FDA Approves Merck’s KEYTRUDA® Plus Chemotherapy, With or Without Bevacizumab, as Treatment for Patients With Persistent, Recurrent or Metastatic Cervical Cancer Whose Tumors Express PD-L1

FDA批准默克公司的Keytruda®加化疗,无论是否贝伐单抗,作为肿瘤表达PD-L1的持续、复发或转移宫颈癌患者的治疗方法

2021-10-14 07:30:14 Investing News Network

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This Is the First Anti-PD-1 Combination Approved as First-Line Treatment for These Patients Merck known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent or metastatic cervical cancer whose … This Is the First Anti-PD-1 Combination Approved as First-Line Treatment for These Patients Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA-approved test. The approval is based on the Phase 3 KEYNOTE-826 trial evaluating KEYTRUDA plus chemotherapy (paclitaxel plus cisplatin or paclitaxel plus carboplatin), with or without bevacizumab, compared to the same chemotherapy regimens, with or without bevacizumab. In this patient population, KEYTRUDA plus chemotherapy, with or without bevacizumab, demonstrated superior overall survival (OS; HR=0.64 [95% CI, 0.50-0.81]; p=0.0001) and progression-free survival (PFS; HR=0.62 [95% CI, 0.50-0.77]; p Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below. “Cervical cancer more commonly affects younger women and certain women of color in the U.S., and unfortunately, women diagnosed with persistent, recurrent or metastatic cervical cancer often have a low survival rate,” said Dr. Bradley Monk, oncologist with Arizona Oncology, medical director of U.S. Oncology Research Gynecology Program and professor of obstetrics and gynecology at University of Arizona’s College of Medicine and Creighton University School of Medicine. “There have been no first-line approvals for women with persistent, recurrent or metastatic cervical cancer in the past seven years. I am excited for today’s approval of a new combination with KEYTRUDA, which offers a new treatment option for appropriate patients.” “Today’s news is a meaningful step forward, as it offers a new therapeutic option for these patients and reinforces the role of KEYTRUDA in treating certain types of cervical cancers, with a second indication for the disease,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “The data showing a 36% reduction in the risk of death are compelling, and this approval brings an important new first-line treatment option to women with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1).” Additionally, the FDA converted the accelerated approval of KEYTRUDA as a single agent for the treatment of 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-approved test, to a regular approval based on confirmatory data from KEYNOTE-826. This approval was originally granted in June 2018 based on results from the KEYNOTE-158 trial. Merck is committed to delivering meaningful advances in women’s cancers. The company is rapidly expanding its extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across gynecologic cancers, including researching KEYTRUDA for the treatment of other types of cervical cancer. About KEYNOTE-826 The approval was based on data from KEYNOTE-826 (ClinicalTrials.gov, NCT03635567 ), a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 617 patients with persistent, recurrent or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumor PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab and PD-L1 status (CPS Patients in the KEYTRUDA arm received KEYTRUDA 200 mg intravenously every three weeks (Q3W) plus investigator’s choice of paclitaxel plus cisplatin or paclitaxel plus carboplatin Q3W, with or without bevacizumab Q3W. Patients in the placebo arm received placebo plus investigator’s choice of paclitaxel plus cisplatin or paclitaxel plus carboplatin Q3W, with or without bevacizumab Q3W. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each three-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every nine weeks for the first year, followed by every twelve weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by investigator review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Additional efficacy outcome measures were ORR and DOR, according to RECIST v1.1, as assessed by investigator review. Of the 617 enrolled patients, 548 patients (89%) had tumors expressing PD-L1 with a CPS ≥1. Among these 548 enrolled patients with tumors expressing PD-L1, 273 patients were randomized to KEYTRUDA in combination with chemotherapy, with or without bevacizumab, and 275 patients were randomized to placebo in combination with chemotherapy, with or without bevacizumab. Sixty-three percent of the 548 patients received bevacizumab as part of study treatment. At study entry, 21% of patients had metastatic disease only, and 79% had persistent or recurrent disease, with or without distant metastases, of whom 39% had received prior chemoradiation only, and 17% had received prior chemoradiation plus surgery. The key efficacy results for patients with tumors expressing PD-L1 (CPS ≥1) are summarized below: Endpoint KEYTRUDA + Chemotherapy* With or Without Bevacizumab n=273 Placebo + Chemotherapy* With or Without Bevacizumab n=275 OS Number of patients with event (%) 118 (43.2) 154 (56.0) Median in months (95% CI) NR (19.8, NR) 16.3 (14.5, 19.4) Hazard ratio † (95% CI) 0.64 (0.50, 0.81) p-Value ‡ 0.0001 PFS Number of patients with event (%) 157 (57.5) 198 (72.0) Median in months (95% CI) 10.4 (9.7, 12.3) 8.2 (6.3, 8.5) Hazard ratio † (95% CI) 0.62 (0.50, 0.77) p-Value § ORR ORR ¶ (95% CI) 68% (62, 74) 50% (44, 56) Complete response rate 23% 13% Partial response rate 45% 37% DOR Median in months (range) 18.0 (1.3+, 24.2+) 10.4 (1.5+, 22.0+) * Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) † Based on the stratified Cox proportional hazard model ‡ p-Value (one-sided) is compared with the allocated alpha of 0.0055 for this interim analysis (with 72% of the planned number of events for final analysis) § p-Value (one-sided) is compared with the allocated alpha of 0.0014 for this interim analysis (with 82% of the planned number of events for final analysis) ¶ Response: Best objective response as confirmed complete response or partial response + Denotes ongoing response NR = not reached Select Safety Profile From KEYNOTE-826 Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA plus chemotherapy, with or without bevacizumab, including three cases of hemorrhage, two cases of sepsis, two cases due to unknown causes and one 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 plus chemotherapy, with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased alanine aminotransferase (ALT) (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased aspartate aminotransferase (AST) and pyrexia (3.3% each), diarrhea, acute kidney injury and increased blood creatinine (2.6% each), colitis (2.3%), and decreased appetite and cough (2% each). For patients treated with KEYTRUDA plus chemotherapy with 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%). The most common adverse reactions (all grades ≥20%) for KEYTRUDA plus chemotherapy, with or without bevacizumab (n=307), 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%). About Cervical Cancer Cervical cancer forms in the cells lining the cervix, which is the lower part of the uterus. While screenings and prevention have resulted in declining cervical cancer rates, the disease continues to affect many people in the U.S. and around the world. Cervical cancer is the fourth most commonly diagnosed cancer in women and the fourth leading cause of cancer-related death in women worldwide. It is estimated there were more than 604,000 new cases of cervical cancer diagnosed and nearly 342,000 deaths resulting from the disease in 2020 globally. In the U.S., it is estimated there will be nearly 14,500 new cases of invasive cervical cancer diagnosed and almost 4,300 deaths resulting from the disease in 2021. For patients in the U.S. who are diagnosed with cervical cancer, the five-year relative survival rate is 66.3%. For patients diagnosed with cervical cancer that has spread to distant parts of the body, this drops to 17.6%. About KEYTRUDA ® (pembrolizumab) Injection, 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. Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. 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: 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. Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS ≥1)] as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Carcinoma KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC): Non-muscle Invasive Bladder Cancer KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ 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 is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC). Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: Cervical Cancer KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of 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-approved test. Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma. Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of 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 is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. 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 PD-1 or the 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. 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 ( 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 ( 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 (20%) and increased aspartate aminotransferase (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 ( 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 ( 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 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 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. It led to permanent discontinuation in Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 ( Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA 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 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. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of 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, 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. Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. 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. 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 treatment. 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 treatment 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 its mechanism of action, KEYTRUDA can 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 and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions 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, 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-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-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-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each). In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%). In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or mUC. 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 mUC. 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-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-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy 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, and insomnia. 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-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab regardless of tumor PD-L1 expression (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer 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 fraction 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 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%). Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%). Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%). 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%). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors 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 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-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%). 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 final dose. Pediatric Use In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 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 24 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%). About the Merck Access Program for KEYTRUDA At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting www.merckaccessprogram-keytruda.com . About Merck’s Patient Support Program for KEYTRUDA Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The KEY+YOU Patient Support Program provides a range of resources and support. For further information and to sign up, eligible patients may call 85-KEYTRUDA (855-398-7832) or visit www.keytruda.com . Merck’s Focus on Cancer Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials . About Merck For over 130 years, Merck, known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA This news release of Merck & Co., Inc., Kenilworth, 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 products that the products 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 the global outbreak of novel coronavirus disease (COVID-19); 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 2020 Annual Report on Form 10-K 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 http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf . 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这是默克公司在美国和加拿大以外的第一个被批准作为一线治疗这些患者的抗PD-1组合,今天宣布,美国食品和药物管理局已经批准了KEYTRUDA,默克公司的抗PD-1疗法,与化疗结合,有或没有贝伐单抗,用于治疗持续、复发或转移的宫颈癌患者,这些患者… 这是第一个被批准作为一线治疗这些患者的抗PD-1组合 默克公司(NYSE:MRK)今天宣布,美国食品药品监督管理局(FDA)已批准默克公司的抗PD-1疗法KEYTRUDA与化疗联合使用,无论是否使用贝伐单抗,用于治疗经FDA批准的试验确定肿瘤表达PD-L1(联合阳性评分[CPS]≥1)的持续、复发或转移性宫颈癌患者。该批准是基于3期KEYNOTE-826试验,该试验评估KEYTRUDA加化疗方案(紫杉醇加顺铂或紫杉醇加卡铂),加或不加贝伐单抗,与相同化疗方案,加或不加贝伐单抗进行比较。 在该患者群体中,KEYTRUDA联合化疗,无论是否加贝伐单抗,均显示出优越的总生存率(OS;HR=0.64[95%CI,0.50-0.81];p=0.0001)和无进展生存率(PFS;HR=0.62[95%CI,0.50-0.77];p 免疫介导的不良反应可能严重或致命,可发生在任何器官系统或组织,并可同时影响多个身体系统。免疫介导的不良反应可在KEYTRUDA治疗过程中或治疗后随时发生,包括肺炎、结肠炎、肝炎、内分泌疾病、肾炎、皮肤病反应、实体器官移植排斥反应、异基因造血干细胞移植并发症等。这里列出的重要免疫介导的不良反应可能不包括所有可能的严重和致命的免疫介导的不良反应。早期识别和管理免疫介导的不良反应对确保安全使用Keytruda至关重要。根据不良反应的严重程度,KEYTRUDA应停用或永久停用,并在适当的情况下给予皮质类固醇。KEYTRUDA也会引起严重或危及生命的输液相关反应。根据其作用机制,KEYTRUDA在给孕妇服用时会导致胎儿伤害。有关更多信息,请参见下面的“选定的重要安全信息”。 亚利桑那州肿瘤学的肿瘤学家、美国肿瘤研究妇科项目医学主任、亚利桑那州大学医学院和克莱顿大学医学院妇产科教授布拉德利·蒙克博士说:“宫颈癌更常见地影响美国的年轻女性和某些有色人种女性,不幸的是,被诊断患有持续性、复发性或转移性宫颈癌的女性通常存活率很低。”“在过去的七年里,没有针对持续性、复发性或转移性宫颈癌妇女的一线批准。我对今天批准与KEYTRUDA的新组合感到兴奋,这为适当的患者提供了一种新的治疗选择。“ 默克研究实验室(Merck Research Laboratories)首席医疗官、高级副总裁兼全球临床开发负责人罗伊·贝恩斯(Roy Baynes)博士说:“今天的消息是向前迈出的有意义的一步,因为它为这些患者提供了一种新的治疗选择,并加强了KEYTRUDA在治疗某些类型宫颈癌方面的作用,为这种疾病提供了第二个适应症。”“显示死亡风险降低36%的数据令人信服,这一批准为肿瘤表达PD-L1(CPS≥1)的持续性、复发性或转移性宫颈癌妇女带来了一个重要的新的一线治疗选择。” 此外,FDA将KEYTRUDA作为治疗复发或转移性宫颈癌患者的单一药物的加速批准转换为基于Keynote-826的确证数据的常规批准,这些复发或转移性宫颈癌患者在化疗时或化疗后疾病进展,其肿瘤表达PD-L1(CPS≥1)由FDA批准的测试确定。这项批准最初是在2018年6月根据KEYNOTE-158试验的结果批准的。 默克公司致力于在女性癌症方面取得有意义的进展。该公司正在迅速扩大其广泛的临床开发项目,用于KEYTRUDA和其他几种妇科癌症研究和批准的药物,包括研究KEYTRUDA用于治疗其他类型的宫颈癌。 关于KEYNOTE-826 这项批准是基于KEYNOTE-826(Clinicaltrials.gov,NCT03635567)的数据,这是一项多中心、随机、双盲、安慰剂对照的3期试验,纳入了617名持续性、复发性或一线转移性宫颈癌患者,他们没有接受过化疗,除非同时作为放射增敏剂使用。无论肿瘤PD-L1表达状态如何,患者均被纳入。在治疗后两年内需要全身治疗的自身免疫性疾病患者或需要免疫抑制的疾病患者是不符合条件的。根据初始诊断时的转移状态、研究者使用贝伐单抗的决定和PD-L1状态进行随机分层(CPS KEYTRUDA臂的患者每三周静脉注射KEYTRUDA 200毫克(Q3W),外加研究者选择的紫杉醇加顺铂或紫杉醇加卡铂Q3W,加或不加贝伐单抗Q3W。安慰剂组的患者接受安慰剂加研究者选择的紫杉醇加顺铂或紫杉醇加卡铂Q3W,加或不加贝伐单抗Q3W。所有研究治疗在每个3周治疗周期的第1天进行。顺铂可在每三周治疗周期的第2天给药。KEYTRUDA的治疗持续到RECIST V1.1定义的疾病进展、不可接受的毒性或最长24个月。如果患者临床稳定,并且研究者认为可以获得临床益处,那么KEYTRUDA的给药是允许的,超过了Recist定义的疾病进展。第一年每9周评估一次肿瘤状况,此后每12周评估一次。主要的疗效观察指标是OS和PFS,根据RECIST V1.1的调查员审查评估,修改为每个器官最多10个目标病灶和最多5个目标病灶。根据RECIST V1.1,其他疗效结果指标是ORR和DOR,由调查员审查评估。 在617例入组患者中,548例(89%)有CPS≥1的PD-L1表达肿瘤。在这548例肿瘤表达PD-L1的患者中,273例患者随机接受KEYTRUDA联合化疗,无论是否接受贝伐单抗,275例患者随机接受安慰剂联合化疗,无论是否接受贝伐单抗。548名患者中有63%接受贝伐单抗作为研究治疗的一部分。在研究开始时,21%的患者仅有转移性疾病,79%的患者有持续性或复发性疾病,有或无远处转移,其中39%的患者仅接受过放化疗,17%的患者接受过放化疗加手术。 