美国FDA扩展批准Keytruda(pembrolizumab)在晚期肺癌中使用，第一个被批准的对在肺癌患者肿瘤表达PD-L1药物
2015年10月2日美国食品和药品监管局(FDA)授权加快批准为Keytruda(pembrolizumab)治疗患者有晚期(转移)非-小细胞肺癌(NSCLC)其疾病在其它治疗和有表达蛋白被称为PD-L1的肿瘤。Keytruda是与批准使用一种协同诊断， PD-L1 IHC 22C3 pharmDx测试，第一个测试被设计检测在非-小细胞肺肿瘤表达PD-L1。
根据美国国家癌症研究所肺癌是美国癌症死亡的首要原因，在2015年有一个估算的221,200 新诊断和158,040例死亡。NSCLC是肺癌最常见类型。
FDA的药品评价和研究中心中血液学和肿瘤室主任Richard Pazdur，M.D.说：“我们对潜在的分子途径和我们的免疫系统如何与癌症的交互作用了解的日益增长导致医疗中重要的进展。” “今天Keytruda的批准给予医生靶向最可能从药物获益的特异性患者的能力。”
Keytruda通过靶向细胞通路被称为(机体的免疫细胞和某些癌症细胞上发现的蛋白)起作用。通过阻断这个通路，Keytruda可能有助于机体免疫系统与癌症细胞斗争。在2014年，Keytruda被批准治疗用普利姆玛[ipilimumab]，免疫治疗的一种类型治疗后有晚期患。在2015年另一种药物，Opdivo (nivolumab)，由Bristol-Meyers Squibb公司制造，也靶向PD-1/PD-L1通路和被批准治疗鳞状上皮非-小细胞肺癌(NSCLC的某种类型)。
在550例有晚期NSCLC患者中研究Keytruda的安全性。Keytruda的最常见副作用包括疲乏，食欲减退，气短或受损的呼吸(呼吸困难)和咳嗽。Keytruda还有潜能致来自Keytruda的免疫系统结果(被称为 “免疫-介导副作用”)严重副作用。
在一项较大多中心，开放，多-部分研究内纳入一个61例患者亚组证实对这个使用Keytruda的有效性。这个亚组由有晚期NSCLC在基于铂化疗后进展或，如适当，对某些遗传突变(ALK或EGFR)靶向治疗患者组成。这个亚组还有PD-L1根据22C3 pharmDx诊断测试阳性肿瘤的结果。研究参加者接受10mg/kg的Keytruda每2或2周。主要结局测量是总体反应率(患者经历他们的肿瘤完全和部分缩小患者的百分率)。用Keytruda治疗患者41%肿瘤缩小和效应持续2.1和9.1个月间。                                                                                                        
在550例有晚期NSCLC研究参加者，严重免疫-介导副作用发生涉及肺，结肠和激素-产生腺。其他不常见免疫-介导副作用为皮疹和血管炎症(血管炎)。妊娠或哺乳喂养妇女不应用 Keytruda因为它可能危害发育中胎儿或新生儿。跨越临床研究，还发生一种疾病其中机体的免疫系统攻击的周围神经系统的一部分(Guillain-Barre综合证)。
FDA授权Keytruda对这个适应证突破性治疗指定因为Merck证实通过初步临床证据药物可能提供超过可得到治疗的一种实质上改进。药物还接受优先审评状态，它被授权于药物在这个时间申请被递交，有将是在一种严重情况治疗中在安全性或有效性显著改进的潜能。
Keytruda是在监管局加快批准程序下被批准，这个程序允许根据临床数据显示该药物对一个替代性终点可能合理地预测对患者临床获益批准一个药物治疗一个严重或危及生命疾病。这个程序提供This program provides earlier 患者较早得到鼓舞人有前途新药而公司进行验证性临床试验。未曽确定用Keytruda 治疗在正在被治疗患者中生存或疾病相关症状改善。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use KEYTRUDA safely and effectively. See full prescribing information for KEYTRUDA.
