FDA Approves Merck’s KEYTRUDA® for Patients With BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer With Carcinoma In Situ With or Without Papillary Tumors Who Are Ineligible for or Have Elected Not to Undergo Cystectomy

Keytruda又获批新适应症,成首款治疗NMIBC的PD-1疗法!

2020-01-09 14:59:36 Business Wire

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KEYTRUDA Is the First Anti-PD-1 Therapy Approved for Certain Patients With High-Risk, Non-Muscle Invasive Bladder Cancer 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, as monotherapy for the treatment of 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. "Today’s approval of KEYTRUDA reinforces our company’s commitment to expanding existing treatment options for certain patients with high-risk, non-muscle invasive bladder cancer," said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. "As the first anti-PD-1 therapy approved in this setting, KEYTRUDA will be a new clinical option for a patient population that previously had limited FDA-approved therapies available." Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or 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. "High-risk, non-muscle invasive bladder cancer is a serious disease, characterized by frequent recurrences and progression," said Arjun V. Balar, M.D., associate professor of Medicine and director of Genitourinary Medical Oncology at NYU Langone Health’s Perlmutter Cancer Center. "Historically, patients with high-risk, non-muscle invasive bladder cancer with CIS whose cancer is unresponsive to BCG treatment had limited non-surgical treatment options. As a physician who specializes in the management of bladder cancer, it is encouraging to now have a new treatment option for these patients." Data Supporting the Approval The approval was based on data from KEYNOTE-057 (NCT02625961), a multicenter, open-label, single-arm trial in 96 patients with 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. In this study, BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every three weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. The study population characteristics were: median age 73 years (range: 44 to 92); 44% age ≥75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumor pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12. The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). KEYTRUDA demonstrated a complete response rate of 41% (range: 31 to 51). Among the 39 patients who achieved a complete response, the median duration of response was 16.2 months (range: 0.0+ to 30.4+), and 46% (n=18) had a response of 12 months or longer. The safety of KEYTRUDA was investigated in KEYNOTE-057, which