对于表达PD-L1(CPS≥1)的肿瘤患者的关键疗效结果总结如下: 端点 KEYTRUDA+ 化疗*与或 不含贝伐单抗 n=273 安慰剂+化疗* 不管有没有 贝伐单抗 n=275 操作系统 事件患者数(%) 118(43.2) 154(56.0) 月中位数(95%可信区间) NR(19.8,NR) 16.3(14.5、19.4) 危险比(95%CI) 0.64(0.50,0.81) P值 0.0001 PFS 事件患者数(%) 157(57.5) 198(72.0) 月中位数(95%可信区间) 10.4(9.7、12.3) 8.2(6.3、8.5) 危险比(95%CI) 0.62(0.50,0.77) p值§. 奥尔 ORR(95%CI) 68%(62,74) 50%(44,56) 完全应答率 23% 13% 部分应答率 45% 37% 多尔 月中位数(幅度) 18.0(1.3+、24.2+) 10.4(1.5+、22.0+) *化疗(紫杉醇和顺铂或紫杉醇和卡铂) 基于分层Cox比例风险模型的设计 p-Value(片面)与本次中期分析的分配alpha为0.0055(最终分析的事件计划数的72%)进行比较 §P值(单侧)与本次中期分析的分配alpha 0.0014进行比较(最终分析的事件计划数为82%) 响应:最佳客观响应为确认的完全响应或部分响应 +表示正在进行的响应 NR=未到达 从KEYNOTE-826中选择安全配置文件 在接受KEYTRUDA加化疗、加或不加贝伐单抗的患者中,4.6%发生致命不良反应,包括出血3例、脓毒症2例、原因不明2例和急性心肌梗死、自身免疫性脑炎、心脏骤停、脑血管意外、股骨骨折伴围术期肺栓塞、肠穿孔和盆腔感染各1例。在接受KEYTRUDA加化疗的患者中,50%发生严重不良反应,无论有无贝伐单抗。≥3%患者的严重不良反应包括发热性中性粒细胞减少(6.8%)、尿路感染(5.2%)、贫血(4.6%)、急性肾损伤和败血症(各3.3%)。 KEYTRUDA因15%的患者出现不良反应而停用。导致KEYTRUDA永久停药(≥1%)的最常见不良反应是结肠炎(1%)。66%的患者出现了导致KEYTRUDA中断的不良反应;导致KEYTRUDA中断最常见的不良反应或实验室异常(≥2%)为血小板减少(15%)、中性粒细胞减少(14%)、贫血(11%)、丙氨酸氨基转移酶(ALT)升高(6%)、白细胞减少(5%)、乏力/乏力(4.2%)、尿路感染(3.6%)、天冬氨酸氨基转移酶(AST)升高和发热各(3.3%)、腹泻、急性肾损伤和血肌酐升高各(2.6%)、结肠炎(2.3%)、食欲下降和咳嗽各(2%)。 KEYTRUDA联合贝伐单抗化疗(n=196)最常见的不良反应(≥20%)为周围神经病变(62%)、脱发(58%)、贫血(55%)、乏力/乏力(53%)、恶心和中性粒细胞减少(各41%)、腹泻(39%)、高血压和血小板减少(各35%)、便秘和关节痛(各31%)、呕吐(30%)、尿路感染(27%)、皮疹(26%)、白细胞减少(24%)、甲状腺功能减退(22%)和食欲下降(21%)。KEYTRUDA联合化疗(不论是否加贝伐单抗)最常见的不良反应(分级≥20%)(n=307)为周围神经病变(58%)、脱发(56%)、乏力(47%)、恶心(40%)、腹泻(36%)、便秘(28%)、关节痛(27%)、呕吐(26%)、高血压和尿路感染(各24%)和皮疹(22%)。 关于宫颈癌 宫颈癌形成于子宫颈内衬的细胞,子宫颈是子宫的下部。虽然筛查和预防导致宫颈癌发病率下降,但这种疾病继续影响着美国和世界各地的许多人。宫颈癌是女性第四大常见癌症,也是全球女性癌症相关死亡的第四大原因。据估计,2020年全球确诊宫颈癌新病例超过60.4万例,近34.2万人死于该疾病。在美国,估计2021年将有近14500例新的浸润性宫颈癌确诊病例和近4300例死于该疾病。在美国,被诊断为宫颈癌的患者的五年相对生存率为66.3%。对于被诊断为宫颈癌并扩散到身体远处的患者,这一比例降至17.6%。 KEYTRUDA®注射液,100毫克 KEYTRUDA是一种抗程序性死亡受体-1(PD-1)疗法,通过提高身体免疫系统的能力来帮助检测和对抗肿瘤细胞。KEYTRUDA是一种人源化的单克隆抗体,它阻断PD-1与其配体PD-L1和PD-L2之间的相互作用,从而激活可能影响肿瘤细胞和健康细胞的T淋巴细胞。 默克公司拥有业界最大的免疫肿瘤临床研究项目。目前有1600多项试验在各种癌症和治疗环境中研究KEYTRUDA。KEYTRUDA临床项目旨在了解KEYTRUDA在癌症中的作用,以及可能预测患者受益于KEYTRUDA治疗的可能性的因素,包括探索几种不同的生物标志物。 美国选定的KEYTRUDA®(pembrolizumab)适应症 黑色素瘤 KEYTRUDA用于治疗不可切除或转移性黑色素瘤患者。 KEYTRUDA适用于完全切除后累及淋巴结的黑色素瘤患者的辅助治疗。 非小细胞肺癌 KEYTRUDA联合培美曲塞和铂类化疗可用于一线治疗转移性非鳞状非小细胞肺癌(NSCLC)患者,且无EGFR或ALK基因组肿瘤畸变。 KEYTRUDA与卡铂、紫杉醇或紫杉醇蛋白结合剂联合应用,可用于转移性鳞状非小细胞肺癌的一线治疗。 KEYTRUDA作为一种单一药物,用于一线治疗表达PD-L1[肿瘤比例评分(TPS)≥1%]的NSCLC患者,该患者由FDA批准的试验确定,且没有EGFR或ALK基因组肿瘤畸变,并且: KEYTRUDA作为一种单一药物,用于治疗转移性NSCLC患者,其肿瘤表达PD-L1(TPS≥1%),FDA批准的测试确定,并在含铂化疗时或后有疾病进展。EGFR或ALK基因组肿瘤畸变的患者在接受Keytruda治疗之前,应该在FDA批准的这些畸变治疗中有疾病进展。 头颈部鳞状细胞癌 KEYTRUDA联合铂金和氟尿嘧啶(FU)用于头颈部鳞状细胞癌(HNSCC)的一线治疗。 KEYTRUDA作为一种单一药物,被指示用于一线治疗转移性或不可切除、复发的HNSCC,其肿瘤表达PD-L1[联合阳性评分(CPS≥1)],由FDA批准的测试确定。 KEYTRUDA作为一种单一药物,适用于治疗在含铂化疗中或化疗后病情进展的复发或转移性HNSCC患者。 经典型霍奇金淋巴瘤 KEYTRUDA适用于成人复发或难治性经典霍奇金淋巴瘤(cHL)的治疗。 KEYTRUDA适用于治疗顽固性cHL的儿童患者,或在2个或2个以上治疗线后复发的cHL。 原发性纵隔大B细胞淋巴瘤 KEYTRUDA适用于成人和儿童难治性原发性纵隔大B细胞淋巴瘤(PMBCL)患者,或在2次或2次以上治疗后复发的患者。KEYTRUDA不推荐用于需要紧急细胞减少治疗的PMBCL患者的治疗。 尿路上皮癌 KEYTRUDA适用于局部晚期或转移性尿路上皮癌(mUC)的治疗: 非肌肉浸润性膀胱癌 KEYTRUDA用于治疗卡介苗无反应、高风险、非肌肉浸润性膀胱癌(NMIBC)、原位癌伴或不伴乳头状肿瘤的患者,这些患者没有资格或选择不接受膀胱切除术。 微卫星不稳定性-高配或错配修复缺陷癌 KEYTRUDA适用于成人和儿童的无法切除或转移的微卫星不稳定-高(MSI-H)或错配修复缺陷(dMMR)实体瘤患者,这些患者在之前的治疗后进展良好,且没有满意的替代治疗方案。 该适应症在基于肿瘤应答率和应答持久性的加速批准下获得批准。这一适应症的继续批准可能取决于验证性试验中对临床益处的验证和描述。KEYTRUDA治疗儿童MSI-H中枢神经系统癌症的安全性和有效性尚未得到证实。 微卫星不稳定-高配或错配修复缺陷性结直肠癌 KEYTRUDA适用于无法切除或转移的MSI-H或dMMR结直肠癌(CRC)患者。 胃癌 KEYTRUDA联合曲妥珠单抗、氟嘧啶和含铂化疗,可用于局部晚期不可切除或转移性HER2阳性胃或胃食管交界(GEJ)腺癌的一线治疗。该适应症在基于肿瘤应答率和应答持久性的加速批准下获得批准。这一适应症的继续批准可能取决于验证性试验中对临床益处的验证和描述。 食管癌 KEYTRUDA适用于局部晚期或转移性食管癌或GEJ(震中位于GEJ以上1至5厘米的肿瘤)的患者,这些患者也不适合手术切除或最终放化疗: 宫颈癌 KEYTRUDA联合化疗,无论是否加用贝伐单抗,均可用于治疗持续、复发或转移性宫颈癌患者,其肿瘤表达PD-L1(CPS≥1)。 KEYTRUDA作为一种单一药物,用于治疗复发或转移性宫颈癌患者,化疗时或化疗后疾病进展,其肿瘤表达PD-L1(CPS≥1)。 肝细胞癌 KEYTRUDA用于治疗曾接受索拉非尼治疗的肝细胞癌(HCC)患者。该适应症在基于肿瘤应答率和应答持久性的加速批准下获得批准。这一适应症的继续批准可能取决于验证性试验中对临床益处的验证和描述。 默克尔细胞癌 KEYTRUDA用于治疗复发、局部晚期或转移性默克尔细胞癌(MCC)的成人和儿童患者。该适应症在基于肿瘤应答率和应答持久性的加速批准下获得批准。这一适应症的继续批准可能取决于验证性试验中对临床益处的验证和描述。 肾细胞癌 KEYTRUDA联合axitinib用于成人晚期肾癌患者的一线治疗。 肿瘤突变负担--高癌 KEYTRUDA用于治疗成人和儿童不可切除或转移的肿瘤突变性高负担(TMB-H)[≥10个突变/兆位]实体瘤,由FDA批准的试验确定,在先前治疗后进展,且没有满意的替代治疗选择。该适应症在基于肿瘤应答率和应答持久性的加速批准下获得批准。这一适应症的继续批准可能取决于验证性试验中对临床益处的验证和描述。KEYTRUDA治疗TMB-H中枢神经系统肿瘤的安全性和有效性尚未得到证实。 皮肤鳞状细胞癌 KEYTRUDA用于治疗复发或转移性皮肤鳞状细胞癌(cSCC)或局部晚期cSCC患者,这些患者不能通过手术或放疗治愈。 