KEYTRUDA ® (pembrolizumab) for injection, for intravenous use
KEYTRUDA ® (pembrolizumab) injection, for intravenous use
Initial U.S. Approval: 2014
RECENT MAJOR CHANGES
Indications and Usage (1.2) 10/2015
Dosage and Administration (2.1, 2.3) 10/2015
Dosage and Administration (2.4) 01/2015
Warnings and Precautions (5.1, 5.2, 5.4, 5.6) 10/2015
Warnings and Precautions (5.4, 5.6, 5.7) 06/2015
INDICATIONS AND USAGE
KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:
patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. (1.1)
patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have 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. (1.2)
These indications are approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.1, 1.2)
DOSAGE AND ADMINISTRATION
Administer 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks. (2.2)
Dilute prior to intravenous infusion. (2.4)
DOSAGE FORMS AND STRENGTHS
For injection: 50 mg lyophilized powder in single-use vial for reconstitution (3)
Injection: 100 mg/4 mL (25 mg/mL) solution in a single-use vial (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Immune-mediated Pneumonitis: Withhold for moderate, and permanently discontinue for severe, life-threatening or recurrent moderate pneumonitis. (5.1)
Immune-mediated Colitis: Withhold for moderate or severe, and permanently discontinue for life-threatening colitis. (5.2)
Immune-mediated Hepatitis: Monitor for changes in hepatic function. Based on severity of liver enzyme elevations, withhold or discontinue. (5.3)
Immune-mediated Endocrinopathies (5.4):
Hypophysitis: Withhold for moderate and withhold or permanently discontinue for severe or life-threatening hypophysitis.
Thyroid disorders: Monitor for changes in thyroid function. Withhold or permanently discontinue for severe or life-threatening hyperthyroidism.
Type 1 diabetes mellitus: Monitor for hyperglycemia. Withhold KEYTRUDA in cases of severe hyperglycemia.
Immune-mediated nephritis: Monitor for changes in renal function. Withhold for moderate, and permanently discontinue for severe or life-threatening nephritis. (5.5)
Infusion-related reactions: Stop infusion and permanently discontinue KEYTRUDA for severe or life-threatening infusion reactions. (5.7)
Embryofetal toxicity: KEYTRUDA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus. (5.8)
ADVERSE REACTIONS
Most common adverse reactions (reported in ≥20% of patients) with:
melanoma included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. (6.1)
NSCLC included fatigue, decreased appetite, dyspnea and cough. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Lactation: Discontinue nursing or discontinue KEYTRUDA. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Melanoma
KEYTRUDA® (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor [see Clinical Studies (14.1)].
This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
1.2 Non-Small Cell Lung Cancer
KEYTRUDA is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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 [see Clinical Studies (14.2)].
This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients for second line or greater treatment of metastatic NSCLC with KEYTRUDA based on the presence of positive PD-L1 expression [see Clinical Studies (14.2)]. Information on FDA-approved tests for the detection of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dosing
The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.
2.3 Dose Modifications
Withhold KEYTRUDA for any of the following:
Grade 2 pneumonitis [see Warnings and Precautions (5.1)]
Grade 2 or 3 colitis [see Warnings and Precautions (5.2)]
Grade 3 or 4 endocrinopathies [see Warnings and Precautions (5.4)]
Grade 2 nephritis [see Warnings and Precautions (5.5)]
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN
Any other severe or Grade 3 treatment-related adverse reaction [see Warnings and Precautions (5.6)]
Resume KEYTRUDA in patients whose adverse reactions recover to Grade 0-1.
Permanently discontinue KEYTRUDA for any of the following:
Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy)
Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity [see Warnings and Precautions (5.1)]
Grade 3 or 4 nephritis [see Warnings and Precautions (5.5)]
AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN
For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week
Grade 3 or 4 infusion-related reactions [see Warnings and Precautions (5.7)]
Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks
Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) that do not recover to Grade 0-1 within 12 weeks after last dose of KEYTRUDA
Any severe or Grade 3 treatment-related adverse reaction that recurs [see Warnings and Precautions (5.6)]
2.4 Preparation and Administration
Reconstitution of KEYTRUDA for Injection (Lyophilized Powder)
Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL).
Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.
Preparation for Intravenous Infusion
Visually inspect the solution for particulate matter and discoloration prior to administration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.
Dilute KEYTRUDA injection (solution) or reconstituted lyophilized powder prior to intravenous administration.
Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.
Discard any unused portion left in the vial.
Storage of Reconstituted and Diluted Solutions
The product does not contain a preservative.
Store the reconstituted and diluted solution from the KEYTRUDA 50 mg vial either:
At room temperature for no more than 6 hours from the time of reconstitution. This includes room temperature storage of reconstituted vials, storage of the infusion solution in the IV bag, and the duration of infusion.
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:
At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the infusion solution in the IV bag, and the duration of infusion.
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.
Do not freeze.
Administration
Administer infusion solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
Do not co-administer other drugs through the same infusion line.
3 DOSAGE FORMS AND STRENGTHS
For injection: 50 mg lyophilized powder in a single-use vial for reconstitution
Injection: 100 mg/4 mL (25 mg/mL) solution in a single-use vial
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Immune-Mediated PneumonitisPneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) or recurrent moderate (Grade 2) pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to development of pneumonitis was 5 months (range 0.3 weeks to 9.9 months). The median duration was 4.9 months (range 1 week to 14.4 months). Five of eight patients with Grade 2 and the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1 to 34) followed by a corticosteroid taper. Pneumonitis led to discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with Grade 2-3 pneumonitis.
NSCLC
Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA in Trial 1. The median time to development of pneumonitis was 1.7 months (range 0.6 weeks to 12.9 months). In patients receiving KEYTRUDA 10 mg/kg every 2 weeks, the median time to development of pneumonitis was shorter (1.5 months) compared with patients receiving 10 mg/kg every 3 weeks (3.5 months). Sixteen of the 19 patients (84%) received corticosteroids, with 14 of the 19 (74%) requiring high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day). The median starting dose of high-dose corticosteroid treatment for these fourteen patients was 60 mg/day with a median duration of treatment of 8 days (range 1 day to 4.2 months). The median duration of pneumonitis was 1.2 months (range 0.7 weeks to 12.4 months). Pneumonitis occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) than in patients without a history of these diseases (3.1%). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.0%) than in patients who did not receive prior thoracic radiation (2.6%). Pneumonitis led to discontinuation of KEYTRUDA in 12 (2.2%) patients. Pneumonitis completely resolved in 9 patients. Pneumonitis was reported as ongoing in 9 patients and one patient with ongoing pneumonitis died within 30 days of the last dose of pembrolizumab.
5.2 Immune-Mediated Colitis
Colitis occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 6.5 months (range 2.3 to 9.8). The median duration was 2.6 months (range 0.6 weeks to 3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4 to 41), followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event.
NSCLC
Colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 1.6 months (range 4 weeks to 2.2 months) and the median duration was 16 days (range 1.0 weeks to 1.3 months).Two patients were started on high-dose corticosteroids (≥40 mg/day of prednisone or equivalent) and two patients were started on low dose corticosteroids. One patient (0.2%) discontinued KEYTRUDA due to colitis. Three patients with colitis experienced complete resolution of the event.
5.3 Immune-Mediated Hepatitis
Hepatitis occurred in patients receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids (initial dose of 0.5 to 1 mg/kg/day [for Grade 2 hepatitis] and 1 to 2 mg/kg/day [for Grade 3 or greater hepatitis] prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event.
5.4 Immune-Mediated Endocrinopathies
Hypophysitis
Hypophysitis occurred in patients receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for moderate (Grade 2) hypophysitis and withhold or discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case (0.2% each), in patients receiving KEYTRUDA in Trial 1. The time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose.
NSCLC
In Trial 1, hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. The time to onset was 3.7 months. The patient was treated with systemic corticosteroids and physiologic hormone replacement therapy. The patient did not discontinue KEYTRUDA due to hypophysitis.
