Subcutaneous administration of pembrolizumab: a paradigm shift toward patient-centered cancer care

Introduction

The evolution of cancer immunotherapy has witnessed remarkable advances in both efficacy and delivery methods. Pembrolizumab, a humanized monoclonal antibody targeting programmed death receptor-1 (PD-1), has transformed the treatment landscape for various malignancies, particularly non-small-cell lung cancer (NSCLC). The recent publication by Felip et al. in Annals of Oncology presents compelling evidence from the phase III 3475A-D77 trial, demonstrating that subcutaneous pembrolizumab achieves noninferior pharmacokinetic exposure compared to intravenous administration while maintaining similar efficacy and safety profiles in patients with metastatic NSCLC (1). This landmark study represents a significant step toward optimizing patient experience and healthcare delivery in oncology practice.

The imperative for developing alternative administration routes stems from the increasing recognition that treatment convenience and quality of life are integral components of comprehensive cancer care. While the therapeutic efficacy of pembrolizumab has been well-established through numerous pivotal trials, the traditional intravenous infusion method presents logistical challenges, including prolonged clinic visits, increased healthcare resource utilization, and patient burden associated with vascular access requirements (2,3). The development of subcutaneous pembrolizumab with berahyaluronidase alfa addresses these concerns while potentially expanding treatment accessibility.

Key findings and clinical implications

The 3475A-D77 study enrolled 377 participants with treatment-naïve metastatic NSCLC across 61 global sites, randomizing them 2:1 to receive either pembrolizumab subcutaneous 790 mg every 6 weeks or pembrolizumab intravenous 400 mg every 6 weeks, both in combination with platinum-doublet chemotherapy. As summarized in Table 1, the study achieved its dual primary endpoints with a clear demonstration of noninferiority for both pharmacokinetic measures.

The geometric mean ratios (GMRs) for cycle-1 area under the concentration-time curve from 0 to 6 weeks (AUC_{0–6 w}) and steady-state trough concentrations (C_trough) were 1.14 [96% confidence interval (CI): 1.06–1.22; P<0.0001] and 1.67 (94% CI: 1.52–1.84; P<0.0001), respectively, both exceeding the prespecified noninferiority margin of 0.80 (1). The higher steady-state C_trough observed with subcutaneous administration reflects the deliberate dose selection strategy to ensure maintained exposure levels while accounting for differences in bioavailability between administration routes.

Perhaps most remarkably, the median injection time for subcutaneous administration was merely 2.0 minutes compared to the typical 30-minute intravenous infusion requirement. This dramatic efficiency gain translates into meaningful benefits for both patients and healthcare systems. It is important to recognize that pembrolizumab is most frequently initiated in combination with platinum-based chemotherapy, where intravenous delivery remains practical and clinically convenient to streamline co-administration. However, in the maintenance phase or when pembrolizumab is administered as monotherapy, the subcutaneous route could substantially improve patient convenience, reduce chair time, and optimize healthcare resource utilization without compromising efficacy. According to supplementary analyses, patients receiving subcutaneous pembrolizumab spent 47.4% less time in treatment rooms compared to those receiving intravenous administration (4). Such improvements in workflow efficiency have become increasingly crucial as oncology practices face growing patient volumes and resource constraints.

The efficacy outcomes further support the clinical equivalence of both administration routes. As detailed in Table 1, objective response rates (ORRs) were comparable between subcutaneous and intravenous arms (45.4% vs. 42.1%, respectively; ORR ratio =1.08; 95% CI: 0.85–1.37), with similar progression-free survival and duration of response. These results align closely with historical data from the KEYNOTE-189 and KEYNOTE-407 trials, providing reassurance regarding the maintained therapeutic benefit of subcutaneous administration (5,6).

Safety profile and tolerability

The safety analysis revealed reassuring findings regarding the subcutaneous formulation, as highlighted in Table 1. Treatment-related adverse events occurred in 90.0% of patients receiving subcutaneous pembrolizumab compared to 96.0% receiving intravenous administration, with similar rates of grade 3–5 events (47.0% vs. 47.6%, respectively). Notably, injection-site reactions were infrequent, occurring in only 2.4% of patients receiving subcutaneous administration, and were uniformly mild (grade 1) and nonserious (1).

The immunogenicity profile represents another crucial safety consideration. Anti-pembrolizumab antibodies were detected in 1.4% of subcutaneous and 0.9% of intravenous recipients, rates that are remarkably low and likely clinically insignificant. Importantly, neutralizing antibodies were detected in only 0.5% of subcutaneous recipients, with no clinically meaningful impact on drug exposure. This low immunogenicity profile contrasts favorably with other subcutaneous immunotherapies, where antibody formation has been more pronounced (7,8).