enrolled 148 patients with high-risk NMIBC, 96 of whom had BCG-unresponsive CIS with or without papillary tumors. The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (29%), diarrhea (24%) and rash (24%). About KEYTRUDA® (pembrolizumab) Injection, 100 mg KEYTRUDA is an anti-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 1,000 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 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 stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. Small Cell Lung Cancer KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. 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 confirmatory trials. 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 head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. 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. 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. 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 confirmatory trials. 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) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA is indicated for the treatment of 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 (MSI-H) 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) 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. Gastric Cancer KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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 recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. Cervical Cancer KEYTRUDA 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. 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. 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 patients with advanced renal cell carcinoma (RCC). Selected Important Safety Information for KEYTRUDA Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis. Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib) Immune-Mediated Hepatitis KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. Hepatotoxicity in Combination With Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes 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. Immune-Mediated Endocrinopathies KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia. Immune-Mediated Nephritis and Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis. Immune-Mediated Skin Reactions Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA. Other Immune-Mediated Adverse Reactions Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients. Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions. In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients. 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 a PD-1 or PD-L1 blocking antibody 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-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%). 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%). Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. 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-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% included 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 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-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 gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. 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 hepatocellular carcinoma (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%). 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 There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%). 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 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. About Merck For more than a century, Merck, a leading global biopharmaceutical company 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. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. 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 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 2018 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 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. View source version on businesswire.com: https://www.businesswire.com/news/home/20200108005864/en/ Contacts
KEYTRUDA 是首个批准用于某些高危非肌肉侵袭性膀胱癌患者的抗 PD-1疗法 默克公司( NYSE : MRK )今天宣布,美国食品药品监督管理局(Food and Drug Administration)( FDA )已批准默克(Merck)公司的抗 PD-1疗法 KEYTRUDA ,作为治疗卡介苗( BCG )患者的单一疗法,无应答、高风险。原位癌( CIS )伴有或不伴有乳头状瘤的非肌性侵袭性膀胱癌( NMIBC ),无资格或选择不进行膀胱切除术。 默克(Merck)研究实验室临床研究副总裁 ScottEbbinghus 博士说:“今天对 KEYTRUDA 的批准加强了我们公司对扩大某些高风险、无肌肉侵袭性膀胱癌患者现有治疗方案的承诺。”作为第一个在此背景下被批准的抗 PD-1疗法, KEYTRUDA 将是一个新的临床选择,患者群体以前已经有限的 FDA 批准的治疗可用。 免疫介导的不良反应,可能是严重或致命的,可发生与 KEYTRUDA ,包括肺炎,结肠炎,肝炎,内分泌病,肾炎和肾功能障碍,严重的皮肤反应,固体器官移植排斥和并发症异基因造血干细胞移植( HSCT )。根据不良反应的严重程度,应停用或停用 KEYTRUDA ,并酌情给予皮质类固醇激素类药物。KEYTRUDA 也可引起严重或危及生命的输液相关反应。根据其作用机制, KEYTRUDA 在给孕妇服用时会造成胎儿伤害。有关更多信息,请参见下面的“选定的重要安全信息”。 “高风险、无肌肉侵袭性膀胱癌是一种严重的疾病,其特点是复发和进展频繁,”纽约朗贡健康公司 Perlmutter 癌症中心的医学副教授兼泌尿外科主任 Arjun V . Balar 说。“从历史上看,患有高风险、无肌肉侵袭性膀胱癌的 CIS 患者的癌症对 BCG 治疗没有反应,但其非手术治疗选择有限。作为一名专门管理膀胱癌的医生,现在鼓励这些病人有一个新的治疗选择。” 支持审批的数据 批准的依据是 KEYNOT-057( NCT02625961)的数据,这是一项多中心、开放标签、单臂试验,适用于96例 BCG 无应答、高风险、无肌肉侵袭性膀胱癌( NMIBC )原位癌( CIS )伴有或不伴有乳头状肿瘤的患者,这些患者不符合或选择不接受膀胱切除术。在本研究中, BCG 无反应高风险 NMIBC 被定义为持续性疾病,尽管有足够的 BCG 治疗,疾病复发后的初始无肿瘤状态后,充分的 BCG 治疗,或 T1疾病后,单一的诱导过程 BCG 。充足的卡介苗治疗被定义为在初始诱导过程中给予至少五次六次剂量的卡介苗治疗,加上:三次维持治疗中至少两次或第二次诱导过程中至少两次六次剂量的卡介苗治疗。治疗前,所有患者均行经尿道切除膀胱肿瘤( TUBT )以切除所有可切除的疾病( Ta 和 T1组分)。剩余 CIS ( Tis 组)不能完全切除被允许。试验排除了肌肉侵袭性患者(如 T2、 T3、 T4)局部晚期非切除或转移性尿路上皮癌,并发膀胱外(即尿道、输尿管或肾盂)无肌肉侵袭性的尿路上皮过渡性细胞癌,或自身免疫性疾病或需要免疫抑制的医疗条件。 