Thyroid Disorders
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) hyperthyroidism [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset was 1.5 months (range 0.5 to 2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event.
Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 3.5 months (range 0.7 weeks to 19 months). All but two of the patients with hypothyroidism were treated with long-term thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management of hypothyroidism.
NSCLC
Hyperthyroidism occurred in 10 (1.8%) of 550 patients receiving KEYTRUDA in Trial 1, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. The median time to onset was 1.8 months (range 2 days to 3.4 months), and the median duration was 4.5 months (range 4 weeks to 7.5 months). No patients discontinued KEYTRUDA due to hyperthyroidism.
Hypothyroidism occurred in 38 (6.9%) of 550 patients receiving KEYTRUDA in Trial 1, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. The median time to onset was 4.2 months (range 2.9 weeks to 11.2 months), and the median duration was 5.8 months (range 1.6 weeks to 22.8 months). No patients discontinued KEYTRUDA due to hypothyroidism.
Type 1 Diabetes mellitus
Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
5.5 Immune-Mediated Nephritis and Renal Dysfunction
Nephritis occurred in patients receiving KEYTRUDA. Monitor patients for changes in renal function. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2), and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) nephritis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3-4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper.
5.6 Other Immune-Mediated Adverse Reactions
Other clinically important immune-mediated adverse reactions can occur.
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. Resume KEYTRUDA when the immune-mediated adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome.
Melanoma
The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.
NSCLC
The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC treated with KEYTRUDA in Trial 1: rash, vasculitis, hemolytic anemia, serum sickness and myasthenia gravis.
5.7 Infusion-Related Reactions
Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA across the clinical development program employing various doses and schedules and enrolling patients with various solid tumors. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)].
5.8 Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA [see Use in Specific Populations (8.1, 8.3)]. 
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
Immune-mediated pneumonitis [see Warnings and Precautions (5.1)].
Immune-mediated colitis [see Warnings and Precautions (5.2)].
Immune-mediated hepatitis [see Warnings and Precautions (5.3)].
Immune-mediated endocrinopathies [see Warnings and Precautions (5.4)].
Immune-mediated nephritis and renal dysfunction [see Warnings and Precautions (5.5)].
Other immune-mediated adverse reactions [see Warnings and Precautions (5.6)].
Infusion-related reactions [see Warnings and Precautions (5.7)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to KEYTRUDA in an uncontrolled, open-label, multiple cohort trial (Trial 1). In Trial 1, the safety data are available from 411 patients with unresectable or metastatic melanoma and 550 patients with metastatic NSCLC who received KEYTRUDA at either 2 mg/kg every 3 weeks (n=61) or 10 mg/kg every 2 or 3 weeks (n=489).
Metastatic Melanoma
Among the 411 patients with metastatic melanoma enrolled in Trial 1, the median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51). The study population characteristics were: median age of 61 years (range 18 to 94), 39% age 65 years or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced or metastatic disease.
KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis.
Table 1 presents adverse reactions identified from analyses of 89 patients with unresectable or metastatic melanoma who received KEYTRUDA 2 mg/kg every three weeks in one cohort of Trial 1. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18 to 88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA for greater than 6 months and 21% for greater than 1 year.
KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.
Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic Melanoma 

KEYTRUDA 2 mg/kg every 3 weeks N=89
Adverse Reaction	All Grades (%)	Grade 3 (%)
General Disorders and Administration Site Conditions
Fatigue	47	7
Peripheral Edema	17	1
Chills	14	0
Pyrexia	11	0
Gastrointestinal Disorders
Nausea	30	0
Constipation	21	0
Diarrhea	20	0
Vomiting	16	0
Abdominal pain	12	0
Respiratory, Thoracic and Mediastinal Disorders
Cough	30	1
Dyspnea	18	2
Skin and Subcutaneous Tissue Disorders
Pruritus	30	0
Rash	29	0
Vitiligo	11	0
Metabolism and Nutrition Disorders
Decreased appetite	26	0
Musculoskeletal and Connective Tissue Disorders
Arthralgia	20	0
Pain in extremity	18	1
Myalgia	14	1
Back pain	12	1
Nervous System Disorders
Headache	16	0
Dizziness	11	0
Blood and Lymphatic System Disorders
Anemia	14	5
Psychiatric Disorders
Insomnia	14	0
Infections and Infestations
	11	1

There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, none was reported as Grade 4.
