Subcutaneous pembrolizumab administered every six weeks with a median injection time of two minutes, in combination with chemotherapy, shows consistent results across reported efficacy and safety endpoints compared to IV KEYTRUDA in combination with chemotherapy
A time and motion descriptive analysis shows nearly 50% reductions in patient chair and treatment room time, and in total active healthcare professional time related to treatment tasks, for subcutaneous pembrolizumab compared to IV KEYTRUDA
Applications for subcutaneous pembrolizumab are under review in the U.S. and Europe
RAHWAY, N.J.--(BUSINESS WIRE)--#MRK--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the first data presentation from the pivotal 3475A-D77 Phase 3 trial, evaluating the subcutaneous administration of pembrolizumab, together with berahyaluronidase alfa (MK-3475A; from now on referred to as “subcutaneous pembrolizumab”). Berahyaluronidase alfa is a variant of human hyaluronidase developed and manufactured by Alteogen Inc. These results are being presented today at the European Lung Cancer Congress (ELCC) 2025 (Abstract #8MO) and published simultaneously in Annals of Oncology.
The study met its primary endpoints, demonstrating noninferior pharmacokinetics (PK) for subcutaneous pembrolizumab administered with chemotherapy with a median injection time of two minutes, versus intravenous (IV) KEYTRUDA® (pembrolizumab) administered with chemotherapy for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC). The secondary endpoints of objective response rate (ORR), progression-free survival (PFS) and duration of response (DOR) and safety were consistent for subcutaneous pembrolizumab with chemotherapy compared to IV KEYTRUDA with chemotherapy. Median overall survival (OS) was not reached in either arm.
Based on these data, the U.S. Food and Drug Administration (FDA) has accepted for review a Biologics License Application (BLA) seeking approval of subcutaneous pembrolizumab across all previously approved solid tumor indications for KEYTRUDA. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of Sept. 23, 2025. Additionally, the European Medicines Agency (EMA) has validated an extension application to introduce a new pharmaceutical form and new route of administration for KEYTRUDA.
In addition, results of a prospective, observational time and motion descriptive analysis conducted alongside study 3475A-D77 show that, compared to IV KEYTRUDA, subcutaneous pembrolizumab reduced time for patients spent in-chair and in the treatment room by 49.7% and 47.4%, respectively, and reduced the total active time spent by healthcare professionals (HCPs) on treatment preparation, administration process and patient monitoring by 45.7%. These results are being presented as a poster at ELCC (Poster #33P). Pharmacokinetic, efficacy, safety and time and motion results are described further below.
“These study findings demonstrate subcutaneous pembrolizumab reduces time demands for both the patient and the healthcare provider, all while providing a consistent efficacy and safety profile with IV pembrolizumab,” said Dr. Enriqueta Felip, head of Thoracic Tumors Group, Vall d’Hebron Institute of Oncology. “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.”
In the 3475A-D77 trial, subcutaneous pembrolizumab, administered every six weeks with a median injection time of two minutes (4.8 mL) along with chemotherapy, demonstrated noninferiority of area under the curve (AUC) exposure of pembrolizumab during the first dosing cycle (geometric mean ratio of 1.14 [96% CI, 1.06-1.22]; p<0.0001) and model-based trough concentration (Ctrough) of pembrolizumab measured at steady state (geometric mean ratio of 1.67 [94% CI, 1.52-1.84]; p<0.0001), compared to IV KEYTRUDA administered every six weeks with chemotherapy.
“KEYTRUDA has helped transform the treatment of certain cancers, and we continue to pursue innovations that build on this breakthrough medicine to give patients and those who treat them better experiences,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “If approved, we are excited about the potential of subcutaneous pembrolizumab to become a new meaningful treatment option that may increase access and save time needed for administration compared to IV KEYTRUDA. We look forward to working with global regulatory authorities to bring the first subcutaneous checkpoint inhibitor that can be administered in approximately two minutes to patients and providers.”
In the prospective, observational time and motion study, patient time in chair during treatment with pembrolizumab was reduced by 49.7% (weighted means [WM]: 59.0 versus 117.2 minutes) for subcutaneous pembrolizumab with chemotherapy compared to IV KEYTRUDA with chemotherapy. Patients receiving subcutaneous pembrolizumab versus IV KEYTRUDA spent 47.4% less time in the treatment room (WM: 66.7 versus 126.9 minutes). Time associated with chemotherapy administration was removed from chair and treatment room duration. Results also show that subcutaneous pembrolizumab with chemotherapy reduced total active HCP time by 45.7% (WM: 14.0 versus 25.8 minutes;), including 44.6% less time on subcutaneous pembrolizumab preparation (WM: 5.1 versus 9.2 minutes) and 46.7% less time on subcutaneous pembrolizumab administration process and patient monitoring (WM: 8.9 versus 16.7 minutes) compared to IV KEYTRUDA with chemotherapy. The differences as measured by a linear mixed model were statistically significant (p<0.0001) for active HCP and patient time endpoints.