三阴性乳腺癌 KEYTRUDA的适应症是用于高危早期三阴性乳腺癌(TNBC)患者联合化疗作为新辅助治疗,术后再作为单剂继续作为辅助治疗。 KEYTRUDA联合化疗可用于治疗局部复发、不可切除或转移的TNBC患者,其肿瘤表达PD-L1(CPS≥10),经FDA批准的试验确定。 选定的KEYTRUDA重要安全信息 严重和致命免疫介导的不良反应 KEYTRUDA是一种单克隆抗体,属于一类与PD-1或PD-L1结合的药物,阻断PD-1/PD-L1通路,从而消除对免疫反应的抑制,潜在地打破外周耐受并诱导免疫介导的不良反应。免疫介导的不良反应,可能是严重的或致命的,可发生在任何器官系统或组织,可同时影响多个机体系统,可在开始治疗后或停止治疗后的任何时间发生。这里列出的重要免疫介导的不良反应可能不包括所有可能的严重和致命的免疫介导的不良反应。 密切监测患者的症状和体征,可能是潜在的免疫介导的不良反应的临床表现。早期识别和管理对于确保抗PD-1/PD-L1治疗的安全使用至关重要。在基线和治疗期间定期评估肝酶、肌酐和甲状腺功能。对于在新辅助环境中使用KEYTRUDA治疗的TNBC患者,在基线、手术前和临床表明时监测血皮质醇。在怀疑免疫介导的不良反应的情况下,启动适当的检查,以排除其他病因,包括感染。及时进行医疗管理,包括适当的专科咨询。 根据免疫介导的不良反应的严重程度,暂停或永久停止KEYTRUDA。一般来说,如果KEYTRUDA需要中断或停用,给予全身皮质类固醇治疗(1至2毫克/千克/天的强的松或等效药物),直到改善到1级或更低。一旦改善到1级或更低,开始皮质类固醇逐渐减少,并继续减少至少1个月。考虑在皮质类固醇治疗不能控制不良反应的患者中使用其他全身免疫抑制剂。 免疫介导性肺炎 KEYTRUDA可引起免疫介导的肺炎。在以前接受过胸部放疗的患者中发病率更高。3.4%(94/2799)接受KEYTRUDA治疗的患者发生免疫介导性肺炎,包括致命性(0.1%)、4级(0.3%)、3级(0.9%)和2级(1.3%)反应。67%(63/94)的患者需要全身皮质类固醇激素。肺炎导致1.3%(36)的患者永久停用KEYTRUDA,而0.9%(26)的患者停用KEYTRUDA。所有暂停治疗的患者在症状改善后重新启动KEYTRUDA;其中23%复发。94例患者中59%的肺炎缓解。 8%(31/389)的成人cHL患者单用KEYTRUDA治疗后出现肺炎,其中3-4级的患者占2.3%。患者接受大剂量皮质类固醇,中位持续时间为10天(范围:2天至53个月)。有无胸部放疗的患者的肺炎发生率相似。5.4%(21)的患者因肺炎而停用KEYTRUDA。在发生肺炎的患者中,42%中断了KEYTRUDA,68%停止了KEYTRUDA,77%解决了问题。 免疫介导性结肠炎 KEYTRUDA可引起免疫介导的结肠炎,可表现为腹泻。在皮质类固醇难治性免疫介导的结肠炎患者中有巨细胞病毒感染/再激活的报道。在糖皮质激素难治性结肠炎的病例中,考虑重复感染性检查以排除其他病因。接受KEYTRUDA治疗的患者中1.7%(48/2799)发生免疫介导性结肠炎,包括4级( 肝毒性与免疫介导的肝炎 KEYTRUDA作为单个代理 KEYTRUDA可以引起免疫介导的肝炎。接受KEYTRUDA的患者中0.7%(19/2799)发生免疫介导性肝炎,包括4级( KEYTRUDA与Axitinib KEYTRUDA与axitinib联合使用可引起肝毒性。在治疗开始前并在整个治疗过程中定期监测肝酶。考虑更频繁地监测,而不是当药物作为单一药物给药时。对于肝酶升高,中断KEYTRUDA和axitinib,并考虑根据需要给予皮质类固醇。与单用KEYTRUDA和axitinib相比,3级和4级丙氨酸氨基转移酶增加(20%)和天冬氨酸氨基转移酶增加(13%)的频率更高。59%的ALT增高患者接受全身皮质类固醇治疗。ALT≥3倍正常上限(ULN)(2-4级,n=116)的患者中,0-1级ALT占94%。在92例单用KEYTRUDA(n=3)或axitinib(n=34)或两者联合用药(n=55)的患者中,1例KEYTRUDA,16例axitinib和24例两者同时用药,观察到ALT≥3倍ULN的复发。所有ALT≥3ULN复发的患者随后都从事件中恢复过来。 免疫介导的内分泌疾病 肾上腺功能不全 KEYTRUDA可导致原发性或继发性肾上腺功能不全。对于2级或更高级别,开始对症治疗,包括临床提示的激素替代。根据严重性保留KEYTRUDA。接受KEYTRUDA治疗的患者中有0.8%(22/2799)出现肾上腺功能不全,包括4级( 垂体炎 KEYTRUDA可引起免疫介导的垂体炎。垂体炎可出现与肿块效应相关的急性症状,如头痛、畏光或视野缺损。垂体炎会引起垂体功能减退。按照指示启动激素替代。根据严重程度保留或永久停止KEYTRUDA。接受KEYTRUDA的患者中有0.6%(17/2799)发生垂体炎,包括4级( 甲状腺疾病 KEYTRUDA可以引起免疫介导的甲状腺疾病。甲状腺炎可伴有或不伴有内分泌病。甲状腺功能亢进后可出现甲状腺功能减退。对甲状腺功能减退症进行激素替代治疗,或根据临床症状对甲状腺功能亢进症进行医学治疗。根据严重程度保留或永久停止KEYTRUDA。接受KEYTRUDA治疗的患者中有0.6%(16/2799)发生甲状腺炎,其中2级(0.3%)。没有一个停产,但KEYTRUDA被扣留在 3.4%(96/2799)接受KEYTRUDA治疗的患者出现甲亢,其中3级(0.1%)和2级(0.8%)。它导致KEYTRUDA在#年永久停止使用 1型糖尿病(DM),可表现为糖尿病酮症酸中毒 监测患者是否有高血糖或糖尿病的其他体征和症状。根据临床提示开始胰岛素治疗。根据严重性保留KEYTRUDA。1型DM在接受Keytruda治疗的患者中发生率为0.2%(6/2799)。导致在 免疫介导肾炎伴肾功能障碍 KEYTRUDA可引起免疫介导肾炎。在接受KEYTRUDA治疗的患者中,0.3%(9/2799)发生免疫介导性肾炎,包括4级( 免疫介导的皮肤科不良反应 KEYTRUDA可引起免疫介导的皮疹或皮炎。抗PD-1/PD-L1治疗已出现剥脱性皮炎,包括Stevens-Johnson综合征、伴有嗜酸性粒细胞增多和全身症状的药疹以及中毒性表皮坏死松解。局部润肤剂和/或局部皮质类固醇可能足以治疗轻中度非剥脱性皮疹。根据严重程度保留或永久停止KEYTRUDA。免疫介导的皮肤科不良反应发生率为1.4%(38/2799),包括3级(1%)和2级(0.1%)。40%(15/38)的患者需要全身皮质类固醇激素。这些反应导致0.1%(2)的患者永久停用,0.6%(16)的患者停用KEYTRUDA。所有暂停治疗的患者在症状改善后重新启动KEYTRUDA;其中6%复发。38例患者中79%的反应消失。 其他免疫介导的不良反应 下列临床上显著的免疫介导的不良反应发生在心脏/血管的发生率:心肌炎、心包炎、血管炎;神经系统:脑膜炎、脑炎、脊髓炎和脱髓鞘、肌无力综合征/重症肌无力(包括加重期)、格林-巴利综合征、神经轻瘫、自身免疫性神经病;眼部:可发生葡萄膜炎、虹膜炎等眼部炎症毒性。有些病例可与视网膜脱离有关。可能会出现包括失明在内的各种级别的视力障碍。如果葡萄膜炎合并其他免疫介导的不良反应,考虑Vogt-Koyanagi-Harada样综合征,因为这可能需要全身类固醇治疗以降低永久视力丧失的风险;胃肠道:胰腺炎,包括血清淀粉酶和脂肪酶水平升高,胃炎,十二指肠炎;肌肉骨骼和结缔组织:肌炎/多发性肌炎、横纹肌溶解症(及相关后遗症,包括肾功能衰竭)、关节炎(1.5%)、风湿性多发性肌痛;内分泌:甲状旁腺功能减退;血液/免疫:溶血性贫血、再生障碍性贫血、噬血细胞性淋巴组织细胞增多症、全身炎症反应综合征、组织细胞坏死性淋巴结炎(菊池淋巴结炎)、结节病、免疫性血小板减少性紫癜、实体器官移植排斥反应。 输液相关反应 KEYTRUDA可引起严重或危及生命的输液相关反应,包括超敏反应和过敏反应,在接受KEYTRUDA的2799例患者中有0.2%报告。监测输液相关反应的体征和症状。对于1级或2级反应,中断或减慢输液速度。对于3级或4级反应,停止输液并永久停用Keytruda。 异基因造血干细胞移植(HSCT)的并发症 在抗PD-1/PD-L1治疗前后接受异体HSCT的患者可出现致命和其他严重并发症。与移植相关的并发症包括超急性移植物抗宿主病(GVHD)、急性和慢性GVHD、低强度条件下的肝静脉闭塞病和需要类固醇的发热综合征(没有明确的感染原因)。尽管在抗PD-1/PD-L1治疗和同种异体HSCT之间进行干预治疗,但仍可能发生这些并发症。密切跟踪患者,寻找这些并发症的证据,并及时干预。考虑在同种异体HSCT之前或之后使用抗PD-1/PD-L1治疗的益处和风险。 多发性骨髓瘤患者死亡率增加 在多发性骨髓瘤患者的试验中,在沙利度胺类似物和地塞米松的基础上添加KEYTRUDA导致死亡率增加。在对照试验之外,不建议在这种联合中使用抗PD-1/PD-L1治疗这些患者。 胚胎毒性 根据其作用机制,KEYTRUDA在给孕妇服用时会导致胎儿伤害。告知女性这种潜在的风险。对有生殖潜力的女性,在开始KEYTRUDA前核实妊娠状况,并建议她们在治疗期间和最后一次剂量后的4个月内使用有效的避孕措施。 不良反应 在KEYNOTE-006中,555例晚期黑色素瘤患者中有9%因不良反应而停用KEYTRUDA;导致永久停药的不良反应有结肠炎(1.4%)、自身免疫性肝炎(0.7%)、过敏反应(0.4%)、多发性神经病(0.4%)和心力衰竭(0.4%)。