患者每三周接受200毫克 KEYTRUDA ,直到不可接受的毒性、持续性或复发性高风险 NMIBC 或进展性疾病。每12周进行一次肿瘤状态评估,为期2年,然后每24周进行3年,无疾病进展的患者可以接受长达24个月的治疗。主要疗效结果指标为完全反应(定义为膀胱镜阴性结果[适用的 TUBT /活检]、尿细胞学和 CT 造影[ CTU ]成像)和反应持续时间。 研究人群特征为:73岁中位数(范围:44~92);44%年龄≥75;84%男性;67%白色;73%和27% ECOG 表现为0或1。在研究进入的肿瘤模式是 CIS 与 T1(13%), CIS 与高级别 TA (25%),和 CIS (63%)。基线高风险 NMIBC 疾病状态为持续性27%,复发率73%。卡介苗前注射次数中位数为12例。 平均随访时间为28.0个月(范围:4.6至40.5个月)。KEYTRUDA 的完全响应率为41%(范围:31至51).39例完全缓解的患者中,平均缓解时间为16.2个月(范围:0.0+至30.4+),46%( n =18)的反应时间为12个月或更长。 KEYNOTE-057研究了 KEYTRUDA 的安全性,该研究共纳入148例高风险 NMIBC 患者,其中96例伴有或不伴有乳头状瘤的 BCG 无反应 CIS 。KEYTRUDA 暴露的平均持续时间为4.3个月(范围:1天至25.6个月)。 由于11%的患者出现不良反应, KEYTRUDA 被停用。导致 KEYTRUDA 永久中断的最常见不良反应(>1%)是肺炎(1.4%)。导致 KEYTRUDA 中断的不良反应发生在22%的患者;最常见的(≥2%)为腹泻(4%)和尿路感染(2%)。28% KEYTRUDA 治疗的患者出现严重不良反应。KEYTRUDA 治疗患者最常见的严重不良反应(≥2%)为肺炎(3%)、心脏缺血(2%)、结肠炎(2%)、肺栓塞(2%)、脓毒症(2%)和尿路感染(2%)。KEYTRUDA 最常见的不良反应(≥20%)为疲劳(29%)、腹泻(24%)和皮疹(24%)。 关于 KEYTRUDA ®注射液,100毫克 KEYTRUDA 是一种抗 PD-1疗法,通过增强机体免疫系统帮助检测和对抗肿瘤细胞的能力而起作用。KEYTRUDA 是一种人源化单克隆抗体,阻断 PD-1及其配体 PD-L1和 PD-L2之间的相互作用,从而激活 T 淋巴细胞,可能影响肿瘤细胞和健康细胞。 默克(Merck)公司拥有业内最大的免疫肿瘤临床研究项目。目前有超过1,000个试验研究 KEYTRUDA ,涉及多种癌症和治疗环境。KEYTRUDA 临床计划旨在了解 KEYTRUDA 在癌症中的作用以及可能预测患者从 KEYTRUDA 治疗中获益的可能性的因素,包括探索几种不同的生物标志物。 选定的 KEYTRUDA ®( pembrolizumab )指示剂 黑色素瘤 KEYTRUDA 用于治疗不可切除或转移性黑色素瘤患者。 KEYTRUDA 适用于完全切除后涉及淋巴结的黑色素瘤患者的辅助治疗。 非小细胞肺癌 KEYTRUDA 与 pemetrexe 联合铂类化疗联合应用于无 EGFR 或 ALK 基因肿瘤异常的转移性非小细胞肺癌( NSCLC )患者的一线治疗。 KEYTRUDA 联合卡铂和紫杉醇或紫杉醇蛋白结合物,用于转移性鳞状非小细胞肺癌(NSCLC)患者的一线治疗。 KEYTRUDA 作为单一药物,用于经 FDA 批准的试验确定的表达 PD-L1[肿瘤比例分数( TPS )≥1%]的非小细胞非小细胞肺癌(NSCLC)患者的一线治疗,无 EGFR 或 ALK 基因肿瘤异常,是第三阶段,患者不适合手术切除或最终化疗或转移。 KEYTRUDA 作为单一的药物,用于治疗经 FDA 批准的试验确定的肿瘤表达 PD-L1( TPS ≥1%)的转移性非小细胞非小细胞肺癌(NSCLC)患者,包括铂类化疗或化疗后的疾病进展。在接受 KEYTRUDA 之前, EGFR 或 ALK 基因肿瘤异常的患者应该在 FDA 批准的治疗这些异常的药物上有疾病进展。 小细胞肺癌 KEYTRUDA 用于治疗转移性小细胞肺癌( SCLC )患者,在铂类化疗基础上或之后有疾病进展,并且至少有1个其他先前的治疗方案。该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的继续批准可能取决于确认试验中临床获益的验证和描述。 头颈部鳞癌 KEYTRUDA 联合铂和氟尿嘧啶( FU )用于一线治疗转移性或复发性头颈部鳞癌( HNSCC )患者。 KEYTRUDA 作为单一药物,用于经 FDA 批准的试验确定的对转移性或复发性 HNSCC 患者的一线治疗,其肿瘤表达 PD-L1[联合阳性评分( CPS )≥1]。 KEYTRUDA 是一种单一的药物,用于治疗反复或转移性头颈部鳞状细胞癌( HNSCC )患者,在铂类化疗中或化疗后病情进展。 经典霍奇金淋巴瘤 KEYTRUDA 用于治疗成人和儿童顽固性经典霍奇金淋巴瘤( cHL )患者,或在3条或更多之前的治疗路线后复发。该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的持续批准可能取决于确认试验中临床效益的验证和描述。 原发性纵隔大 B 细胞淋巴瘤 KEYTRUDA 用于治疗成人和儿童顽固性原发性纵隔大 B 细胞淋巴瘤( PMBCL )的患者,或在2个或更多先前治疗项目后复发的患者。该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的继续批准可能取决于确认试验中临床获益的验证和描述。KEYTRUDA 不推荐用于治疗需要紧急细胞减少治疗的 PMBCL 患者。 泌尿系癌 KEYTRUDA 用于治疗局部晚期或转移性尿路上皮癌( mUC )患者,这些患者没有资格接受含有顺铂的化疗,其肿瘤表达 PD-L1[联合阳性分数( CPS )≥10],由 FDA 批准的试验确定。或不符合任何含铂化疗条件的患者,不论 PD-L1状态如何。根据肿瘤的反应率和反应持续时间,该适应症在加速审批下获得批准。该适应症的继续批准可能取决于确认试验中临床获益的验证和描述。 