Japan Approves Subcutaneous Pembrolizumab, First Subcutaneous Checkpoint Inhibitor in the Country
核心洞察
Japan's Ministry of Health, Labor and Welfare approved KEYTRUDA QLEX (搜索), a fixed-dose combination of pembrolizumab and berahyaluronidase alfa (搜索), for subcutaneous use across all 22 approved KEYTRUDA indications.
The product, to be marketed in Japan as KEYJECT (搜索), can be given by a healthcare provider in one minute every three weeks or two minutes every six weeks.
Approval was based on the Phase 3 MK-3475A-D77 trial, which showed comparable pembrolizumab exposure and an objective response rate of 45.4% versus 42.1% for intravenous KEYTRUDA.
Japan's Ministry of Health, Labor and Welfare has approved KEYTRUDA QLEX (搜索) (pembrolizumab and berahyaluronidase alfa (搜索)-pmph) injection for subcutaneous use across all indications approved in Japan for intravenous KEYTRUDA (pembrolizumab), Merck (搜索)'s anti-PD-1 (搜索) therapy. The approval covers all 22 KEYTRUDA indications currently authorized in Japan. In Japan, the product is planned to be marketed under the trademark KEYJECT (搜索).
KEYJECT (搜索) is a fixed-dose combination of pembrolizumab, a humanized monoclonal antibody targeting PD-1 (搜索), and berahyaluronidase alfa (搜索), an enzyme that hydrolyzes hyaluronic acid and enhances dispersion and permeability to enable subcutaneous delivery. Berahyaluronidase alfa is a variant of hyaluronidase developed and manufactured by Alteogen Inc. The subcutaneous injection is given into the thigh or abdomen, avoiding the 5 cm area around the navel, over one minute every three weeks (2.4 mL) or over two minutes every six weeks (4.8 mL).
"KEYJECT (搜索) is the first and only subcutaneous immune checkpoint inhibitor available in Japan that can be administered by a healthcare provider in as little as one minute," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck (搜索) Research Laboratories. "This approval is a significant milestone for patients and healthcare providers in Japan and reflects our commitment to advancing new patient-centered care options like KEYJECT that offers patients two dosing options and more choices of health care settings where they can receive therapy."
Pivotal Trial Results
The approval is based on results from the pivotal Phase 3 MK-3475A-D77 trial (ClinicalTrials.gov, NCT05722015), a multicenter, randomized, open-label, active-controlled study that compared KEYJECT (搜索) with KEYTRUDA, both administered every six weeks in combination with platinum doublet chemotherapy. The trial enrolled 377 patients with treatment-naive metastatic non-small cell lung cancer (搜索) (NSCLC) with no EGFR, ALK or ROS1 genomic tumor aberrations, randomized 2:1 to receive either KEYJECT (790 mg/9,600 units) every six weeks with chemotherapy (n=251) or KEYTRUDA (400 mg) every six weeks with chemotherapy (n=126). The study included 23 Japanese patients.
The primary outcome measure was pembrolizumab exposure, assessed as Cycle 1 AUC0-6 weeks and Cycle 3 steady-state Ctrough. The trial demonstrated comparable pharmacokinetic exposure levels between KEYJECT (搜索) and KEYTRUDA.
In descriptive efficacy analyses, the overall response rate was 45% (95% CI, 39-52) in the KEYJECT (搜索) plus chemotherapy arm and 42% (95% CI, 33-51) in the KEYTRUDA plus chemotherapy arm. In Japan, the primary efficacy endpoint was objective response rate based on blinded independent central review under RECIST version 1.1 criteria. KEYJECT posted an objective response rate of 45.4% (95% CI: 39.1 to 51.8) versus 42.1% (95% CI: 33.3 to 51.2) for KEYTRUDA. Using a synthesis method, the ratio of objective response rates was 1.08 (95% CI, 0.85 to 1.37; p=0.00051), demonstrating non-inferiority. Merck (搜索) reported no notable differences in progression-free survival or overall survival between the treatment groups.
Safety Profile
In the safety analysis set of the MK-3475A-D77 trial, adverse drug reactions were reported in 226 of 251 patients (90.0%), including all 18 Japanese patients evaluated for safety. The most common adverse drug reactions occurring in at least 20% of patients were anemia in 131 cases (52.2%), neutropenia in 105 (41.8%), thrombocytopenia in 71 (28.3%), leukopenia in 70 (27.9%) and nausea in 56 (22.3%).
In the study, when KEYTRUDA QLEX (搜索) was administered with chemotherapy in metastatic NSCLC, serious adverse reactions occurred in 39% of patients. Serious adverse reactions in at least 1% of patients who received KEYTRUDA QLEX were pneumonia (10%), thrombocytopenia (4%), febrile neutropenia (4%), neutropenia (2.8%), musculoskeletal pain (2%), pneumonitis (2%), diarrhea (1.6%), rash (1.2%), respiratory failure (1.2%), and anemia (1.2%). Fatal adverse reactions occurred in 10% of patients. KEYTRUDA QLEX was permanently discontinued due to an adverse reaction in 16% of 251 patients, and dosage interruptions due to an adverse reaction occurred in 45% of patients. The most common adverse reactions (at least 20%) were nausea (25%), fatigue (25%), and musculoskeletal pain (21%).
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue with anti-PD-1 (搜索)/PD-L1 treatments. In the trial, immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX (搜索) in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) reactions. Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX with chemotherapy, including Grade 2 (11%), and hyperthyroidism occurred in 8% (20/251), including Grade 2 (3.2%). KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa (搜索), hyaluronidase or to any of its excipients.
Regulatory Context
The Japanese approval adds to regulatory clearances for subcutaneous pembrolizumab in the United States and the European Union. In September 2025, the U.S. Food and Drug Administration approved KEYTRUDA QLEX (搜索), which is now approved for adults in all the same solid tumor indications as KEYTRUDA. The European Commission approved subcutaneous pembrolizumab, known as KEYTRUDA SC in the EU, in November 2025, and it is now approved for all KEYTRUDA indications in Europe.
Pembrolizumab has been marketed in Japan as Keytruda intravenous infusion 100 mg since 2017 and is used across a broad range of cancers. Intravenous KEYTRUDA administration has required about 30 minutes per dose, compared with one to two minutes for subcutaneous KEYJECT (搜索). According to Merck (搜索), subcutaneous administration may offer added convenience because it provides more options for where patients can receive treatment, from an infusion center to a doctor's office or a local community-based clinic. For patients who do not require a port or whose veins are difficult to access, subcutaneous administration may simplify treatment administration.
Merck (搜索) describes KEYTRUDA as an anti-programmed death receptor-1 (PD-1 (搜索)) therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. The company states it has the industry's largest immuno-oncology clinical research program, with more than 2,800 trials studying KEYTRUDA across a wide variety of cancers and treatment settings.