Other clinically important adverse reactions observed in up to 10% of patients treated with KEYTRUDA were:
Infections and infestations: sepsis
Table 2: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients with Unresectable or Metastatic Melanoma

KEYTRUDA 2 mg/kg every 3 weeks N=89
Laboratory Test	All Grades %	Grades 3-4 %
Chemistry
Hyperglycemia	40	2
Hyponatremia	35	9
Hypoalbuminemia	34	0
Hypertriglyceridemia	25	0
Increased Aspartate Aminotransferase	24	2
Hypocalcemia	24	1
Hematology
Anemia	55	8

Grade 4 abnormalities in this table limited to hyperglycemia, increased aspartate aminotransferase, and anemia (one patient each)
NSCLC
Among the 550 patients with metastatic NSCLC enrolled in Trial 1, the median duration of therapy was 2.8 months (range: 1 day to 25.6 months). Patients with NSCLC and autoimmune disease, a medical condition that required immunosuppression, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible for Trial 1. The median age of patients was 64 years (range: 28 to 93), 47% were age 65 years or older, 53% were male, 83% were white, and 67% received two or more prior systemic treatments. Disease characteristics were Stage III (4%), Stage IV (96%), and brain metastases (11%). Baseline ECOG performance status was 0 (35%) or 1 (65%).
KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The incidence of adverse reactions, including serious adverse reactions, was similar between the two 10 mg/kg dosing schedules; therefore, these data were pooled. The majority of patients treated with KEYTRUDA 2 mg/kg every three weeks had shorter follow-up compared with patients treated with the 10 mg/kg schedules; therefore, comparisons of adverse reactions between doses were not appropriate.
Table 3 summarizes adverse reactions that occurred in at least 10% of patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, dyspnea, and cough.
Table 3: Adverse Reactions in ≥10% of Patients with NSCLC 

KEYTRUDA 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks N=550
Adverse Reaction	All Grades (%)	Grade 3 (%)
General Disorders and Administration Site Conditions
Fatigue†	44	4
Pyrexia	12	1
Peripheral Edema	10	0
Metabolism and Nutrition Disorders
Decreased appetite	25	1
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	23	4
Cough	29	<1
Gastrointestinal Disorders
Nausea	18	1
Diarrhea	15	1
Constipation	15	<1
Vomiting	12	1
Musculoskeletal and Connective Tissue Disorders
Arthralgia	15	1
Back pain	10	2
Blood and Lymphatic System Disorders
Anemia	12	2
Skin and Subcutaneous Tissue Disorders
Pruritus	12	0
Rash	18	<1

Of the ≥10% adverse reactions, none was reported as Grade 4 or 5.
Includes the terms fatigue and asthenia
Includes the terms cough, productive cough and hemoptysis
Includes the terms dermatitis, dermatitis acneiform, erythema multiforme, drug eruption, rash, rash generalized, rash pruritic, rash macular/maculo-papular, papular
Table 4: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients with NSCLC

KEYTRUDA N=550
Laboratory Test	All Grades %	Grades 3-4 %
Chemistry
Hyperglycemia	48	3
Hyponatremia	38	6
Hypoalbuminemia	32	1
Increased alkaline phosphatase	26	1
Hypertriglyceridemia	23	0
Increased aspartate aminotransferase	20	1
Hypercholesterolemia	20	1
Hematology
Anemia	36	2

Grade 4 abnormalities in this table limited to hyperglycemia (n=4), hypercholesterolemia (n=3), and anemia (n=1).