KEYTRUDA 用于治疗局部晚期或转移性尿路上皮癌( mUC )患者,这些患者在含铂化疗期间或之后发生疾病进展,或在含铂化疗的新辅助或辅助治疗的12个月内。 KEYTRUDA 用于治疗卡介苗芽孢杆菌( BCG )--无反应、高风险、无肌肉侵袭性膀胱癌( NMIBC )的患者,这些膀胱癌原位( CIS )伴有或不伴有乳头状肿瘤,不符合或选择不进行膀胱切除术。 微卫星不稳定性高( MSI-H )癌症 KEYTRUDA 用于治疗成人和儿童患者的不可切除或转移性微卫星不稳定性高( MSI-H )或错配修复缺陷( dMMR ) 该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的持续批准可能取决于确认试验中临床效益的验证和描述。儿童 MSI-H 中枢神经系统癌症患者 KEYTRUDA 的安全性和有效性尚未确定。 胃癌 KEYTRUDA 用于治疗复发的局部晚期或转移性胃或胃食管交界( GEJ )腺癌患者,其肿瘤表现为 PD-L1( CPS ≥1),由 FDA 批准的试验确定。在两种或两种以上的先前治疗路线上或之后出现疾病进展,包括含氟嘧啶和含铂的化疗,如果适当的话, HER2/ neu 靶向治疗。该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的持续批准可能取决于确认试验中临床效益的验证和描述。 食管癌 KEYTRUDA 用于治疗复发的局部晚期或转移性食管鳞状细胞癌,其肿瘤表现为 PD-L1( CPS ≥10),由 FDA 批准的试验确定,在一个或多个先前的系统治疗线之后疾病进展。 子宫颈癌 KEYTRUDA 用于治疗复发或转移性宫颈癌患者,其肿瘤在化疗中或化疗后表现为 PD-L1( CPS ≥1),由 FDA 批准的试验确定。该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的持续批准可能取决于确认试验中临床效益的验证和描述。 肝细胞癌 KEYTRUDA 用于治疗以前用索拉非尼治疗的肝癌患者。该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的持续批准可能取决于确认试验中临床效益的验证和描述。 Merkel 细胞癌 KEYTRUDA 用于治疗成人和儿童复发的局部晚期或转移性 Merkel 细胞癌( MCC )。该适应症在加快审批的基础上,肿瘤的反应率和反应的耐久性。该适应症的持续批准可能取决于确认试验中临床效益的验证和描述。 肾细胞癌 KEYTRUDA 联合阿维尼替尼用于晚期肾细胞癌( RCC )的一线治疗。 KEYTRUDA 选定的重要安全信息 免疫介导肺炎 KEYTRUDA 可引起免疫介导的肺炎,包括致命病例。接受 KEYTRUDA 治疗的各种癌症患者中,3.4%(94/279)发生肺炎,包括1级(0.8%)、2级(1.3%)、3级(0.9%)、4级(0.3%)和5级(0.1%)。在接受 KEYTRUDA 作为单一药物的非小细胞非小细胞肺癌(NSCLC)患者中,8.2%(65/790)发生肺炎,其中3.2%的患者发生3-4级肺炎,与未接受(7.7%)的患者相比,有胸前放射史的患者(17%)发生频率更高。以 KEYTRUDA 为单一药物的 HNSCC 患者中有6%(18/300)发生肺炎,其中1.6%患者中有3-5级,5.4%(15/276)患者接受 KEYTRUDA 联合铂金和 FU 作为一线治疗晚期疾病,其中1.5%患者中有3-5级。 监测病人肺炎的症状和体征。用影像学方法评估疑似肺炎.管理2级或以上肺炎的皮质类固醇激素.2级停用 KEYTRUDA ;3级或4级或2级经常性肺炎永久停用 KEYTRUDA 。 免疫介导的结肠炎 KEYTRUDA 可引起免疫介导的结肠炎。感染 KEYTRUDA 的患者中发生了1.7%(48/279),包括2级(0.4%)、3级(1.1%)和4级(0.1%)。监测病人结肠炎的症状和体征。管理2型或更大结肠炎的皮质类固醇。2级或3级停用 KEYTRUDA ;4级结肠炎永久停用 KEYTRUDA 。 免疫介导肝炎( KEYTRUDA )和肝毒性( KEYTRUDA 与 Axitinib 联合应用) 免疫介导肝炎 KEYTRUDA 可引起免疫介导的肝炎。接受 KEYTRUDA 治疗的患者中,有0.7%(19/279)发生了肝炎,包括2级(0.1%)、3级(0.4%)和4级(0.1%)。监测患者肝功能的变化.管理2型或更大肝炎的皮质类固醇激素类药物,根据肝脏酶升高的严重程度,停用或停用 KEYTRUDA 。 与阿奇替尼联合治疗肝毒性 与单纯的 KEYTRUDA 相比, KEYTRUDA 联合亚乙替尼可导致肝脏毒性,其3、4级 ALT 和 AST 升高的频率高于预期。结合 KEYTRUDA 和 axitinib ,3级和4级增加 ALT (20%), AST (13%)。在开始治疗前监测肝酶,并在整个治疗过程中定期监测。与药物作为单一药物使用相比,考虑更频繁地监测肝脏酶。对于肝脏酶升高,中断 KEYTRUDA 和 axitinib ,并考虑按需要服用皮质类固醇。 免疫介导的内膜病 KEYTRUDA 可引起肾上腺功能不全(原发性和继发性)、垂体炎、甲状腺功能紊乱和1型糖尿病。其中2级(0.3%)、3级(0.3%)和4级(0.1%)患者出现肾上腺功能不全。其中2级(0.2%)、3级(0.3%)和4级(0.1%)患者发生垂体炎。甲状腺功能亢进发生在8.5%(237/279)名患者,包括2级(6.2%)和3级(0.1%)。在1185例接受 KEYTRUDA 治疗的 HNSCC 患者(16%)中,新的或恶化的甲状腺功能亢进发生率较高,或与铂和 FU 联合使用,包括3级(0.3%)甲状腺功能低下。甲状腺功能亢进发生在3.4%(96/279)名患者中,其中2级(0.8%)和3级(0.1%),甲状腺炎发生在0.6%(16/279)名患者中,包括2级(0.3%)。1型糖尿病,包括糖尿病酮症酸中毒,发生在0.2%(6/279)的患者。 监测患者肾上腺功能不全、垂体炎(包括垂体下垂体)、甲状腺功能(治疗前和治疗期间定期)和高血糖的症状和体征。对于肾上腺功能不全或垂体炎,按临床表现给予皮质类固醇和激素替代。停用 KEYTRUDA 治疗2级肾上腺功能不全或垂体炎,停用或停用 KEYTRUDA 治疗3级或4级肾上腺功能不全或垂体炎。