Enfortumab Vedotin-ejfv

RAHWAY, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the Ministry of Health, Labor and Welfare (MHLW) in Japan has approved KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use for all indications approved in Japan for KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy. In Japan, KEYJECT®, for subcutaneous injection is the planned trademark for KEYTRUDA QLEX. KEYJECT can be administered in one minute every three weeks or in two minutes every six weeks. Berahyaluronidase alfa is a variant of hyaluronidase developed and manufactured by Alteogen Inc. For a list of select indications for which KEYTRUDA and KEYTRUDA QLEX are approved in the United States, see Selected Indications in the U.S. below. “KEYJECT 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 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.” The approval of KEYJECT is based on results from the pivotal Phase 3 MK-3475A-D77 trial which compared KEYJECT to KEYTRUDA, both administered every six weeks, each in combination with chemotherapy, in patients with treatment-naïve metastatic non-small cell lung cancer (NSCLC) with no EGFR, ALK or ROS1 genomic tumor aberrations. This trial demonstrated comparable pharmacokinetic exposure levels between KEYJECT and KEYTRUDA. In descriptive analyses, overall response rates (ORR) were consistent between KEYJECT and KEYTRUDA. The ORR in the KEYJECT with chemotherapy arm was 45% (95% CI, 39-52) and 42% (95% CI, 33-51) in the KEYTRUDA with chemotherapy arm. There were no notable differences in progression-free survival (PFS) and overall survival (OS) observed in patients who received KEYJECT compared to patients who received KEYTRUDA. In September 2025, the U.S. Food and Drug Administration (FDA) approved KEYTRUDA QLEX and it 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 European Union (EU)] in November 2025, and it is now approved for all KEYTRUDA indications in Europe. About Study MK-3475A-D77 Study 3475A-D77 is a multicenter, randomized, open-label, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT05722015) conducted in patients with treatment-naïve metastatic non-small cell lung cancer (NSCLC) with no EGFR, ALK or ROS1 genomic tumor aberrations. The primary outcome measure was pembrolizumab exposure [Cycle 1 AUC0-6 weeks and Cycle 3 (i.e. Steady State) Ctrough] of KEYJECT as compared to KEYTRUDA. Additional descriptive efficacy outcome measures were ORR by blinded independent central review (BICR), PFS by BICR and OS. A total of 377 patients were randomized 2:1 to receive either KEYJECT (790 mg/9,600 units) every six weeks with platinum doublet chemotherapy (n=251) or KEYTRUDA (400 mg) every six weeks with platinum doublet chemotherapy (n=126). About subcutaneous administration Subcutaneous administration is a method of delivering medications under the skin. Subcutaneous administration may provide added convenience because it offers more options where patients can receive their treatment because it can be administered by healthcare providers in multiple settings 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. 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 2,800 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. About KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) injection for subcutaneous use, 165 mg + 2,000 units/mL KEYTRUDA QLEX is a fixed-combination drug product of pembrolizumab and berahyaluronidase alfa. Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody and berahyaluronidase alfa enhances dispersion and permeability to enable subcutaneous administration of pembrolizumab. KEYTRUDA QLEX is administered as a subcutaneous injection 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). Selected Indications in the U.S. for KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) Melanoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic melanoma. KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with stage IIB, IIC, or III melanoma following complete resection. Non-Small Cell Lung Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with metastatic nonsquamous non–small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, for the first-line treatment of adult patients with metastatic squamous NSCLC. