Subcutaneous Pembrolizumab in mNSCLC: A Potential Shift in the Delivery Landscape

In crowded infusion suites where every chair is booked back-to-back, the pressure to improve efficiency without compromising outcomes is intensifying. For patients with metastatic non-small-cell lung cancer (mNSCLC) receiving checkpoint inhibitors, that question now includes how therapy is delivered.

The global, open-label phase III 3475A-D77 study examined whether subcutaneous (SC) administration of the PD-L1 inhibitor pembrolizumab, co-formulated with berahyaluronidase alfa, could match its intravenous (IV) counterpart in efficacy, safety, and pharmacokinetics, while offering gains in clinic flow.

Here’s a closer look at the study and what it could mean for frontline care.

A Trial Design Focused on Pharmacokinetics

The study enrolled 377 treatment-naive patients with newly diagnosed, stage IV squamous or nonsquamous NSCLC, with no tumor-activating EGFR, ALK, or ROS1 alterations. These patients were then randomized 2:1 to SC pembrolizumab (790 mg every six weeks) or IV (400 mg on the same schedule), both in combination with platinum-doublet chemotherapy. No significant differences were observed between treatment arms at baseline.

The dual primary endpoints focused solely on the following pharmacokinetic metrics:

• Total body exposure after one six-week cycle (AUC₀–₆_wks)
• Steady-state trough concentration (C_trough)

SC delivery met both noninferiority benchmarks, with exposure slightly higher than IV:

• A geometric mean ratio of 1.14 for AUC₀–₆_wks
• 1.67 for C_trough
• P-values <0.0001 for both metrics

These findings confirm that systemic availability of the SC formulation is at least equivalent—if not superior—to IV.

Result: No Drop in Efficacy, and a Major Gain in Time

While the 3475A-D77 trial wasn’t powered to establish noninferiority for secondary efficacy endpoints, the study’s efficacy data tracked closely with expectations. Objective response rates were 45.4 percent for SC and 42.1 percent for IV. Median progression-free survival was 8.1 and 7.8 months, respectively, with consistent findings across subgroups including PD-L1 expression, tumor histology, and geography. Overall survival data remains immature, though interim signals show no concern.

It’s important to keep in mind that what separated the two arms wasn’t clinical performance, but the logistics of delivery. SC administration took a median of two minutes compared with approximately 30 minutes for IV infusion. It also avoided pre-medication, IV-line placement, and prolonged chair time.

In high-volume centers, these efficiencies could significantly reduce nursing workload and patient wait times.

Result: Safety Profile Reassuring, with Low Immunogenicity

Toxicity data also supported the SC formulation. Grade 3 or higher treatment-related adverse events occurred at similar rates in both arms at 47 percent for SC and 47.6 percent for IV. Discontinuation rates due to pembrolizumab regardless of route of administration was 8.4 percent and 8.7 percent for SC and IV, respectively. Investigators reported 12 treatment-related deaths between both arms: nine in the SC arm and three in the IV arm.

The most common adverse events in both arms of the study were anemia, neutropenia, and thrombocytopenia. The most common immune-mediated adverse event was hypothyroidism in both arms. Injection-site reactions, which are often a concern with subcutaneous monoclonals, were minimal at 2.4 percent of patients; all were grade 1, and none were treatment-limiting.

Immunogenicity was also low in both arms of the study. Anti-pembrolizumab antibodies were detected in 1.4 percent of SC recipients compared with 0.9 percent in the IV group, with no impact on efficacy or drug exposure observed.

Practical Implications: From Efficiency to Access

The real-world impact of a two-minute injection means more than convenience. For patients, community practices, or rural clinics, SC delivery may expand access to immunotherapy where infusion infrastructure and time are limited. In larger centers, it can unburden scheduling grids already packed with overlapping biologics and supportive care infusions, among others.

Over time, even modest time savings per cycle compound across patient volumes, potentially reshaping resource utilization. And as pembrolizumab moves into other indications, the flexibility of SC administration, especially in combination regimens with mixed scheduling demands, may further enhance adherence and patient satisfaction.

Clinical Caution Still Applies, But a New Delivery Norm May Be Coming

It’s important to note that 3475A-D77 was not designed to demonstrate clinical noninferiority for survival outcomes. While pharmacokinetic and early efficacy data are compelling, long-term durability remains unknown. Still, the results track closely with the pivotal KEYNOTE-189 and KEYNOTE-407 trials that originally established pembrolizumab plus chemotherapy as standard first-line care in mNSCLC.

If approved for broader use, SC pembrolizumab may follow the trajectory of SC trastuzumab: same molecule, same outcome, different delivery, with wide-reaching effects on how and where therapy is provided.

Reference
Felip E, Rojas CI, Schenker M, et al. Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non-small-cell lung cancer: the phase III 3475A-D77 trial. Ann Oncol. 2025;36(7):775-785. doi:10.1016/j.annonc.2025.03.012