Japan Approves Subcutaneous Pembrolizumab for All Approved Pembrolizumab Indications

Japan’s Ministry of Health, Labor and Welfare has approved pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; Keyject) for subcutaneous administration across all indications for which intravenous (IV) pembrolizumab (Keytruda) is approved in Japan.¹

The subcutaneous formulation can be administered in as little as 1 minute every 3 weeks or 2 minutes every 6 weeks. This regulatory decision was backed by data from the pivotal phase 3 3475A-D77 trial (NCT05722015), which compared subcutaneous pembrolizumab with IV pembrolizumab, each administered every 6 weeks in combination with chemotherapy, in patients with treatment-naive metastatic non–small cell lung cancer (NSCLC) without EGFR, ALK, or ROS1 alterations.^1,2 The trial met its dual primary pharmacokinetic end points, demonstrating noninferior pembrolizumab exposure with the subcutaneous formulation, and showed consistent efficacy and safety between the 2 administration routes.²

“[Pembrolizumab and berahyaluronidase alfa] is the first and only subcutaneous immune checkpoint inhibitor available in Japan that can be administered by a health care provider in as little as 1 minute,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, stated in a news release.¹

Berahyaluronidase alfa is a variant of human hyaluronidase that enhances permeation by temporarily degrading hyaluronan in the extracellular matrix to enable subcutaneous administration of pembrolizumab.²

What did the 3475A-D77 trial show?

The global, open-label 3475A-D77 trial randomly assigned 377 patients 2:1 to receive subcutaneous pembrolizumab at 790 mg every 6 weeks (n = 251) or IV pembrolizumab at 400 mg every 6 weeks (n = 126), each given with platinum doublet chemotherapy for up to 18 cycles. The dual primary end points were area under the curve at cycle 1 (AUC_{0-6 weeks}) and steady-state trough concentration (C_trough) of pembrolizumab, with a noninferiority margin of 0.8 for the geometric mean ratios of the subcutaneous vs IV formulations.

The geometric mean ratio for AUC_{0-6 weeks} was 1.14 (96% CI, 1.06-1.22; P < .0001), and the geometric mean ratio for steady-state C_trough was 1.67 (94% CI, 1.52-1.84; P < .0001), both meeting the noninferiority criteria. The median injection time for subcutaneous pembrolizumab was 2.0 minutes (range, 1-12), compared with an approximately 30-minute infusion for the IV formulation.

In descriptive efficacy analyses, the objective response rate (ORR) by blinded independent central review was 45.4% (95% CI, 39.1%-51.8%) with subcutaneous pembrolizumab vs 42.1% (95% CI, 33.3%-51.2%) with IV pembrolizumab (ORR ratio, 1.08; 95% CI, 0.85-1.37). The median progression-free survival values were 8.1 months (95% CI, 6.3-8.3) vs 7.8 months (95% CI, 6.2-9.7), respectively (HR, 1.05; 95% CI, 0.78-1.43), and the overall survival data were immature at the time of the analysis. The median duration of response was 9.1 months (range, 6.9-not reached [NR]) with the subcutaneous formulation vs 8.0 months (range, 7.4-NR) with IV pembrolizumab.

The overall safety profile was consistent between the treatment arms. Grade 3 to 5 treatment-related adverse effects (TRAEs) occurred in 47.0% of patients treated with subcutaneous pembrolizumab vs 47.6% of those given IV pembrolizumab, and TRAEs led to discontinuation of pembrolizumab in 8.4% and 8.7% of patients, respectively. Injection-site reactions in the subcutaneous arm were infrequent, reported in 2.4% of patients; all were grade 1 and nonserious. Anti-pembrolizumab antibodies were detected in 1.4% of patients in the subcutaneous arm and 0.9% of those in the IV arm.

What is the global regulatory status of subcutaneous pembrolizumab?

In September 2025, the FDA approved subcutaneous pembrolizumab for adult and pediatric patients at least 12 years of age in all solid tumor indications for which IV pembrolizumab is approved.^1,3 In November 2025, the European Commission approved the subcutaneous formulation of pembrolizumab (Keytruda SC) across all adult pembrolizumab indications.^1,4

References

1. Merck’s Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) approved in Japan for subcutaneous administration for all Keytruda (pembrolizumab) indications approved in Japan. News release. Merck. September 21, 2026. Accessed September 21, 2026. https://www.merck.com/news/mercks-keytruda-qlex-pembrolizumab-and-berahyaluronidase-alfa-pmph-approved-in-japan-for-subcutaneous-administration-for-all-keytruda-pembrolizumab-indications-approved-in/
2. 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
3. FDA approves pembrolizumab and berahyaluronidase alfa-pmph for subcutaneous injection. FDA. September 19, 2025. Accessed September 21, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-and-berahyaluronidase-alfa-pmph-subcutaneous-injection
4. European Commission approves subcutaneous administration of Keytruda (pembrolizumab) for all adult indications approved in the European Union. News Release. Merck. November 19, 2025. Accessed September 21, 2026. https://www.merck.com/news/european-commission-approves-subcutaneous-administration-of-keytruda-pembrolizumab-for-all-adult-indications-approved-in-the-european-union/