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-authorized 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 and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-authorized 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 or KEYTRUDA QLEX. KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult 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 and KEYTRUDA QLEX, as single agents, are each indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Malignant Pleural Mesothelioma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with pemetrexed and platinum chemotherapy, for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). Head and Neck Squamous Cell Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-authorized test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with platinum and fluorouracil (FU), for the first-line treatment of adult patients with metastatic or with unresectable, recurrent HNSCC. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the first-line treatment of adult patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Urothelial Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with enfortumab vedotin-ejfv, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with enfortumab vedotin-ejfv, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment for the treatment of adult patients with muscle invasive bladder cancer (MIBC). KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-authorized test. Gastric Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. Esophageal Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with tumors that express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. Cervical Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemoradiotherapy (CRT), for the treatment of adult patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III-IVA). KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemotherapy, with or without bevacizumab, for the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test. Hepatocellular Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1–containing regimen. Biliary Tract Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with gemcitabine and cisplatin, for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Merkel Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). For this indication, KEYTRUDA also is indicated for the treatment of pediatric patients, and KEYTRUDA QLEX also is indicated for the treatment of pediatric patients 12 years and older. Renal Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with axitinib, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA and KEYTRUDA QLEX are each indicated for the adjuvant treatment of adult patients with renal cell carcinoma (RCC) at intermediate high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with carboplatin and paclitaxel, followed by KEYTRUDA or KEYTRUDA QLEX as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA and KEYTRUDA QLEX, as single agents, are each indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Cutaneous Squamous Cell Carcinoma KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated for the treatment of adult patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then each continued as a single agent as adjuvant treatment after surgery. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with acituzumab govitecan-hziy, for the first-line treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. Ovarian Cancer KEYTRUDA and KEYTRUDA QLEX are each indicated, in combination with paclitaxel, with or without bevacizumab, for the treatment of adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-authorized test, and who have received 1 or 2 prior systemic treatment regimens. Selected Safety Information for KEYTRUDA and KEYTRUDA QLEX in the U.S. Contraindications KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA and KEYTRUDA QLEX are monoclonal antibodies that belong 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 or KEYTRUDA QLEX 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 and KEYTRUDA QLEX depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA and KEYTRUDA QLEX require 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 and KEYTRUDA QLEX 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. Immune-mediated pneumonitis occurred in 5% (13/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including fatal (0.4%), Grade 3 (2%), and Grade 2 (1.2%) adverse reactions. 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 and KEYTRUDA QLEX 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. Immune-mediated colitis occurred in 1.2% (3/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.8%) and Grade 2 (0.4%) adverse reactions. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA and KEYTRUDA QLEX 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. Immune-mediated hepatitis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%) adverse reactions. KEYTRUDA With Axitinib or KEYTRUDA QLEX With Axitinib KEYTRUDA and KEYTRUDA QLEX, when either is used 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 or KEYTRUDA QLEX 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 and KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA and KEYTRUDA QLEX 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. Adrenal insufficiency occurred in 2% (5/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions. Hypophysitis KEYTRUDA and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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 and KEYTRUDA QLEX 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 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. Thyroiditis occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (0.4%). Hyperthyroidism occurred in 8% (20/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (3.2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%). 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 and KEYTRUDA QLEX depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Type 1 DM occurred in 0.4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA and KEYTRUDA QLEX can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA and KEYTRUDA QLEX depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Immune-mediated dermatologic adverse reactions occurred in 1.6% (4/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 4 (0.8%) and Grade 3 (0.8%) adverse reactions. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA, KEYTRUDA QLEX, or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis (2.8%), duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection; Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap syndrome, reported as the co-occurrence of either two or all three adverse reactions. Hypersensitivity and Infusion- or Administration-Related Reactions KEYTRUDA and KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. With KEYTRUDA and KEYTRUDA QLEX, monitor for signs and symptoms of infusion- and administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Infusion-related reactions have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Hypersensitivity and administration related systemic reactions occurred in 3.2% (8/251) of patients receiving KEYTRUDA QLEX in combination with platinum doublet chemotherapy, including Grade 2 (2.8%). Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate systemic reactions. For severe or life-threatening systemic reactions, stop injection and permanently discontinue KEYTRUDA QLEX. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT. Increased Mortality in Patients With Multiple Myeloma In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials. Embryofetal Toxicity Based on their mechanism of action, KEYTRUDA and KEYTRUDA QLEX can each cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA or KEYTRUDA QLEX and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In study MK-3475A-D77, when KEYTRUDA QLEX was administered with chemotherapy in metastatic non–small cell lung cancer (NSCLC), serious adverse reactions occurred in 39% of patients. Serious adverse reactions in ≥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 including pneumonia (3.2%), neutropenic sepsis (2%), death not otherwise specified (1.6%), respiratory failure (1.2%), parotitis (0.4%), pneumonitis (0.4%), pneumothorax (0.4%), pulmonary embolism (0.4%), neutropenic colitis (0.4%), and seizure (0.4%). KEYTRUDA QLEX was permanently discontinued due to an adverse reaction in 16% of 251 patients. Adverse reactions which resulted in permanent discontinuation of KEYTRUDA QLEX in ≥2% of patients included pneumonia and pneumonitis. Dosage interruptions of KEYTRUDA QLEX due to an adverse reaction occurred in 45% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia, anemia, thrombocytopenia, pneumonia, rash, and increased aspartate aminotransferase. The most common adverse reactions (≥20%) were nausea (25%), fatigue (25%), and musculoskeletal pain (21%). In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%). In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy or chemoradiotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain. In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%). Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. Adverse reactions observed in KEYNOTE-483 were generally similar to those occurring in other patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. In KEYNOTE-689, the most common adverse reactions (≥20%) in patients receiving KEYTRUDA were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%). In the neoadjuvant phase of KEYNOTE-689, of the 361 patients who received at least one dose of single agent KEYTRUDA, 11% experienced serious adverse reactions. Serious adverse reactions that occurred in more than one patient were pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune-mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%). Fatal adverse reactions occurred in 1.1% of patients, including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 2.8% of patients who received KEYTRUDA as neoadjuvant treatment. The most frequent adverse reaction which resulted in permanent discontinuation of neoadjuvant KEYTRUDA in more than one patient was arthralgia (0.6%). Of the 361 patients who received KEYTRUDA as neoadjuvant treatment, 11% did not receive surgery. Surgical cancellation on the KEYTRUDA arm was due to disease progression in 4%, patient decision in 3%, adverse reactions in 1.4%, physician’s decision in 1.1%, unresectable tumor in 0.6%, loss of follow-up in 0.3%, and use of non-study anti-cancer therapy in 0.3%. Of the 323 KEYTRUDA-treated patients who received surgery following the neoadjuvant phase, 1.2% experienced delay of surgery (defined as on-study surgery occurring ≥9 weeks after initiation of neoadjuvant KEYTRUDA) due to adverse reactions, and 2.8% did not receive adjuvant treatment due to adverse reactions. In the adjuvant phase of KEYNOTE-689, of the 255 patients who received at least one dose of KEYTRUDA, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of KEYTRUDA-treated patients were pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2.0%), pneumonitis (1.6%), COVID-19 (1.2%), death not otherwise specified (1.2%), diarrhea (1.2%), dysphagia (1.2%), gastrostomy tube site complication (1.2%), and immune-mediated hepatitis (1.2%). Fatal adverse reactions occurred in 5% of patients, including death not otherwise specified (1.2%), acute renal failure (0.4%), hypercalcemia (0.4%), pulmonary hemorrhage (0.4%), dysphagia/malnutrition (0.4%), mesenteric thrombosis (0.4%), sepsis (0.4%), pneumonia (0.4%), COVID-19 (0.4%), respiratory failure (0.4%), cardiovascular disorder (0.4%), and gastrointestinal hemorrhage (0.4%). Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were pneumonitis, colitis, immune-mediated hepatitis, and death not otherwise specified. In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%). In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%). In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism. In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin-ejfv to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin-ejfv; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin-ejfv were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%). In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%). In KEYNOTE-B15, the most common adverse reactions (≥20%) occurring in cisplatin-eligible patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin-ejfv (n=403) were rash (63%), fatigue (48%), pruritus (46%), peripheral neuropathy (43%), diarrhea (36%), alopecia (32%), decreased appetite (29%), nausea and dysgeusia (28% each), constipation (27%), urinary tract infection (UTI) and dry eye (25% each), weight loss (22%), and hyperglycemia (20%). In the neoadjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 27% (n=403) of patients; the most frequent (≥1.5%) were rash (3.2%), pneumonitis/interstitial lung disease (ILD) (2.2%), and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients, including multiple organ dysfunction syndrome (0.5%) and COVID-19 pneumonia, cardiac arrest, pneumonia, septic shock, and urosepsis (0.2% each). Additional fatal adverse reactions were reported in 2 patients in the post-surgery phase before adjuvant treatment started, including pneumonia and sepsis (1 patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (>1%) adverse reactions resulting in permanent discontinuation of KEYTRUDA were rash (2.2%), increased alanine aminotransferase (ALT) and pneumonitis/ILD (1.7% each), and hepatitis (1.2%). Of the 403 patients in the KEYTRUDA in combination with enfortumab vedotin-ejfv arm who received neoadjuvant treatment, 13 patients (3.2%) did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were multiple organ dysfunction syndrome (0.5%) and adenocarcinoma