来源：肿瘤资讯
今日，FDA批准默沙东研发的免疫疗法新药pembrolizumab用于治疗PD-L1高表达（>50%）的转移性非小细胞肺癌患者。这是目前唯一获批用于一线治疗非小细胞肺癌的抗PD-1免疫疗法。而就在不久之前FDA刚刚批准罗氏免疫疗法药物atezolizumab用于二线治疗NSCLC。肿瘤资讯相关报道：重磅！唯一PD－L1抑制剂获得转移性NSCLC适应症
KEYTRUDA是一款人源化的PD-1抗体，能阻断T细胞表面PD-1受体与其配体的结合，起到激活T细胞，让其对肿瘤展开攻击的作用。今年9月，它获得了由FDA颁发的第6项突破性疗法认定，用于晚期非小细胞肺癌的治疗，并获得了优先审评资格。本次获批，主要依据研究为KeyNote－024研究。
KEYNOTE-024研究结果
KEYNOTE-024是一项随机、公开标注的3期临床试验中，研究人员检验了pembrolizumab作为单一疗法治疗非小细胞肺癌初治患者的疗效，这些患者的PD-L1表达量都超过了50%。与标准的含铂化疗相比，使用KEYTRUDA的患者其无进展生存期(HR, 0.50 [95% CI, 0.37, 0.68]; p<0.001)与总体生存率(HR, 0.60 [95% CI, 0.41, 0.89]; p=0.005)都得到了显著的改善，分别抵达了主要与次要临床终点。因此，这项试验也在今年6月提前终止，让化疗组的患者能够第一时间接受pembrolizumab的治疗。
默沙东研究实验室的总裁Roger Perlmutter博士指出：“在肿瘤表达高水平PD-L1的非小细胞肺癌患者身上，KEYTRUDA与常规化疗相比能够提高生存率，”“KEYTRUDA获批用于一线治疗转移性非小细胞肺癌有望彻底改变这些患者的治疗情况。”
耶鲁大学癌症中心的Roy Herbst教授指出：“在新适应症下，pembrolizumab现在能取代化疗，作为一线疗法治疗那些高表达PD-L1的转移性非小细胞肺癌患者，这些数据再次表明在非小细胞肺癌中检测PD-L1表达量的重要性。这能找到那些最有可能从pembrolizumab治疗中受益的患者。”
关于安全性：
pembrolizumab可引起免疫介导的肺炎，该副反应在pembrolizumab的2799例患者中有94例（3.4％）；免疫介导的结肠炎，在2799例接受KEYTRUDA的患者中，48例（1.7％）。关于PD－1类药物的副反应，请看肿瘤资讯的相关综述：免疫检查点抑制剂所致的免疫相关不良反应的治疗
另外：在Keynote-010研究中，默沙东的pembrolizumab也有在NSCLC二线研究的结果。
参考资料：
[1] FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Metastatic NSCLC for First-Line Treatment of Patients Whose Tumors Have High PD-L1 Expression (Tumor Proportion Score [TPS] of 50 Percent or More) With No EGFR or ALK Genomic Tumor Aberrations
[2] 默沙东官方网站
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新闻原文：
FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Metastatic NSCLC for First-Line Treatment of Patients Whose Tumors Have High PD-L1 Expression (Tumor Proportion Score [TPS] of 50 Percent or More) With No EGFR or ALK Genomic Tumor Aberrations
KEYTRUDA is the Only Anti-PD-1 Therapy Approved in First-Line Treatment of Metastatic NSCLC; KEYTRUDA Demonstrated Superior Progression-Free and Overall Survival Compared to Chemotherapy in Patients Whose Tumors Expressed High Levels of PD-L1
FDA Also Approves a Labeling Update for KEYTRUDA for the Treatment of Patients with Metastatic NSCLC Whose Tumors Express PD-L1 (TPS of One Percent or More) 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
Monday, October 24, 2016 6:04 pm EDT
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KENILWORTH, N.J.--(BUSINESS WIRE)--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® (pembrolizumab), the company’s anti-PD-1 (programmed death receptor-1) therapy, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (tumor proportion score [TPS] of 50 percent or more) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. With this new indication, KEYTRUDA is now the only anti-PD-1 therapy to be approved in the first-line treatment setting for these patients. In addition, the FDA approved a labeling update to include data from KEYNOTE-010 in the second-line or greater treatment setting for patients with metastatic NSCLC whose tumors express PD-L1 (TPS of one percent or more) 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. In metastatic NSCLC, KEYTRUDA is approved for use at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA (pembrolizumab) should be withheld or discontinued and corticosteroids administered when appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions and for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see “Selected Important Safety Information” below.
