Clinical Trial Data With Subcutaneous Pembrolizumab
Panelists discuss how the phase 3 MK-3475-877 trial findings demonstrated subcutaneous pembrolizumab’s pharmacokinetic comparability to intravenous (IV) formulation with similar efficacy (45% vs 42% objective response rate [ORR]) and safety profiles in treatment-naive patients with metastatic non–small cell lung cancer, with indication-specific dosing of 395 mg every 3 weeks or 790 mg every 6 weeks combined with vorhyaluronidase.
Pembrolizumab Subcutaneous Data and Integration Strategies
Subcutaneous pembrolizumab recently received FDA approval based on the phase 3 KEYNOTE-MK3758-077 trial, an open-label randomized study evaluating subcutaneous pembrolizumab with vorhyaluronidase alfa (a different hyaluronidase formulation than used with nivolumab) vs IV pembrolizumab in patients with treatment-naive metastatic non–small cell lung cancer. Patients were randomly assigned 1:1 to receive either subcutaneous pembrolizumab every 6 weeks with platinum-doublet chemotherapy or standard IV pembrolizumab every 6 weeks with platinum-doublet chemotherapy. Subcutaneous administration required slightly over 10 minutes of injection time with approximately 5-mL injection volume. The primary objective assessed pharmacokinetic comparability via cycle 1 drug exposure (area under the curve, 0-6 weeks) and cycle 3 steady-state concentration, whereas secondary end points measured ORR, progression-free survival (PFS), and overall survival (OS) by blinded independent central review.
Pharmacokinetic comparability was successfully demonstrated, with lower boundaries of geometric mean ratios exceeding 0.8. ORRs proved highly comparable (45% subcutaneous vs 42% IV), with no meaningful differences in PFS or OS. The safety profile remained consistent with IV pembrolizumab, showing no new safety signals. Dosing varies by schedule: the regimen every 3 weeks uses 395 mg pembrolizumab with 4800 U vorhyaluronidase alfa, whereas the regimen every 6 weeks doubles to 790 mg pembrolizumab with 9600 U vorhyaluronidase alfa. Across all subcutaneous checkpoint inhibitor trials (nivolumab, atezolizumab, pembrolizumab), immune-related adverse events showed no significant differences between subcutaneous and IV formulations, particularly for grade 3/4 events. Injection site reactions occurred more frequently with subcutaneous administration but remained manageable, mild, and transient in all studies, with no new safety signals identified with subcutaneous formulations.
Institutional implementation requires navigating multiple administrative and operational hurdles. Pharmacy and therapeutics committees must approve formulary additions before clinical use, creating a timeline gap between FDA approval and practical availability. Electronic medical record systems require updating to accommodate new treatment plans with indication-specific dosing schedules. Rather than rebuilding every treatment plan from scratch (adding significant information technology workload and implementation delays), efficient solutions involve creating drop-down menus within existing plans, allowing selection between IV and subcutaneous formulations. Pharmacy workflows may simplify with subcutaneous products, but coordination across multidisciplinary teams remains essential. Treatment pathway integration must consider concurrent chemotherapy regimens, as checkpoint inhibitor scheduling often aligns with companion agents (eg, adjusting to schedules of every 3 weeks when combining with oxaliplatin-based regimens). The choice of checkpoint inhibitor formulation and schedule will depend on FDA-approved indications, concurrent treatment requirements, and institutional formulary decisions as more subcutaneous options become available across tumor types.