最常见的不良反应(≥20%)为疲劳(28%)、腹泻(26%)、皮疹(24%)和恶心(21%)。 在KEYNOTE-054中,KEYTRUDA因509例患者中14%出现不良反应而永久停用;最常见(≥1%)为肺炎(1.4%)、结肠炎(1.2%)、腹泻(1%)。25%接受Keytruda的患者出现严重不良反应。KEYTRUDA最常见的不良反应(≥20%)是腹泻(28%)。 在KEYNOTE-189中,当KEYTRUDA联合培美曲塞和铂类化疗治疗转移性非鳞状非小细胞肺癌时,405例患者中有20%因不良反应而停用KEYTRUDA。导致KEYTRUDA永久停用最常见的不良反应是肺炎(3%)和急性肾损伤(2%)。最常见的不良反应(≥20%)为恶心(56%)、乏力(56%)、便秘(35%)、腹泻(31%)、食欲下降(28%)、皮疹(25%)、呕吐(24%)、咳嗽(21%)、呼吸困难(21%)和发热(20%)。 在KEYNOTE-407中,当KEYTRUDA与卡铂、紫杉醇或紫杉醇蛋白结合剂一起应用于转移性鳞状非小细胞肺癌时,在101例患者中,15%的患者因不良反应而停用KEYTRUDA。在至少2%的患者中,最常见的严重不良反应是发热性中性粒细胞减少、肺炎和尿路感染。在KEYNOTE-407中观察到的不良反应与在KEYNOTE-189中观察到的相似,除了在KEYNOTE-407中观察到的脱发(47%比36%)和周围神经病变(31%比25%)的发生率在KEYTRUDA和化疗臂中与安慰剂和化疗臂相比有所增加。 在KEYNOTE-042中,636例晚期NSCLC患者中有19%因不良反应而停用KEYTRUDA;最常见的是肺炎(3%)、死因不明(1.6%)、肺炎(1.4%)。在至少2%的患者中,最常见的严重不良反应是肺炎(7%)、肺炎(3.9%)、肺栓塞(2.4%)和胸腔积液(2.2%)。最常见的不良反应(≥20%)为疲劳(25%)。 在KEYNOTE-010中,682例转移性NSCLC患者中有8%因不良反应而停止KEYTRUDA单药治疗;最常见的是肺炎(1.8%)。最常见的不良反应(≥20%)为食欲减退(25%)、乏力(25%)、呼吸困难(23%)和恶心(20%)。 在KEYNOTE-048中,KEYTRUDA单一疗法因300例HNSCC患者中12%的不良事件而停止;导致永久停药最常见的不良反应是败血症(1.7%)和肺炎(1.3%)。最常见的不良反应(≥20%)为疲劳(33%)、便秘(20%)、皮疹(20%)。 在KEYNOTE-048中,当KEYTRUDA与铂(顺铂或卡铂)和FU化疗联合使用时,在276例HNSCC患者中,16%的患者因不良反应而停用KEYTRUDA。导致KEYTRUDA永久停用最常见的不良反应是肺炎(2.5%)、肺炎(1.8%)和感染性休克(1.4%)。最常见的不良反应(≥20%)为恶心(51%)、乏力(49%)、便秘(37%)、呕吐(32%)、黏膜炎症(31%)、腹泻(29%)、食欲下降(29%)、口腔炎(26%)、咳嗽(22%)。 在KEYNOTE-012中,KEYTRUDA因192例HNSCC患者中17%的不良反应而停用。45%的患者出现严重不良反应。至少2%的患者报告的最常见的严重不良反应是肺炎、呼吸困难、混乱状态、呕吐、胸腔积液和呼吸衰竭。最常见的不良反应(≥20%)为疲劳、食欲下降和呼吸困难。HNSCC患者发生的不良反应与接受KEYTRUDA单药治疗的黑色素瘤或NSCLC患者发生的不良反应大致相似,除了面部水肿和新的或恶化的甲状腺功能减退的发生率增加。 在KEYNOTE-204中,由于148例CHL患者中14%的不良反应,KEYTRUDA被停用。30%接受Keytruda的患者出现严重不良反应;≥1%者为肺炎、肺炎、发热、心肌炎、急性肾损伤、发热性中性粒细胞减少、败血症。3例死于疾病进展以外的原因:2例死于异体HSCT术后并发症,1例死于不明原因。最常见的不良反应(≥20%)为上呼吸道感染(41%)、肌肉骨骼疼痛(32%)、腹泻(22%)以及发热、乏力、皮疹和咳嗽(各20%)。 在KEYNOTE-087中,由于210例CHL患者中5%的不良反应,KEYTRUDA被停用。16%的患者出现严重不良反应;≥1%者为肺炎、肺炎、发热、呼吸困难、GVHD、带状疱疹。2例患者死于疾病进展以外的原因:1例死于继发异基因HSCT后的GVHD,1例死于感染性休克。最常见的不良反应(≥20%)为乏力(26%)、发热(24%)、咳嗽(24%)、肌肉骨骼疼痛(21%)、腹泻(20%)和皮疹(20%)。 在KEYNOTE-170中,由于53例PMBCL患者中8%的不良反应,KEYTRUDA被停用。26%的患者出现严重不良反应,包括心律失常(4%)、心脏压塞(2%)、心肌梗死(2%)、心包积液(2%)、心包炎(2%)。6名(11%)患者在开始治疗后30天内死亡。最常见的不良反应(≥20%)为肌肉骨骼疼痛(30%)、上呼吸道感染和发热(各28%)、咳嗽(26%)、乏力(23%)、呼吸困难(21%)。 在KEYNOTE-052中,370例局部晚期或MUC患者中有11%因不良反应而停用KEYTRUDA。42%的患者出现严重不良反应;≥2%者为尿路感染、血尿、急性肾损伤、肺炎、尿路败血症。最常见的不良反应(≥20%)为疲劳(38%)、肌肉骨骼疼痛(24%)、食欲下降(22%)、便秘(21%)、皮疹(21%)和腹泻(20%)。 在KEYNOTE-045中,266例局部晚期或MUC患者中有8%因不良反应KEYTRUDA停用。导致KEYTRUDA永久停用最常见的不良反应是肺炎(1.9%)。39%的Keytruda治疗患者出现严重不良反应;≥2%者为尿路感染、肺炎、贫血、肺炎。最常见的不良反应(≥20%)为疲劳(38%)、肌肉骨骼疼痛(32%)、瘙痒(23%)、食欲下降(21%)、恶心(21%)和皮疹(20%)。 在KEYNOTE-057中,KEYTRUDA在148例高危NMIBC患者中有11%因不良反应而停用。导致KEYTRUDA永久停用最常见的不良反应是肺炎(1.4%)。28%的患者出现严重不良反应;≥2%者为肺炎(3%)、心脏缺血(2%)、结肠炎(2%)、肺栓塞(2%)、脓毒血症(2%)、尿路感染(2%)。最常见的不良反应(≥20%)为乏力(29%)、腹泻(24%)和皮疹(24%)。 MSI-H或dMMR CRC患者的不良反应与接受KEYTRUDA单药治疗的黑色素瘤或NSCLC患者相似。 在KEYNOTE-811中,当KEYTRUDA与曲妥珠单抗、氟嘧啶和含铂化疗联合使用时,在217例局部晚期不可切除或转移的HER2+胃或GEJ腺癌患者中,6%因不良反应而停用KEYTRUDA。导致永久停药最常见的不良反应是肺炎(1.4%)。在KEYTRUDA arm与安慰剂相比,KEYTRUDA治疗的患者与护理标准相比,腹泻(53%对44%)和恶心(49%对44%)的发病率差异≥5%。 KEYTRUDA联合化疗患者最常见的不良反应(报告≥20%)为疲劳/乏力、恶心、便秘、腹泻、食欲下降、皮疹、呕吐、咳嗽、呼吸困难、发热、脱发、周围神经病变、黏膜炎症、口腔炎、头痛、体重减轻、腹痛、关节痛、肌痛和失眠。 在KEYNOTE-590中,当KEYTRUDA联合顺铂和氟尿嘧啶治疗转移性或局部晚期食管癌或GEJ(震中位于GEJ上方1至5厘米的肿瘤)的患者时,由于370例患者中15%出现不良反应,KEYTRUDA被停用。导致KEYTRUDA永久停药的不良反应最多(≥1%)为肺炎(1.6%)、急性肾损伤(1.1%)和肺炎(1.1%)。KEYTRUDA联合化疗最常见的不良反应(≥20%)为恶心(67%)、乏力(57%)、食欲下降(44%)、便秘(40%)、腹泻(36%)、呕吐(34%)、口腔炎(27%)和体重减轻(24%)。 食管癌患者接受KEYTRUDA单药治疗的不良反应与黑色素瘤或非小细胞肺癌患者接受KEYTRUDA单药治疗的不良反应相似。 在KEYNOTE-826中,当KEYTRUDA与紫杉醇和顺铂或紫杉醇和卡铂联合给药时,不论肿瘤PD-L1的表达情况(n=307),对于持续、复发或一线转移的宫颈癌患者,除同时作为放射增敏剂外,未接受化疗的患者,有4.6%的患者发生致命不良反应,包括出血3例,脓毒症和不明原因各2例,急性心肌梗死、自身免疫性脑炎、心脏骤停、脑血管意外、股骨部分伴围手术期肺栓塞、肠穿孔和盆腔感染各1例。50%接受KEYTRUDA联合化疗加或不加贝伐单抗的患者出现严重不良反应;≥3%者为发热性中性粒细胞减少(6.8%)、尿路感染(5.2%)、贫血(4.6%)、急性肾损伤和败血症(各3.3%)。 15%的患者因不良反应而停用KEYTRUDA。导致永久停药(≥1%)的最常见不良反应是结肠炎(1%)。 对于KEYTRUDA、化疗和贝伐单抗(n=196)治疗的患者,最常见的不良反应(≥20%)为周围神经病变(62%)、脱发(58%)、贫血(55%)、疲劳/乏力(53%)、恶心和中性粒细胞减少(各41%)、腹泻(39%)、高血压和血小板减少(各35%)、便秘和关节痛(各31%)、呕吐(30%)、尿路感染(27%)、皮疹(26%)、白细胞减少(24%)、甲状腺功能减退(22%)和食欲下降(21%)。 对于KEYTRUDA联合化疗或不联合贝伐单抗的患者,最常见的不良反应(≥20%)为周围神经病变(58%)、脱发(56%)、乏力(47%)、恶心(40%)、腹泻(36%)、便秘(28%)、关节痛(27%)、呕吐(26%)、高血压和尿路感染(各24%)和皮疹(22%)。 