6.2 Immunogenicity
As with all therapeutic proteins, there is the potential for immunogenicity. Because trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results, a subset analysis was performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In this analysis, none of the 225 patients who were treated with 2 mg/kg every 3 weeks tested positive for treatment-emergent anti-pembrolizumab antibodies.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to KEYTRUDA with the incidences of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue [see Data]. Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. There are no available human data informing the risk of embryo-fetal toxicity. Apprise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development, but an assessment of the effects on reproduction was provided. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.
8.2 Lactation
Risk Summary
It is not known whether KEYTRUDA is excreted in human milk. No studies have been conducted to assess the impact of KEYTRUDA on milk production or its presence in breast milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for at least 4 months following the final dose.
8.4 Pediatric Use
Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.
8.5 Geriatric Use
Of the 411 patients with melanoma treated with KEYTRUDA, 39% were 65 years and over. No overall differences in safety or efficacy were reported between elderly patients and younger patients.
Of the 550 patients with NSCLC treated with KEYTRUDA, 47% were 65 years and over. No overall differences in safety or efficacy were reported between elderly patients and younger patients.
8.6 Renal Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with renal impairment [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST]. KEYTRUDA has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)]. 
10 OVERDOSAGE
There is no information on overdosage with KEYTRUDA.
11 DESCRIPTION
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa.
KEYTRUDA for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.
KEYTRUDA injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
12.3 Pharmacokinetics
The pharmacokinetics of pembrolizumab was studied in 1645 patients who received doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on population pharmacokinetic analyses in patients with solid tumors, the geometric mean [% coefficient of variation (CV%)] for clearance, steady-state volume of distribution, and terminal half-life were 209 mL/day (38%), 7.75 L (20%) and 28 days (41%), respectively.
Steady-state concentrations of pembrolizumab were reached by 18 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was approximately 2-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.
Specific Populations: The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The CL of pembrolizumab increased with increasing body weight; the resulting exposure differences were adequately addressed by the administration of a weight-based dose. The following factors had no clinically important effect on the CL of pembrolizumab: age (range 15 to 94 years), gender, renal impairment, mild hepatic impairment, and tumor burden. The effect of race could not be assessed due to limited data available in non-White patients.
Renal Impairment: The effect of renal impairment on the CL of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with various solid tumors and mild (eGFR 60 to 89 mL/min/1.73 m2; n=705), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=159), or severe (eGFR 15 to 29 mL/min/1.73 m2; n=4) renal impairment compared to patients with normal (eGFR greater than or equal to 90 mL/min/1.73 m2; n=756) renal function. No clinically important differences in the CL of pembrolizumab were found between patients with renal impairment and patients with normal renal function [see Use in Specific Populations (8.6)].
Hepatic Impairment: The effect of hepatic impairment on the CL of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with various solid tumors and mild hepatic impairment (TB less than or equal to ULN and AST greater than ULN or TB between 1 and 1.5 times ULN and any AST; n=192) compared to patients with normal hepatic function (TB and AST less than or equal to ULN; n=1407). No clinically important differences in the CL of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function. There is insufficient information to determine whether there are clinically important differences in the CL of pembrolizumab in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity.
Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.
13.2 Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus (LCMV). Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.
14 CLINICAL STUDIES
14.1 Melanoma
The efficacy of KEYTRUDA was investigated in a multicenter, open-label, randomized (1:1), dose-comparative, activity-estimating cohort of Trial 1. Key eligibility criteria were unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with autoimmune disease; a medical condition that required immunosuppression; and a history of severe immune-mediated adverse reactions with ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks. Patients were randomized to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of KEYTRUDA every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Assessment of tumor status was performed every 12 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review and duration of response.
Among the 173 patients enrolled, the median age was 61 years (36% age 65 or older); 60% male; 97% White; and 66% and 34% with an ECOG performance status 0 and 1, respectively. Disease characteristics were BRAF V600 mutation (17%), elevated lactate dehydrogenase (39%), M1c (82%), brain metastases (9%), and two or more prior therapies for advanced or metastatic disease (73%).
