FDA Approves Use of Subcutaneous Pembrolizumab for NSCLC

The FDA approved the use of pembrolizumab (Keytruda; Merck) and berahyaluronidase alfa-pmph (Keytruda Qlex; Merck) for use in patients 12 years and older with solid tumor indications approved for the intravenous formulation of pembrolizumab.1

Pembrolizumab is a PD-1 inhibitor that works by keeping T cells from attacking normal cells. The medication aims to avoid the binding of PD-1 to PD-L1, which encourages T cells not to attack the cancerous cells within the body.2 The intravenous use of pembrolizumab could be used for non–small cell lung cancer (NSCLC) without abnormal EGFR or ALK genes and takes 30 minutes to administer every 3 to 6 weeks at the doctor's office.3 Subcutaneous forms could reduce the amount of time needed to administer and receive the treatment.

The approval is based on the Study MK-3475A-D77 trial that evaluated the efficacy in patients with NSCLC who were treatment naive and had no genomic tumor aberrations of EGFR, ALK, or ROS1.4 The use of pembrolizumab with berahyaluronidase, administrated subcutaneously along with chemotherapy, was tested against intravenous pembrolizumab alone.

There were 377 patients enrolled in the study who were randomized 2:1 between the subcutaneous form of pembrolizumab with berahyaluronidase and the intravenous form of pembrolizumab, both in combination with chemotherapy.5 A median (range) time of 9.6 (6.2-16.4) months elapsed from randomization to data cut off.

The trial met the acceptance margin with an overall response rate of 45.4% (95% CI, 39%-52%) in the subcutaneous pembrolizumab and berahyaluronidase arm compared with 42.1% (95% CI, 33%-51%) in the intravenous pembrolizumab arm, making the subcutaneous treatment noninferior to that of the intravenous treatment while featuring a median time of injection of 2.0 (1-12) minutes.4,5

The subcutaneous form of the treatment was also able to achieve a median duration of response of 9.1 months (95% CI, 6.9–not reached) compared with 8.0 months (95% CI, 7.4–not reached) in the intravenous group. Median progression-free survival and overall survival were not significantly different across the 2 groups.6

"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,” Enriqueta Felip, head of the Thoracic Tumors Group and coauthor of the phase 3 trial, said in a statement after the results were reported in March 2025.6

Merck is also testing the efficacy of subcutaneous pembrolizumab alone for use in NSCLC compared with intravenous use of pembrolizumab, both in combination with chemotherapy, in the MK-3475-A86 trial (NCT04956692).7 The phase 3 study is still ongoing and is aiming to assess whether subcutaneous pembrolizumab is noninferior to the intravenous dose. The study is expected to conclude in October 2026 after 5 years of evaluation.

Patients are recommended to take doses of either 395 mg of pembrolizumab with 4800 units of berahyaluronidase every 3 weeks or 790 mg of pembrolizumab and 9600 units of berahyaluronidase every 6 weeks.1

Merck had previously announced that it was prepared to meet market demand of the product, stating that it would ship the product within the first week or two after the approval came through, with the expectation that 30% to 40% of those already on pembrolizumab would switch to the subcutaneous option now that it is available in the US.8

Reference

1. FDA approves pembrolizaumab and berahyaluronidase alfa-pmph for subcutaneous injection. News release. FDA. September 19, 2025. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-and-berahyaluronidase-alfa-pmph-subcutaneous-injection

2. Immune checkpoint inhibitors and their side effects. American Cancer Society. Updated July 7, 2025. Accessed September 19, 2025. https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html

3. Pembrolizumab. Mayo Clinic. Updated September 1, 2025. Accessed September 19, 2025. https://www.mayoclinic.org/drugs-supplements/pembrolizumab-intravenous-route/description/drg-20122552

4. Merck announces phase 3 trial of subcutaneous pembrolizumab with berahyaluronidase alfa met primary endpoints. News release. November 19, 2024. Accessed September 19, 2025. https://www.merck.com/news/merck-announces-phase-3-trial-of-subcutaneous-pembrolizumab-with-berahyaluronidase-alfa-met-primary-endpoints/

5. Felip E, Rojas CI, Schenker M, et al. Subcutaneous versus intravenous pembrolizumab, incombination 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

6. 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 September 19, 2025. https://www.merck.com/news/mercks-investigational-subcutaneous-pembrolizumab-with-berahyaluronidase-alfa-demonstrates-noninferior-pharmacokinetics-compared-to-intravenous-iv-keytruda-pembrolizumab-in-pivotal/

7. Study of pembrolizumab (MK-3475) subcutaneous (SC) versus pembrolizumab intravenous (IV) administered with platinum doublet chemotherapy in participants with metastatic squamous or nonsquamous non-small cell lung cancer (NSCLC) (MK-3475-A86). Clinicaltrials.gov. Updated December 3, 2024. Accessed September 19, 2025. https://www.clinicaltrials.gov/study/NCT04956692

8. Erman M. Merck plans to launch US subcutaneous version of Keytruda on October 1. Reuters. Updated March 27, 2025. Accessed September 19, 2025. https://www.reuters.com/business/healthcare-pharmaceuticals/merck-plans-us-launch-subcutaneous-version-keytruda-october-1-2025-03-27/