Broader context and healthcare impact

The development of subcutaneous immunotherapy administration reflects a broader paradigm shift toward patient-centered care in oncology. Comparable clinical programs have validated subcutaneous formulations for other monoclonal antibodies, including atezolizumab (IMscin002) and amivantamab, which similarly demonstrated preserved pharmacokinetic exposure and patient preference for shorter administration times. These data reinforce the feasibility and acceptability of transitioning immune-oncology antibodies to subcutaneous delivery. Beyond the immediate time savings demonstrated in Table 1, subcutaneous administration offers several potential advantages, including reduced need for venous access, decreased infusion-related reaction risk, and improved treatment flexibility. For patients in rural or resource-limited settings, subcutaneous administration could significantly improve treatment accessibility by reducing the specialized infrastructure requirements associated with intravenous infusion.

Healthcare economic considerations also favor subcutaneous administration. The dramatic reduction in administration time from over 30 minutes to a median of 2 minutes represents substantial cost-saving opportunities through improved clinic throughput, reduced nursing supervision requirements, and decreased facility utilization. A recent time-and-motion study suggested that subcutaneous pembrolizumab could improve administration workflow efficiency while reducing both active provider time and patient chair time (9).

However, implementation considerations must be carefully addressed. Healthcare providers will require training on proper subcutaneous injection techniques, appropriate injection site rotation, and management of potential injection-site reactions. Patient education regarding self-monitoring for local adverse events will also be essential, particularly given the novel formulation containing berahyaluronidase alfa as a permeation enhancer.

Future directions and regulatory implications

The successful demonstration of noninferiority for subcutaneous pembrolizumab in NSCLC, as comprehensively outlined in Table 1, provides a foundation for potential regulatory bridging to other pembrolizumab-approved indications. Given the mechanistic basis for PD-1 inhibition and the established pharmacokinetic-pharmacodynamic relationships, regulatory authorities may consider approving subcutaneous administration across multiple tumor types based on these robust data.

The every-6-week dosing schedule employed in this study offers additional clinical advantages, particularly for patients receiving adjuvant therapy or combination regimens with varying dosing schedules. This regimen itself represented a prior advance in reducing treatment burden compared with the earlier every-3-week schedule, and the advent of subcutaneous administration further complements this evolution toward less frequent and more convenient care. This flexibility could facilitate treatment planning and improve patient compliance in complex therapeutic scenarios, while the higher steady-state C_trough observed with subcutaneous dosing provides pharmacokinetic reassurance for extended dosing intervals.

Long-term follow-up data from this study will be crucial for confirming sustained efficacy and identifying any delayed safety signals. Additionally, patient-reported outcome measures evaluating treatment satisfaction, quality of life, and preference between administration routes would provide valuable insights into the patient experience benefits quantified in Table 1.

Limitations and considerations

While the 3475A-D77 study provides robust evidence supporting subcutaneous pembrolizumab, several limitations warrant consideration. The median follow-up of 9.6 months is relatively short for definitive overall survival conclusions, though the pharmacokinetic noninferiority demonstrated in Table 1 provides a strong biological rationale for equivalent long-term outcomes. The open-label design, while necessary for practical reasons, may introduce bias in subjective outcome assessments.

The study population consisted primarily of patients with good performance status [Eastern Cooperative Oncology Group (ECOG) 0–1] and limited representation from certain geographic regions. Validation in more diverse populations, including those with poorer performance status or specific comorbidities, will be important for broader clinical implementation. Furthermore, while the 2:1 randomization favoring the subcutaneous arm was appropriate for this noninferiority study, longer-term comparative effectiveness data will be valuable.

Cost–effectiveness analyses comparing subcutaneous versus intravenous administration across different healthcare systems would provide valuable economic data to guide implementation decisions. While the time savings shown in Table 1 appear substantial, the overall economic impact will depend on factors including drug acquisition costs, administration fees, and healthcare system structures.

Conclusions

The 3475A-D77 trial provides compelling evidence that subcutaneous pembrolizumab is an effective alternative to the standard intravenous infusion. The study successfully demonstrated that the subcutaneous formulation has comparable pharmacokinetic profiles, clinical efficacy, and a consistent safety record. The most significant advantage is the dramatic reduction in administration time to a median of just 2 minutes, which offers tangible benefits for both patient convenience and clinic efficiency. This development marks a meaningful step toward more patient-centered cancer care, offering a more flexible treatment delivery method without compromising outcomes.

Acknowledgments

The author acknowledges the patients, investigators, and research teams who contributed to the 3475A-D77 trial.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1825/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1825/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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