管理甲状腺机能减退的激素替代,并酌情使用硫胺类和β受体阻滞剂管理甲状腺机能亢进。3级或4级甲亢停用或停用 KEYTRUDA 。管理1型糖尿病的胰岛素,并抑制 KEYTRUDA 和治疗严重高血糖患者的抗高血糖。 免疫介导肾炎与肾功能不全 KEYTRUDA 可引起免疫介导的肾炎。接受 KEYTRUDA 治疗的患者中,有0.3%(9/279)发生肾炎,包括2级(0.1%)、3级(0.1%)和4级(0.1%)。肾炎发生在1.7%(7/405)的患者接受 KEYTRUDA 联合培美曲塞和铂化疗。监测患者肾功能的变化.管理2型或更大肾炎的皮质类固醇。2级停用 KEYTRUDA ;3级或4级肾炎永久停用。 免疫介导的皮肤反应 免疫介导的皮疹,包括史蒂文斯-约翰逊综合征( SJS ),有毒表皮坏死( TEN )(一些具有致命结果的病例),剥离性皮炎,和大疱性天疱疮,可以发生。监测疑似严重皮肤反应的患者,并根据不良反应的严重程度,停用或永久停用 KEYTRUDA 并给予皮质激素类药物。对于 SJS 或 TEN 的症状或体征,保留 KEYTRUDA ,并建议患者进行专门的评估和治疗。如果确认了 SJS 或 TEN ,则永久停止 KEYTRUDA 。 其他免疫介导的不良反应 免疫介导的不良反应可能是严重或致命的,可以发生在接受 KEYTRUDA 的患者的任何器官系统或组织,也可能发生在停止治疗后。对于可疑的免疫介导的不良反应,确保充分的评估,以确认病因或排除其他原因。根据不良反应的严重程度,停用 KEYTRUDA 并给予皮质激素类药物。改善至1级或以下时,启动皮质类固醇锥体,并持续至少1个月以上。根据临床研究的有限数据,对那些免疫相关不良反应不能用皮质激素控制的患者,可以考虑给予其他系统性免疫抑制剂。恢复 KEYTRUDA 时,不良反应保持在1级或更低的皮质类固醇锥体。持续停用 KEYTRUDA 治疗复发的任何3级免疫介导的不良反应和任何危及生命的免疫介导的不良反应。 以下临床上显著的免疫介导不良反应发生在279例患者中不到1%(除非另有说明):关节炎(1.5%)、葡萄膜炎、肌炎、 Guillain-Barr é综合征、重症肌无力、血管炎、胰腺炎、溶血性贫血、结节病和脑炎。此外,其他临床试验也报告了骨髓炎和心肌炎,包括经典霍奇金淋巴瘤和上市后使用。 使用 KEYTRUDA 治疗可能会增加实体器官移植受体排斥的风险。考虑治疗的益处和这些患者可能的器官排斥的风险。 与输液有关的反应 KEYTRUDA 可引起严重或危及生命的输液相关反应,包括过敏和过敏症,已报告在0.2%(6/279)的患者。监测患者输液相关反应的症状和体征。对于3级或4级反应,停止输液并永久停止 KEYTRUDA 。 异基因造血干细胞移植的并发症. 免疫介导的并发症,包括致命事件,发生在患者接受异基因 HSCT 治疗后, KEYTRUDA 。在 KEYTRUDA 后进行异基因 HSCT 治疗的23例 cHL 患者中,6例(26%)发生移植物抗宿主病( GVHD )(1例死亡),2例(9%)发生严重肝静脉闭塞性疾病( VOD )(1例死亡)。异基因 HSCT 致死性超急性 GVHD 的病例在移植前接受 PD-1受体阻断抗体的淋巴瘤患者中也有报道。密切关注患者早期移植相关并发症的证据,如高急性移植物抗宿主病( GVHD )、3-4级急性 GVHD 、类固醇需要发热综合征、肝静脉闭塞病( VOD )和其他免疫介导的不良反应。 在有异基因 HSCT 病史的患者中,用 KEYTRUDA 治疗后报告了急性 GVHD (包括致死性 GVHD )。移植后经历 GVHD 的患者在 KEYTRUDA 后可能增加 GVHD 的风险。考虑 KEYTRUDA 对这些患者 GVHD 风险的益处。 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,将 KEYTRUDA 加入沙利度胺类似物加地塞米松可提高死亡率。这些患者的治疗 PD-1或 PD-L1阻断抗体在这一组合不建议在控制试验之外。 胚胎毒性 根据其作用机制, KEYTRUDA 在给孕妇服用时会造成胎儿伤害。建议妇女注意这一潜在风险。在有生育潜力的女性中,在开始 KEYTRUDA 之前,验证怀孕状态,并建议她们在治疗期间和最后一次注射后4个月内使用有效的避孕方法。 不良反应 在 KEYNOT-006中,555例晚期黑色素瘤患者中有9%的患者因不良反应而停止使用 KEYTRUDA ;导致一个以上患者永久停止使用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%)、多发性神经病变(0.4%)和心脏衰竭(0.4%)。KEYTRUDA 最常见的不良反应(≥20%)为疲劳(28%)、腹泻(26%)、皮疹(24%)和恶心(21%)。 在 KEYNOT-002中,357例晚期黑色素瘤患者中,12%的患者因不良反应而永久停止 KEYTRUDA ;最常见的(≥1%)是全身健康恶化(1%)、乏力(1%)、呼吸困难(1%)、肺炎(1%)和全身水肿(1%)。最常见的不良反应是疲劳(43%)、瘙痒(28%)、皮疹(24%)、便秘(22%)、恶心(22%)、腹泻(20%)和食欲减退(20%)。 在 KEYNote-054中,由于509例患者中14%的不良反应, KEYTRUDA 被永久中止;最常见的(≥1%)是肺炎(1.4%)、结肠炎(1.2%)和腹泻(1%)。25%接受 KEYTRUDA 的患者发生严重不良反应。KEYTRUDA 最常见的不良反应(≥20%)为腹泻(28%)。 在 KEYNote-189中,当 KEYTRUDA 在转移性非定量非小细胞非小细胞肺癌(NSCLC)中应用培美曲塞和铂类化疗时,由于405例患者中的20%的不良反应, KEYTRUDA 被终止。导致 KEYTRUDA 永久中断的最常见不良反应是肺炎(3%)和急性肾损伤(2%)。KEYTRUDA 最常见的不良反应(≥20%)为恶心(56%)、疲劳(56%)、便秘(35%)、腹泻(31%)、食欲减退(28%)、皮疹(25%)、呕吐(24%)、咳嗽(21%)、呼吸困难(21%)和发热(20%)。 在 KEYNOT-407中,当 KEYTRUDA 在转移性鳞状非小细胞肺癌(NSCLC)中应用卡铂和紫杉醇或紫杉醇蛋白结合时,由于101例患者中的15%的不良反应, KEYTRUDA 被终止。