In addition to the 3475A-D77 trial, Merck’s subcutaneous pembrolizumab clinical development program includes the 3475A-F84 Phase 3 trial evaluating subcutaneous pembrolizumab administered alone compared to IV KEYTRUDA alone for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] ≥50%), as well as the 3475A-F65 Phase 2 trial evaluating subcutaneous pembrolizumab administered alone in relapsed or refractory classical Hodgkin lymphoma and relapsed or refractory primary mediastinal large B-cell lymphoma. Merck is also conducting a patient preference Phase 2 study, 3475A-F11, evaluating participant-reported preference for subcutaneous pembrolizumab compared to IV KEYTRUDA.
Study design and additional data from 3475A-D77
Study 3475A-D77 is a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT05722015) evaluating the subcutaneous administration of pembrolizumab together with berahyaluronidase alfa administered every six weeks with chemotherapy compared to IV KEYTRUDA administered every six weeks in combination with chemotherapy for the first-line treatment of adult patients with metastatic NSCLC, regardless of PD-L1 TPS expression. The study is designed to assess the dual primary PK endpoints of the AUC of pembrolizumab exposure during the first dosing cycle and the Ctrough of pembrolizumab measured at steady state. Secondary endpoints include additional PK parameters as well as efficacy (ORR, DOR, PFS and OS) and safety. The trial enrolled 377 patients who were randomized (2:1) to receive either subcutaneous pembrolizumab administered with chemotherapy or IV KEYTRUDA in combination with chemotherapy.
Secondary efficacy endpoints of the study, which were descriptive, showed:
- An ORR of 45.4% (95% CI, 39.1-51.8) for subcutaneous pembrolizumab with chemotherapy versus 42.1% (95% CI, 33.3-51.2) for IV KEYTRUDA with chemotherapy (ORR ratio of 1.08 [95% CI, 0.85-1.37])
- Median DOR of 9.1 months (95% CI, 6.9-not reached [NR]) for subcutaneous pembrolizumab with chemotherapy versus 8.0 months (95% CI, 7.4-NR) for IV KEYTRUDA with chemotherapy
- Median PFS for subcutaneous pembrolizumab with chemotherapy of 8.1 months (95% CI, 6.3-8.3) versus 7.8 months (95% CI, 6.2-9.7) for IV KEYTRUDA with chemotherapy (HR=1.05 [95% CI, 0.78-1.43])
- Median OS was not reached in either arm (HR=0.81 [95% CI, 0.53-1.22])
Among patients who received subcutaneous pembrolizumab with chemotherapy (n=251), Grade ≥3 adverse events (AEs) occurred in 47% of patients versus 47.6% of patients who received IV KEYTRUDA with chemotherapy (n=126). The incidence of local injection site reactions for subcutaneous pembrolizumab with chemotherapy was 2.4%, all of which were low grade. Treatment-related adverse events (TRAEs) led to discontinuation of subcutaneous pembrolizumab in 8.4% of patients in the subcutaneous pembrolizumab with chemotherapy arm and in 8.7% of patients in the IV KEYTRUDA with chemotherapy arm. Additionally, TRAEs led to discontinuation of chemotherapy in 15.1% of patients in the subcutaneous pembrolizumab with chemotherapy arm and 11.9% of patients in the IV KEYTRUDA with chemotherapy arm. Treatment-related deaths occurred in 3.6% of patients who received subcutaneous pembrolizumab with chemotherapy and 2.4% of patients who received IV KEYTRUDA with chemotherapy.
Study design from time and motion study
The global observational time and motion study enrolled 17 sites across eight countries in Europe (4), South America (3) and Asia (1) from the 3475A-D77 trial. Primary endpoints were patient time in chair during treatment, patient time in treatment room and total active HCP time for tasks related to subcutaneous pembrolizumab preparation, administration process and patient monitoring. Time was measured by trained observers using a stopwatch, and time associated with chemotherapy administration was removed from patient in-chair and treatment room duration. Descriptive statistics were calculated including WM to account for unequal sample sizes across countries in each group. Statistical differences between subcutaneous and IV arms were explored via a linear mixed model.
About KEYTRUDA® (pembrolizumab) injection for intravenous use, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
- Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
- metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA.
Contacts
Media Contacts:
Olivia Finucane
+44 7881 262476
Diane Foley
(862) 260-0060
Investor Contacts:
Peter Dannenbaum
(732) 594-1579
Steven Graziano
(732) 594-1583