在KEYNOTE-158中,KEYTRUDA在98例复发或转移宫颈癌患者中有8%因不良反应而停用。39%接受Keytruda的患者出现严重不良反应;最常见的包括贫血(7%)、瘘管、出血和感染(尿路感染除外)(各4.1%)。最常见的不良反应(≥20%)为乏力(43%)、肌肉骨骼疼痛(27%)、腹泻(23%)、疼痛和腹痛(各22%)和食欲下降(21%)。 HCC患者的不良反应与接受KEYTRUDA单药治疗的黑色素瘤或非小细胞肺癌患者相似,但腹水发生率增加(8%3-4级)和免疫介导肝炎发生率增加(2.9%)。实验室异常(3-4级)发生率较高的是AST升高(20%)、ALT(9%)和高胆红素血症(10%)。 在纳入研究KEYNOTE-017的50名MCC患者中,MCC患者发生的不良反应与接受KEYTRUDA单药治疗的黑色素瘤或非小细胞肺癌患者发生的不良反应大致相似。实验室异常(3-4级)发生率较高的是AST升高(11%)和高血糖(19%)。 在KEYNOTE-426中,当KEYTRUDA与axitinib联合给药时,429名患者中3.3%发生致命不良反应。40%的患者出现严重不良反应,最常见(≥1%)为肝毒性(7%)、腹泻(4.2%)、急性肾损伤(2.3%)、脱水(1%)和肺炎(1%)。31%的患者因不良反应而永久停药;只有KEYTRUDA(13%),只有axitinib(13%)和组合(8%);最常见的是肝毒性(13%)、腹泻/结肠炎(1.9%)、急性肾损伤(1.6%)和脑血管意外(1.2%)。最常见的不良反应(≥20%)为腹泻(56%)、乏力/乏力(52%)、高血压(48%)、肝毒性(39%)、甲状腺功能减退(35%)、食欲减退(30%)、掌跖红感障碍(28%)、恶心(28%)、口腔炎/黏膜炎(27%)、发音困难(25%)、皮疹(25%)、咳嗽(21%)和便秘(21%)。 在TMB-H癌患者中发生的不良反应与在其他实体瘤患者中接受KEYTRUDA作为单一药物时发生的不良反应相似。 复发或转移性cSCC或局部晚期cSCC患者的不良反应与接受KEYTRUDA单药治疗的黑色素瘤或非小细胞肺癌患者的不良反应相似。 在KEYNOTE-522中,当KEYTRUDA与新辅助化疗(卡铂和紫杉醇,随后是阿霉素或表阿霉素和环磷酰胺)一起使用,然后是手术和KEYTRUDA作为单一药物(n=778)对新诊断的、以前未经治疗的高风险早期TNBC患者继续辅助治疗时,0.9%的患者发生了致命的不良反应,包括肾上腺危象、自身免疫性脑炎、肝炎、肺炎、肺炎、肺栓塞和败血症各1例,与多器官功能障碍综合征和心肌梗死相关。44%接受Keytruda的患者出现严重不良反应;≥2%者为发热性中性粒细胞减少(15%)、发热(3.7%)、贫血(2.6%)、中性粒细胞减少(2.2%)。20%的患者因不良反应而停用KEYTRUDA。导致永久停药的最常见的反应(≥1%)是ALT升高(2.7%)、AST升高(1.5%)和皮疹(1%)。最常见的不良反应(≥20%)为乏力(70%)、恶心(67%)、脱发(61%)、皮疹(52%)、便秘(42%)、腹泻和周围神经病变(各41%)、口腔炎(34%)、呕吐(31%)、头痛(30%)、关节痛(29%)、发热(28%)、咳嗽(26%)、腹痛(24%)、食欲下降(23%)、失眠(21%)和肌痛(20%)。 在KEYNOTE-355中,当KEYTRUDA和化疗(紫杉醇、紫杉醇蛋白结合或吉西他滨和卡铂)对局部复发的不可切除或转移的TNBC患者进行治疗(n=596)时,2.5%的患者发生了致命的不良反应,包括心肺骤停(0.7%)和感染性休克(0.3%)。30%接受KEYTRUDA联合化疗的患者出现严重不良反应;≥2%的严重反应为肺炎(2.9%)、贫血(2.2%)、血小板减少(2%)。11%的患者因不良反应而停用KEYTRUDA。导致永久停药(≥1%)的最常见的反应是ALT升高(2.2%)、AST升高(1.5%)和肺炎(1.2%)。KEYTRUDA联合化疗患者最常见的不良反应(≥20%)为乏力(48%)、恶心(44%)、脱发(34%)、腹泻和便秘(各28%)、呕吐和皮疹(各26%)、咳嗽(23%)、食欲下降(21%)和头痛(20%)。 泌乳 由于母乳喂养的儿童潜在的严重不良反应,建议妇女在治疗期间和最后剂量后的4个月内不要母乳喂养。 儿科用途 在KEYNOTE-051中,161名儿童患者(62名6个月至12岁以下的儿童患者和99名12岁至17岁的儿童患者)每3周服用KEYTRUDA 2毫克/公斤。中位暴露持续时间为2.1个月(范围:1天至24个月)。 与成人相比,儿科患者的不良反应发生率≥10%高:发热(33%)、呕吐(30%)、白细胞减少(30%)、上呼吸道感染(29%)、中性粒细胞减少(26%)、头痛(25%)和3级贫血(17%)。 关于默克公司对KEYTRUDA的访问计划 在默克,我们致力于支持我们的癌症药物的可及性。默克公司提供多种方案来帮助开了KEYTRUDA的合适患者获得我们的抗PD-1治疗。Merck Access项目为接受KEYTRUDA的患者提供报销支持,包括帮助支付自付费用和为符合条件的患者提供共同支付援助的信息。更多信息可拨打855-257-3932或访问www.merckaccessprogram-keytruda.com。 关于默克公司对KEYTRUDA的患者支持计划 默克公司致力于帮助患者及其护理人员在Keytruda治疗过程中提供支持。Key+You患者支持计划提供了一系列的资源和支持。欲了解更多信息并报名,符合条件的患者可拨打85-keytruda(855-398-7832)或访问www.keytruda.com。 默克对癌症的关注 我们的目标是将突破性的科学转化为创新的肿瘤药物,以帮助世界各地的癌症患者。在默克,为癌症患者带来新希望的潜力推动了我们的目标,支持癌症药物的可及性是我们的承诺。作为我们专注于癌症的一部分,默克致力于探索免疫肿瘤学的潜力,在30多种肿瘤类型中,默克是行业中最大的开发项目之一。我们还继续通过战略收购来加强我们的投资组合,并优先开发几种有潜力改善晚期癌症治疗的有前途的肿瘤候选药物。欲了解更多关于我们肿瘤临床试验的信息,请访问www.merck.com/clinicaltrials。 关于默克 130多年来,默克一直致力于生命发明,为世界上许多最具挑战性的疾病提供药物和疫苗,以追求我们拯救和改善生命的使命。默克在美国和加拿大以外被称为MSD。我们通过影响深远的政策、方案和伙伴关系,增加获得医疗保健的机会,以此表明我们对病人和人口健康的承诺。今天,默克继续走在预防和治疗威胁人类和动物的疾病的研究前沿,包括癌症、艾滋病毒和埃博拉等传染病以及新出现的动物疾病,因为我们渴望成为世界上首屈一指的研究密集型生物制药公司。欲了解更多信息,请访问www.merck.com,并在Twitter、Facebook、Instagram、YouTube和LinkedIn上与我们联系。 美国新泽西州肯尼尔沃思默克公司的前瞻性声明 美国新泽西州肯尼尔沃思默克公司(“公司”)的本新闻稿包括1995年美国私人证券诉讼改革法案安全港条款所指的“前瞻性陈述”。该等陈述乃基于本公司管理层目前的信念及预期,并受到重大风险及不确定因素的影响。对于管道产品,不能保证该产品将获得必要的监管批准或证明其在商业上是成功的。如果基础假设被证明不准确或风险或不确定因素成为现实,实际结果可能与前瞻性陈述中所述的结果有重大差异。 风险和不确定性包括但不限于一般行业状况和竞争;一般经济因素,包括利率和货币汇率波动;全球爆发新型冠状病毒病(COVID-19)的影响;美国和国际医药行业监管和医疗立法的影响;全球卫生保健成本控制趋势;竞争对手取得的技术进步、新产品和专利;新产品开发中固有的挑战,包括获得监管批准;公司准确预测未来市场行情的能力;制造困难或延误;国际经济的金融不稳定与主权风险;对公司专利有效性的依赖以及对创新产品的其他保护;以及面临诉讼的风险,包括专利诉讼和/或监管行动。 本公司没有义务公开更新任何前瞻性声明,无论是由于新信息、未来事件或其他原因。可能导致结果与前瞻性陈述中描述的结果有重大差异的其他因素可在公司2020年年度报告10-K表和公司向证券交易委员会(SEC)提交的其他文件中找到,这些文件可在SEC的网站(www.SEC.gov)上查阅。 请参见http://www.merck.com/product/usa/pi_circulars/k/KEYTRUDA/keytruda_pi.pdf和http://www.merck.com/product/usa/pi_circulars/k/KEYTRUDA/keytruda_mg.pdf的KEYTRUDA用药指南。 在businesswire.com查看源代码版本:https://www.businesswire.com/news/home/20211013006053/en/ 媒体联系人:梅丽莎·穆迪(215)407-3536 安德里亚·帕克(929)481-2599 投资者联系人:Peter Dannenbaum(908)740-1037 雷切尔·克鲁珀(908)740-2107 《商业电讯报》通过QuoteMedia提供的新闻

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