至少2%的患者最常见的严重不良反应是发热、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 KEYNOT-189中观察到的相似,但在 KEYTRUDA 和化疗药物臂中观察到的脱发(47% vs36%)和周围神经病变(31% vs25%)的发生率高于 KEYNOT-407中的安慰剂和化疗药物臂。 在 KEYNote-042中,在636名晚期非小细胞肺癌患者中,19%的患者由于不良反应而停止 KEYTRUDA ;最常见的是肺炎(3%),不明原因死亡(1.6%),肺炎(1.4%)。最常见的严重不良反应报告至少2%的患者是肺炎(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, KEYTRUDA 单药治疗由于对682例转移性非小细胞非小细胞肺癌(NSCLC)患者的不良反应而停止;最常见的是肺炎(1.8%)。最常见的不良反应(≥20%)为食欲下降(25%)、疲劳(25%)、呼吸困难(23%)和恶心(20%)。 SCLC 患者的不良反应与其他实体肿瘤患者的不良反应相似。 在 KEYNote-048中,300例 HNSCC 患者中有12%的患者因不良事件而停止使用 KEYTRUDA 单一疗法;导致永久停用的最常见不良反应是败血症(1.7%)和肺炎(1.3%)。最常见的不良反应(≥20%)为疲劳(33%)、便秘(20%)和皮疹(20%)。 在 KEYNote-048中,当 KEYTRUDA 与铂(顺铂或卡铂)和 FU 化疗联合使用时,由于对276例 HNSCC 患者的不良反应, KEYTRUDA 停止使用。导致 KEYTRUDA 永久中断的最常见不良反应是肺炎(2.5%)、肺炎(1.8%)和败血症(1.4%)。最常见的不良反应(≥20%)为恶心(51%)、疲劳(49%)、便秘(37%)、呕吐(32%)、粘膜炎症(31%)、腹泻(29%)、食欲减退(29%)、口腔炎(26%)、咳嗽(22%)。 在 KEYNote-012中,192例 HNSCC 患者中有17%发生不良反应,导致 KEYTRUDA 停止使用。45%的患者出现严重不良反应。最常见的严重不良反应报告至少2%的患者是肺炎,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%)是疲劳、食欲下降和呼吸困难。HNSCC 患者发生的不良反应通常类似于黑色素瘤或非小细胞非小细胞肺癌(NSCLC)患者,他们接受 KEYTRUDA 作为单一疗法,除了增加面部水肿和新的或恶化的甲状腺功能减退的发生率。 在 KEYNote-087中,由于对210例 cHL 患者中的5%的不良反应, KEYTRUDA 被终止。16%患者发生严重不良反应,其中肺炎、肺炎、发热、呼吸困难、 GVHD 、带状疱疹等发生率≥1%。两名患者死于疾病进展以外的原因;1名 GVHD 患者在随后的异基因 HSCT 和1名败血症休克。最常见的不良反应(≥20%)为疲劳(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,53例 PMBCL 患者中有8%的患者由于不良反应而终止 KEYTRUDA 。26%的患者发生严重不良反应,包括心律失常(4%)、心包填塞(2%)、心肌梗死(2%)、心包积液(2%)和心包炎(2%)。六名(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%),疲劳(23%),呼吸困难(21%)。 在 KEYNote-052中,在370例局部晚期或转移性尿路上皮癌患者中,11%的患者由于不良反应而终止 KEYTRUDA 。42%患者发生严重不良反应,其中尿路感染、血尿、急性肾损伤、肺炎、尿败血症发生率≥2%。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,由于8%的局部晚期或转移性尿路上皮癌患者出现不良反应, KEYTRUDA 被停用。导致 KEYTRUDA 永久停止的最常见的不良反应是肺炎(1.9%)。39% KEYTRUDA 治疗的患者发生严重不良反应,其中≥2%为尿路感染、肺炎、贫血、肺炎。接受 KEYTRUDA 的患者最常见的不良反应(≥20%)是疲劳(38%)、肌肉骨骼疼痛(32%)、瘙痒(23%)、食欲减退(21%)、恶心(21%)和皮疹(20%)。 在 KEYNote-057中,在148例高风险 NMIBC 患者中,11%的患者由于不良反应而终止 KEYTRUDA 。导致 KEYTRUDA 永久停止的最常见的不良反应是肺炎(1.4%)。28%患者发生严重不良反应,其中肺炎(3%)、心缺血(2%)、结肠炎(2%)、肺栓塞(2%)、败血症(2%)、尿路感染(2%)。最常见的不良反应(≥20%)为疲劳(29%)、腹泻(24%)和皮疹(24%)。 胃癌患者发生的不良反应与接受 KEYTRUDA 治疗的黑色素瘤或非小细胞非小细胞肺癌(NSCLC)患者相似。 食管癌患者发生的不良反应类似于黑色素瘤或非小细胞非小细胞肺癌(NSCLC)患者,他们接受 KEYTRUDA 作为单一疗法。 在 KEYNote-158中,98例复发性或转移性宫颈癌患者中有8%的患者因不良反应而停止 KEYTRUDA 治疗。39%接受 KEYTRUDA 的患者发生严重不良反应,最常见的包括贫血(7%)、瘘管病、出血和感染[除泌尿道感染外](各占4.1%)。最常见的不良反应(≥20%)为疲劳(43%),肌肉骨骼疼痛(27%),腹泻(23%),疼痛和腹痛(22%),食欲下降(21%)。 肝细胞癌( HCC )患者发生的不良反应一般类似于黑色素瘤或非小细胞非小细胞肺癌(NSCLC)患者,他们接受 KEYTRUDA 作为单一疗法,但腹水(8%3-4级)和免疫介导肝炎(2.9%)发病率增加的情况除外。实验室异常(3-4级)发生在较高的发病率是升高的 AST (20%), ALT (9%)和高胆红素血症(10%)。 在纳入 KEYNOTE-017研究的50例 MCC 患者中, MCC 患者发生的不良反应与接受 KEYTRUDA 治疗的黑色素瘤或非小细胞非小细胞肺癌(NSCLC)患者相似。