of colon, COVID-19 pneumonia, cardiac arrest, chronic obstructive pulmonary disease, coronary artery disease, glomerulonephritis, immune-mediated lung disease, myocarditis, pneumonia, pneumonitis, and urosepsis (0.2% each). Of the 351 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin-ejfv and underwent radical cystectomy, 26 patients (7%) experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions. In the adjuvant phase of KEYNOTE-B15, serious adverse reactions occurred in 35% (n=249) of patients; the most frequent (≥1.5%) were UTI (8%), sepsis (2.8%), and diarrhea, hyperglycemia, and pneumonitis/ILD (1.6% each). Fatal adverse reactions occurred in 3.2% of patients, including death (0.8%) and cardiac arrest, duodenal ulcer perforation, acute pancreatitis, renal failure, small cell lung cancer, and toxic shock syndrome (0.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 23% of patients; the most frequent (>1%) were diarrhea and pneumonitis/ILD (2.4% each), rash (2%), and hyperglycemia and sepsis (1.2% each). In KEYNOTE-905, the most common adverse reactions (≥20%) occurring in cisplatin-ineligible patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin-ejfv (n=167) were rash (54%), pruritus (47%), fatigue (47%), peripheral neuropathy (39%), alopecia (35%), dysgeusia (35%), diarrhea (34%), constipation (28%), decreased appetite (28%), nausea (26%), UTI(24%), dry eye (21%), and weight loss (20%). In the neoadjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 27% (n=167) of patients; the most frequent (≥2%) were UTI (3.6%) and hematuria (2.4%). Fatal adverse reactions occurred in 1.2% of patients, including myasthenia gravis and toxic epidermal necrolysis (0.6% each). Additional fatal adverse reactions were reported in 2.7% of patients in the post-surgery phase before adjuvant treatment started, including sepsis and intestinal obstruction (1.4% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of patients; the most frequent (>1%) were rash (2.4%, including generalized exfoliative dermatitis) and increased ALT, increased aspartate aminotransferase, diarrhea, dysgeusia, and toxic epidermal necrolysis (1.2% each). Of the 167 patients in the KEYTRUDA in combination with enfortumab vedotin-ejfv arm who received neoadjuvant treatment, 7 patients (4.2%) did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery were acute myocardial infarction, bile duct cancer, colon cancer, respiratory distress, UTI, and two deaths due to myasthenia gravis and toxic epidermal necrolysis (0.6% each). Of the 146 patients who received neoadjuvant treatment with KEYTRUDA in combination with enfortumab vedotin-ejfv and underwent radical cystectomy, 6 patients (4.1%) experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions. In the adjuvant phase of KEYNOTE-905, serious adverse reactions occurred in 45% (n=96) of patients; the most frequent (≥2%) were UTI (8%); acute kidney injury and pyelonephritis (5% each); urosepsis (4.2%); and hypokalemia, intestinal obstruction, and sepsis (2.1% each). Fatal adverse reactions occurred in 7% of patients, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome, and pseudomonal pneumonia (1% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 29% of patients; the most frequent (>2%) were diarrhea (5%), peripheral neuropathy, acute kidney injury, and pneumonitis (2% each). In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%). Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. In KEYNOTE-811, fatal adverse reactions occurred in 3 patients who received KEYTRUDA in combination with trastuzumab and CAPOX (capecitabine plus oxaliplatin) or FP (5-FU plus cisplatin) and included pneumonitis in 2 patients and hepatitis in 1 patient. KEYTRUDA was discontinued due to adverse reactions in 13% of 350 patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. Adverse reactions resulting in permanent discontinuation of KEYTRUDA in ≥1% of patients were pneumonitis (2.0%) and pneumonia (1.1%). In the KEYTRUDA arm vs placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 47%), rash (35% vs 28%), hypothyroidism (11% vs 5%), and pneumonia (11% vs 5%). In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%). In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%). Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 294 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 34% of patients; those ≥1% included urinary tract infection (3.1%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 9% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (51%), urinary tract infection (35%), vomiting (34%), fatigue (28%), hypothyroidism (23%), constipation (20%), weight loss (19%), decreased appetite (18%), pyrexia (14%), abdominal pain and hyperthyroidism (13% each), dysuria and rash (12% each), back and pelvic pain (11% each), and COVID-19 (10%). In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%). In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%). In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritus (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%). In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%). In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). In KEYNOTE-868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=382), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy (n=377). Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA with chemotherapy followed by KEYTRUDA alone were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-D19, when KEYTRUDA was administered in combination with sacituzumab govitecan-hziy to patients with unresectable locally advanced or metastatic TNBC who had not been previously treated with systemic therapy for advanced disease and whose tumors express PD-L1 (n=221), fatal adverse reactions occurred in 3.2% of patients, including death due to unknown cause (0.9%), completed suicide, neutropenic sepsis, sepsis, pneumonia, and pulmonary embolism (0.5% each). Serious adverse reactions occurred in 38% of patients receiving KEYTRUDA in combination with sacituzumab govitecan-hziy. Serious adverse reactions in ≥2% of patients were febrile neutropenia (7%), neutropenia (6%), diarrhea (5%), fatigue and pneumonia (2.3% each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 9% of patients. The adverse reactions which resulted in permanent discontinuation of KEYTRUDA most commonly (≥1%) were pneumonitis and rash (1.4% each). Dosage interruptions of KEYTRUDA due to adverse reactions occurred in 67% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia (36%), diarrhea (7%), upper respiratory tract infection (4.5%), anemia (4.1%), fatigue (4.1%), increased alanine aminotransferase (ALT) (3.2%), cough, leukopenia, nausea, pyrexia, rash, vomiting (2.7% each), and COVID-19 (2.3%). The most common (≥25%) adverse reactions, including laboratory abnormalities, occurring in patients treated with KEYTRUDA in combination with sacituzumab govitecan-hziy were decreased neutrophil count and decreased hemoglobin (86% each), decreased leukocyte count (84%), diarrhea (72%), nausea (68%), decreased lymphocyte count (61%), fatigue (58%), alopecia (52%), increased alkaline phosphatase and increased glucose (50% each), increased ALT (47%), constipation (41%), increased aspartate aminotransferase (40%), rash (37%), decreased potassium (35%), increased lactate dehydrogenase (34%), vomiting (29%), abdominal pain, headache, increased eosinophils (26% each), and decreased albumin (25%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). In KEYNOTE-B96, when KEYTRUDA in combination with paclitaxel, with or without bevacizumab, was administered to patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS ≥1), serious adverse reactions occurred in 54% of patients receiving KEYTRUDA and paclitaxel with or without bevacizumab. Serious adverse reactions in ≥2% of patients were pneumonia (4.3%), urinary tract infection (3.9%), adrenal insufficiency, hyponatremia (3% each), COVID-19, decreased neutrophil count, pulmonary embolism (2.6% each), abdominal pain, anemia, colitis, diarrhea, febrile neutropenia, pyrexia, and vomiting (2.1% each). Fatal adverse reactions occurred in 3.9% of patients receiving KEYTRUDA and paclitaxel, with or without bevacizumab, including assisted suicide (0.9%), death, intestinal perforation, sepsis, COVID-19, cardio-respiratory arrest, colitis, and embolic stroke (0.4% each). KEYTRUDA was permanently discontinued for adverse reactions in 16% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were colitis and increased alanine aminotransferase (1.3% each). Adverse reactions leading to the interruption of KEYTRUDA occurred in 44% of patients. The most common adverse reactions leading to interruption of KEYTRUDA in ≥2% were urinary tract infection (3.9%), adrenal insufficiency, pyrexia, pneumonitis, upper respiratory tract infection (2.6% each), neutropenia, diarrhea, and COVID-19 (2.1% each). The most common adverse reactions (≥20%) for patients treated with KEYTRUDA in combination with paclitaxel, with or without bevacizumab, were diarrhea (45%), fatigue (43%), nausea (41%), alopecia, peripheral neuropathy (38% each), epistaxis (31%), urinary tract infection (27%), constipation (25%), abdominal pain, decreased appetite, vomiting (24% each), hypothyroidism (21%), cough, hypertension, and rash (20% each). For patients treated with KEYTRUDA in combination with paclitaxel and bevacizumab (N=169), decreased white blood cell count (27%), stomatitis (22%), and pyrexia (21%) were also reported as adverse reactions. Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose. Pediatric Use In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). The safety and effectiveness of KEYTRUDA QLEX for the treatment of pediatric patients 12 years and older who weigh greater than 40 kg have been established for: Stage IIB, IIC, or III melanoma following complete resection Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors Recurrent locally advanced or metastatic Merkel cell carcinoma Use of KEYTRUDA QLEX in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies of KEYTRUDA in adults and additional pharmacokinetic and safety data for KEYTRUDA in pediatric patients 12 years and older. Pembrolizumab exposures in pediatric patients 12 years and older who weigh greater than 40 kg are predicted to be within range of those observed in adults at the same dosage. The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma (stage IIB, IIC, or III melanoma following complete resection in pediatric patients 12 and older), MCC, and MSI-H or dMMR cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of KEYTRUDA QLEX have not been established in pediatric patients younger than 12 years of age for the treatment of melanoma, MCC, and MSI-H or dMMR cancer. The safety and effectiveness of KEYTRUDA and KEYTRUDA QLEX have not been established in pediatric patients for other approved indications shown. Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (30%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Geriatric Use Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin-ejfv, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin-ejfv experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Of the 570 patients with MIBC treated with KEYTRUDA in combination with enfortumab vedotin-ejfv, 45% (n=259) were 65-74 years and 22% (n=125) were 75 years or older. No overall differences in effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin-ejfv experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 3.6% in patients younger than 75 and 11% in patients 75 years or older. Of 221 adult patients with TNBC who were treated with KEYTRUDA in combination with sacituzumab govitecan-hziy in KEYNOTE-D19, 26% of patients were 65 years and over and 5% were 75 years and older. No overall differences in effectiveness were observed between elderly patients and younger patients. There was a higher rate of serious adverse reactions in patients aged 65 years or older (48%) compared with younger adult patients (34%). Merck’s focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 20 novel mechanisms. With one of the largest clinical development programs across more than 25 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit www.merck.com/research/oncology. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2025 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov). Please see Prescribing Information for KEYTRUDA® (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA® at https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf. Please see Prescribing Information for KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_pi.pdf and Medication Guide for KEYTRUDA QLEX™ at https://www.merck.com/product/usa/pi_circulars/k/keytruda_qlex/keytruda_qlex_mg.pdf.

DAILY  ·  ONCOLOGY DIGEST 2026.09.23  |  阅读约 9 分钟 ESMO 2026 LBA 主席论坛四席中国研究入选，监管核药开新路： ESMO 2026（10 月 23—27 日马德里）突破性摘要日程正式公布，陆舜、徐瑞华、周俭、谢璐四位中国学者牵头的 III 期研究占据主席论坛四席，为历届最多；康方依沃西单抗 HARMONi-GI1 在晚期胆道癌取得首个击败 PD-(L)1 联合化疗的 OS 阳性 III 期数据；科伦博泰 sac-TMT TroFuse-005 在子宫内膜癌以 PFS+OS 双阳完成全球首个 TROP2 ADC 在该场景的注册证据。监管端，Lantheus BRAVNETSA 经仿制药路径获 FDA 批准，为核药开辟新通道；博锐创合与诺华达成最高 9 亿美元放射性配体疗法全球独家许可。 01   CLINICAL今日要闻 · 5 条 ① ESMO 2026 突破性摘要日程公布，中国四项研究入选主席论坛口头报告 2026 年 9 月 22 日，欧洲肿瘤内科学会（ESMO）官网正式披露 2026 年会（10 月 23—27 日，西班牙马德里）突破性摘要（LBA）日程。在三场主席研讨会中，中国学者牵头的四项 III 期研究入选：陆舜教授 LBA6（SAFFRON，奥希替尼联合赛沃替尼治疗 EGFR 突变伴 MET 过表达／扩增晚期 NSCLC）、徐瑞华院士 LBA7（CLARITY-Gastric 01，Claudin 18.2 ADC 治疗胃食管癌）、周俭院士 LBA8（HARMONi-GI1，依沃西单抗一线治疗晚期胆道癌）、谢璐教授 LBA9（ARTEMIS-011，瑞康立伏妥塔单抗治疗复发难治骨肉瘤）。此外药物研发专场与免疫治疗研发专场亦有多项中国研究入选，为历届最多。 