates noninferior pharmacokinetics compared to intravenous (IV) KEYTRUDA® (pembrolizumab) in pivotal 3475A-D77 trial. News release. Merck. March 27, 2025. Accessed March 27, 2025. https://tinyurl.com/2sc44pnz
A study of subcutaneous (SC) pembrolizumab coformulated with berahyaluronidase alfa (MK-3475A) vs intravenous pembrolizumab in adult participants with metastatic non-small cell lung cancer (NSCLC) (MK-3475A-D77). ClinicalTrials.gov. Updated March 25, 2025. Accessed March 27, 2025. https://clinicaltrials.gov/study/NCT05722015