The ORR was 24% (95% confidence interval: 15, 34) in the 2 mg/kg arm, consisting of 1 complete response and 20 partial responses. Among the 21 patients with an objective response, 3 (14%) had progression of disease 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86%) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer. One additional patient developed two new asymptomatic lesions at the first tumor assessment concurrent with a 75% decrease in overall tumor burden; KEYTRUDA was continued and this reduction in tumor burden was durable for 5+ months.
There were objective responses in patients with and without BRAF V600 mutation-positive melanoma. Similar ORR results were observed in the 10 mg/kg arm.
14.2 Non-Small Cell Lung Cancer
The efficacy of KEYTRUDA was investigated in a sub-group of a cohort of 280 patients enrolled in a multicenter, open-label multi-cohort, activity-estimating study (Trial 1). The cohort consisted of patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for ALK or EGFR mutations and any evidence of PD-L1 expression by a clinical trial immunohistochemistry assay. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
A prospectively defined sub-group was retrospectively analyzed using an analytically validated test for PD-L1 expression tumor proportion score (TPS). This retrospectively identified sub-group of 61 patients accounts for 22% of the 280 patients in the cohort. Patients included in this sub-group had a PD-L1 expression TPS of greater than or equal to 50% tumor cells as determined by the PD-L1 IHC 22C3 pharmDx Kit. Patients received KEYTRUDA 10 mg/kg every 2 (n=27) or 3 (n=34) weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR according to RECIST 1.1 as assessed by blinded independent central review (IRC) and duration of response.
Among the 61 patients with a TPS greater than or equal to 50%, the baseline characteristics were: median age 60 years (34% age 65 or older); 61% male; 79% White; and 34% and 64% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous (21%) and non-squamous (75%); M1 (98%); brain metastases (11%); one (26%), two (30%), or three or more (44%) prior therapies; and the incidence of genomic aberrations was EGFR (10%) or ALK (0%).
Efficacy results are summarized in Table 5. The ORR and duration of response were similar regardless of schedule (every 2 weeks or every 3 weeks) and thus the data below are pooled.
Table 5: Efficacy Results

Endpoint	N=61
Overall Response Rate
ORR %, (95% CI)	41% (29, 54)
Complete Response	0%
Partial Response	41%

Among the 25 responding patients, 21 (84%) patients had ongoing responses at the final analysis of ORR; 11 (44%) patients had ongoing responses of 6 months or longer.
In a separate subgroup of 25 patients with limited follow-up with PD-L1 expression TPS greater than or equal to 50% receiving KEYTRUDA at a dose of 2 mg/kg every 3 weeks in Trial 1, activity was also observed.
16 HOW SUPPLIED/STORAGE AND HANDLING
KEYTRUDA for injection (lyophilized powder): carton containing one 50 mg single-use vial (NDC 0006-3029-02).
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F).
KEYTRUDA injection (solution): carton containing one 100 mg/4 mL (25 mg/mL), single-use vial (NDC 0006-3026-02)
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm
----------------------------------------
产地国家：美国
原产地英文商品名:
KEYTRUDA Injection 50mg/vial
原产地英文药品名:
pembrolizumab
中文参考商品译名:
KEYTRUDA注射液 50毫克/瓶
中文参考药品译名:
派姆单抗
生产厂家中文参考译名:
默克
生产厂家英文名:
Merck

-------------------------------------
产地国家：美国
原产地英文商品名:
KEYTRUDA Injection 100mg/4ml（25mg/ml）/Vial
原产地英文药品名:
pembrolizumab
中文参考商品译名:
KEYTRUDA注射液 100毫克/4毫升(25毫克/毫升)/瓶
中文参考药品译名:
派姆单抗
生产厂家中文参考译名:
默克
生产厂家英文名:
Merck

----------------------------------------
产地国家：德国
原产地英文商品名:
KEYTRUDA Injection 50mg/vial
原产地英文药品名:
pembrolizumab
中文参考商品译名:
KEYTRUDA注射液 50毫克/瓶
中文参考药品译名:
派姆单抗
生产厂家中文参考译名:
默克
生产厂家英文名:
Merck