📎 ESMO 2026 官方摘要日程 · 医药魔方 · 2026/9/22 🔗 https://www.esmo.org/meetings/esmo-congress-2026 ② 依沃西单抗 HARMONi-GI1 达到主要终点，成为全球首个在晚期胆道癌中 OS 击败 PD-(L)1 联合化疗的 III 期研究 9 月 22 日康方生物与 Summit Therapeutics 披露，中国开展的随机、对照、双盲、多中心 III 期 HARMONi-GI1 研究（682 例）在预设中期分析中，依沃西单抗（PD-1／VEGF 双抗）联合吉西他滨＋顺铂对比度伐利尤单抗联合化疗一线治疗晚期胆道癌，总生存期（OS）取得统计学显著且具有临床意义的优效，关键次要终点无进展生存期（PFS）与客观缓解率（ORR）亦同步达标。这是已知首个在晚期胆道癌中证实 OS 优于抗 PD-(L)1 联合化疗方案的 III 期研究，也是依沃西单抗在肺癌之外（既往四项肺癌 III 期阳性）的首个 III 期阳性结果，详细数据将于 10 月 25 日 ESMO 2026 主席论坛 II（LBA8）公布。 📎 Summit Therapeutics 新闻稿 · 康方生物公告 · 2026/9/22 🔗 https://stockhouse.com/news/press-releases/2026/09/22/harmoni-gi1-a-phase-iii-trial-featuring-ivonescimab-plus-chemotherapy-compared ③ 芦康沙妥珠单抗 TroFuse-005 子宫内膜癌 III 期 PFS 与 OS 双阳性，全球首个且唯一在该治疗场景达成的 ADC 9 月 22 日公开信息显示，默沙东与科伦博泰的 TROP2 ADC 芦康沙妥珠单抗（sac-TMT）首个全球 III 期研究 TroFuse-005 详细数据入选 ESMO 2026 主席论坛 III（LBA11）。该研究为随机、阳性对照、开放标签、多中心全球 III 期，共入组 776 例既往接受过铂类化疗和抗 PD-1／PD-L1 免疫治疗的子宫内膜癌患者，随机接受 sac-TMT 或医生选择的化疗（多柔比星或紫杉醇）。预设中期分析中，sac-TMT 相较对照组显示出具有统计学意义和临床意义的 OS 与 PFS 双重改善，并达到 ORR 关键次要终点，安全性特征与既往一致、未发现新信号。默沙东围绕 sac-TMT 已启动 18 项全球 III 期试验。 📎 医药魔方 · 默沙东／科伦博泰公告 · 2026/9/22 🔗 https://www.163.com/dy/article/L7E70BNO0534Q32Z.html ④ FDA 批准 BRAVNETSA，全球首个经仿制药（ANDA）途径获批的放射配体疗法 2026 年 9 月 22 日，Lantheus Holdings 宣布 FDA 对 BRAVNETSA（lutetium Lu 177 dotatate，镥[177Lu]多他肽，中文通用名尚待官方公布）授予最终批准，用于治疗生长抑素受体阳性（SSTR+）的成人胃肠胰神经内分泌肿瘤（GEP-NET），包括前肠、中肠与后肠神经内分泌肿瘤。这是 FDA 唯一认定与参比制剂 LUTATHERA 生物等效且治疗等效的放射性药物，也是首个通过简略新药申请（ANDA）途径获批的放射配体疗法，为核药开辟了新的监管路径。该品种曾于 2026 年 3 月获临时批准，受 LUTATHERA 专利与独占期限制而延后生效。说明书含辐射暴露、骨髓抑制、骨髓增生异常综合征与白血病风险、肝肾毒性等黑框与警示信息。 📎 FDA 肿瘤药物批准公告 · Lantheus 企业公告 · 2026/9/22 🔗 https://www.stocktitan.net/news/LNTH/lantheus-receives-final-fda-approval-for-bravnetsatm-lutetium-lu-177-hbqohxym3cs8.html ⑤ 博锐创合与诺华达成放射性配体疗法全球独家许可，总交易金额最高 9 亿美元 2026 年 9 月 22 日，苏州博锐创合医药宣布与诺华就一项临床前放射性配体疗法（RLT）资产达成全球独家许可协议。根据条款，博锐创合将有资格获得最高达 9 亿美元的总交易付款，涵盖首付款、开发里程碑、监管里程碑以及商业化销售里程碑，并有权就未来全球净销售额收取特许权使用费。这是国内核药领域继此前多笔出海交易后，临床前阶段资产即获跨国药企全球授权的又一案例，反映放射性配体疗法仍是全球肿瘤领域最活跃的并购与授权方向。 📎 医药魔方 · 博锐创合公告 · 2026/9/22 🔗 https://bydrug.pharmcube.com/news/detail/b8f34532801a3912300f9364a1dc978e ✦ 今 日 看 点 「ESMO 兑现 × 监管破冰」——ESMO 2026 主席论坛 4 项中国 III 期研究入选为历届最多，陆舜（SAFFRON）、徐瑞华（CLARITY-Gastric 01）、周俭（HARMONi-GI1）、谢璐（ARTEMIS-011）分别覆盖 EGFR/MET 联合、Claudin 18.2 ADC、PD-1/VEGF 双抗与 B7-H3 ADC 四个前沿方向。疗效端，依沃西单抗 HARMONi-GI1 是首个在晚期胆道癌 OS 击败 PD-(L)1 联合化疗的 III 期研究，也是该药在肺癌之外的首个非肺癌阳性 III 期（既往 4 项肺癌阳性）；sac-TMT TroFuse-005 在子宫内膜癌以 PFS+OS 双阳完成全球首个 TROP2 ADC 在该场景的注册证据，默沙东已围绕该分子启动 18 项全球 III 期。监管端，Lantheus BRAVNETSA 以 ANDA 路径获 FDA 最终批准，成为首个通过仿制药通道获批的放射配体疗法，为核药开辟新通道；同日博锐创合与诺华达成最高 9 亿美元 RLT 全球独家许可，RLT 仍是跨国药企并购与授权的最活跃方向。 02   LITERATURE顶刊论文 · 6 篇 📕 The Lancet Oncology ① 依沃西单抗联合化疗对比安慰剂联合化疗治疗 EGFR 酪氨酸激酶抑制剂进展后晚期 EGFR 突变非小细胞肺癌（HARMONi）：一项多中心、随机、双盲、III 期试验（PMID 42636833） 🔗 https://pubmed.ncbi.nlm.nih.gov/42636833/ ② 度伐利尤单抗联合替西木单抗加或不加仑伐替尼联合经动脉化疗栓塞治疗适合栓塞的肝细胞癌（EMERALD-3）：一项全球、随机、开放标签、申办方盲法的 III 期研究（PMID 42636832） 🔗 https://pubmed.ncbi.nlm.nih.gov/42636832/ ③ SHR-A2102（一种靶向 Nectin-4 的抗体偶联药物）治疗既往经治的晚期实体瘤：一项多中心、单臂、I 期试验（PMID 42636836） 🔗 https://pubmed.ncbi.nlm.nih.gov/42636836/ 📗 Journal of Clinical Oncology（JCO） ① 瑞康曲妥珠单抗（Trastuzumab Rezetecan）在 HER2 高表达与低表达队列晚期唾液腺癌中的生物标志物分层 II 期试验（PMID 42579830） 🔗 https://pubmed.ncbi.nlm.nih.gov/42579830/ ② 激光间质热疗治疗脑肿瘤：来自 LAANTERN 研究的前瞻性多中心分析（PMID 42607280） 🔗 https://pubmed.ncbi.nlm.nih.gov/42607280/ ③ COMBI-I：Spartalizumab 联合达拉非尼与曲美替尼治疗 BRAF V600 突变晚期黑色素瘤的长期总生存（PMID 42585631） 🔗 https://pubmed.ncbi.nlm.nih.gov/42585631/ 03   MEETINGS会议摘要 · 2 条 ① ESMO 2026（主席论坛 I，LBA2）：VOLGA —— 围手术期度伐利尤单抗联合或不联合替西木单抗加新辅助维恩妥尤单抗治疗肌层浸润性膀胱癌的 III 期试验结果。 📎 ESMO 2026 ② ESMO 2026（主席论坛 II，LBA7）：CLARITY-Gastric 01 —— Sonesitatug vedotin（Claudin 18.2 ADC）用于二线及以上 Claudin 18.2 阳性晚期或转移性胃食管癌的 III 期研究（讲者：徐瑞华院士）。 📎 ESMO 2026 04   REGULATORY监管动态 · 2 条 🇨🇳 NMPA（中国国家药监局） ① 天演药业 ADG138 获临床试验（IND）批准（2026/9/22）—— 一款基于 SAFEbody 精准掩蔽技术构建的双掩蔽 HER2×CD3 双特异性 T 细胞衔接器，拟用于 HER2 表达的晚期实体瘤，I 期首次人体研究计划于 2026 年第四季度在中国启动；临床前数据显示其对 Enhertu（T-DXd）耐药模型仍有强效抗肿瘤活性，且细胞因子释放显著降低。 📎 天演药业公告 · 国家药监局药品审评中心 · 2026/9/22 ② 吉伦泰 99mTc-HP-Ark2 获临床试验补充申请批准（2026/9/22）—— 北京吉伦泰医药申报的化药 1 类放射性诊断新药锝[99mTc]肼基烟酰胺双链 Ark 肽注射液，一款用于 SPECT/CT 显像的 HER2 靶向放射性诊断药物，拟用于 HER2 阳性乳腺癌的鉴别诊断，为乳腺癌精准分型、靶向治疗选择及疗效监测提供无创分子影像工具。 📎 吉伦泰公告 · 国家药监局药品审评中心 · 2026/9/22 05   DEALS药企公告 · 1 条 ① 同源康医药与齐鲁制药认购协议失效，核心产品商业化合作未断 2026/9/22：公司公告截至 9 月 20 日最后截止日，齐鲁制药 6322.27 万股 H 股认购（约 4 亿港元）先决条件未达成或获豁免，认购协议失效；围绕第三代 EGFR 抑制剂 TY-9591（甲磺酸艾多替尼，商品名卡达沙）的许可及商业化协议继续有效，9 月 21 日公司股价收涨 15.05%。 「 把 每 一 天 的 进 展 ，都 留 在 记 忆 里 。」 — · — 关注我们，把临床的每一次曙光， 以最温柔的方式，悉数赠予你。 ————————— END ————————— 如果觉得有用，欢迎点赞 · 在看 · 分享给身边需要的朋友 文 / 肿瘤临床研究进展日报编辑部 编辑 /i Hope医学 审稿人/赵宁