实验室异常(3-4级)发生在较高的发病率是升高的 AST (11%)和高血糖(19%)。 在 KEYNote-426中,当 KEYTRUDA 联合阿维尼替尼治疗时,429例患者中有3.3%发生了致命的不良反应。40%患者发生严重不良反应,最常见的(≥1%)为肝毒性(7%)、腹泻(4.2%)、急性肾损伤(2.3%)、脱水(1%)、肺炎(1%)。31%的患者因不良反应而永久中断;仅 KEYTRUDA (13%),仅阿维菌素(13%),联合用药(8%);最常见的是肝毒性(13%)、腹泻/结肠炎(1.9%)、急性肾损伤(1.6%)和脑血管事故(1.2%)。最常见的不良反应(≥20%)为腹泻(56%)、疲劳/乏力(52%)、高血压(48%)、肝毒性(39%)、甲状腺功能低下(35%)、食欲减退(30%)、掌跖红肿(28%)、恶心(28%)、口腔炎/粘膜炎症(27%)、失语症(25%)、皮疹(25%)、咳嗽(21%)和便秘(21%)。 哺乳期 由于母乳喂养的儿童可能出现严重的不良反应,建议妇女在治疗期间和最后一次注射后4个月内不要母乳喂养。 儿童用途 儿科患者的经验有限。在一项试验中,40名患有各种癌症(包括未经批准的使用)的儿童患者(16名2岁至12岁的儿童和24名12岁至18岁的青少年)每3周给予2毫克/千克 KEYTRUDA 。患者接受 KEYTRUDA ,平均剂量为3次(范围1-17次),34名患者(85%)接受2次或更多。这些儿童患者的安全状况与成人相似;与65岁以下成人相比,这些患者发生的不良反应发生率更高(≥15%),分别是疲劳(45%)、呕吐(38%)、腹痛(28%)、转氨酶(28%)和低钠血症(18%)。 默克(Merck)公司对癌症的关注 我们的目标是将突破性科学转化为创新的肿瘤药物,以帮助全世界癌症患者。在默克(Merck),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。作为我们对癌症关注的一部分,默克(Merck)致力于探索免疫肿瘤的潜力,该领域拥有30多个肿瘤类型,是业内最大的发展项目之一。我们还继续通过战略性收购加强我们的投资组合,并优先考虑发展几个有潜力改善晚期癌症治疗的有前途的肿瘤候选人。有关我们肿瘤临床试验的更多信息,请访问 www.merck.com / clinicaltrials 。 关于默克(Merck)公司 KEYTRUDA 访问计划 在默克(Merck),我们致力于支持癌症药物的可及性。默克(Merck)公司提供多个项目,帮助处方 KEYTRUDA 的适当患者获得我们的抗 PD-1疗法。默克(Merck)准入计划为接受 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共同支付援助的信息。更多信息可致电855-257-3932或访问 www.merskccessprogram-keytruda 。com 。 关于默克(Merck)公司 KEYTRUDA 患者支持计划 默克(Merck)公司致力于在 KEYTRUDA 治疗过程中帮助患者及其护理人员提供支持。KEY + YOU 患者支持计划提供一系列资源和支持。如需更多信息和注册,符合条件的患者可致电85-KEYTRUDA (855-398-7832)或访问 www.keytruda.com 。 关于默克(Merck)公司 一个多世纪以来,默克(Merck)作为全球领先的生物制药公司,在美国和加拿大以外被称为默沙东(MSD),一直致力于生命的发明,为世界上许多最具挑战性的疾病提供药物和疫苗。通过我们的处方药、疫苗、生物治疗和动物保健品,我们与客户合作,在140多个国家开展业务,提供创新的健康解决方案。我们还表明,我们致力于通过影响深远的政策、方案和伙伴关系增加获得保健的机会。今天,默克(Merck)公司继续站在研究的前沿,推进对威胁世界各地人民和社区的疾病的预防和治疗,包括癌症、心脏代谢疾病、新兴动物疾病、阿尔茨海默氏症和包括艾滋病毒和埃博拉(Ebola)在内的传染病。有关更多信息,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 Kenilworth 默克(Merck)& Co ., Inc .前瞻性陈述 美国新泽西州 Kenilworth 的默克(Merck)& Co ., Inc .(以下简称“公司”)发布的这份新闻稿中包括了1995年美国私人证券诉讼改革法案安全港条款中的“前瞻性陈述”。这些声明是基于公司管理层目前的信念和预期,具有重大风险和不确定性。对于管道产品,无法保证产品将获得必要的监管批准,或证明产品在商业上取得成功。如果基本假设被证明不准确或风险或不确定性成为现实,实际结果可能与前瞻性陈述中的结果存在重大差异。 风险和不确定性包括但不限于一般行业条件和竞争;一般经济因素包括利率和汇率波动;美国和国际制药业监管和保健立法的影响;全球保健费用控制趋势;技术进步、竞争者获得的新产品和专利;新产品开发固有的挑战,包括获得监管机构的批准;公司准确预测未来市场状况的能力;制造困难或延误;国际经济的金融不稳定和主权风险;依赖公司专利的有效性和对创新产品的其他保护;以及诉讼风险,包括专利诉讼和/或监管行动。 公司不承担因新信息、未来事项或其他原因而公开更新任何前瞻性声明的义务。其他可能导致结果与前瞻性声明中描述的结果存在重大差异的因素,请参见公司2018年10-K报表年度报告以及公司向美国证券交易委员会( SEC )提交的其他文件,这些文件可在 SEC 的互联网网站( www.sec.gov )上查阅。 有关 KEYTRUDA 的压力信息,请参见 http://www.merck.com/products/usa/pi_discerns/k/keytruda/keytruda_pi 。http://www.merck.com/products/usa/pi_cleans/k/keytruda/keytruda_mg 。pdf 。 查看 businesswire 上的源代码。http://www.businesswire.com/news/home/202001088005864/en/ 联系人

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