“KEYTRUDA improved survival, compared to traditional chemotherapy, in patients with non-small cell lung cancer whose tumors express high levels of PD-L1,” said Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories. “The approval of KEYTRUDA for the first-line treatment of metastatic non-small cell lung cancer has the potential to change the treatment landscape for these patients.”
“With this new indication, KEYTRUDA can now be a first treatment option instead of chemotherapy for patients with metastatic non-small cell lung cancer whose tumors express high levels of PD-L1,” said Roy S. Herbst, M.D., Ph.D., professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. “These data reaffirm the importance of testing for PD-L1 expression in non-small cell lung cancer in order to identify those patients who are most likely to benefit from treatment with KEYTRUDA.”
Data Supporting First-Line Approval
The approval was based on data from KEYNOTE-024, a randomized, open-label, phase 3 study evaluating KEYTRUDA monotherapy compared to standard of care (SOC) platinum-containing chemotherapy for the treatment of patients with both squamous (18%) and non-squamous (82%) metastatic NSCLC. The study enrolled patients who had not received prior systemic chemotherapy treatment for their metastatic disease and whose tumors had high PD-L1 expression (TPS of 50 percent or more) and with no EGFR or ALK aberrations. The study randomized 305 patients to receive KEYTRUDA (200 mg every three weeks) or investigator-choice SOC platinum-based chemotherapy (pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin). Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies. The primary endpoint was progression-free survival (PFS); additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR).
Based on an interim analysis demonstrating KEYTRUDA (pembrolizumab) was superior compared to chemotherapy for both the primary endpoint of PFS and the secondary endpoint of OS, the trial was stopped early in June 2016 to give patients still on chemotherapy the opportunity to receive KEYTRUDA.
Findings demonstrated that KEYTRUDA reduced the risk of progression or death by 50 percent compared to chemotherapy (HR, 0.50 [95% CI, 0.37, 0.68]; p<0.001). Additionally, KEYTRUDA resulted in a 40 percent reduction in the risk of death compared to chemotherapy (HR, 0.60 [95% CI, 0.41, 0.89]; p=0.005).
“The approval of KEYTRUDA in the first-line setting adds to the momentum of progress that has been made to treat lung cancer, particularly in the area of immunotherapy,” said Laurie Fenton Ambrose, president and CEO, Lung Cancer Alliance. “Patients now have an option beyond chemotherapy at initial diagnosis. This approval reinforces the need for biomarker testing so care can be personalized and most effective.”
Selected Important Safety Information for KEYTRUDA ® (pembrolizumab)
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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.
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 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. See additional “Selected Important Safety Information” below.
Data Supporting Second-Line Labeling Update
KEYNOTE-010 is a randomized, open-label, phase 2/3 trial evaluating KEYTRUDA (2 mg/kg [n=344] or 10 mg/kg [n=346] every three weeks) compared to SOC chemotherapy (docetaxel, 75 mg/m2 every three weeks [n=343]) in 1,033 patients with squamous (21%) and non-squamous (70%) metastatic NSCLC with all levels of PD-L1 expression (TPS of one percent or more) who had progressed following platinum-containing chemotherapy and, if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Additionally, results were reported in a subset of patients who had high PD-L1 expression (TPS of 50 percent or more) in the KEYTRUDA 2 mg/kg (n=139), KEYTRUDA 10 mg/kg (n=151), and chemotherapy cohorts (n=152). The primary endpoints were OS and PFS. Additional efficacy measures included ORR and response duration.
KEYTRUDA demonstrated superior OS versus docetaxel in patients with all levels of PD-L1 expression. Based on exploratory analyses, higher OS was associated with higher PD-L1 expression level.
In KEYNOTE-010, treatment was discontinued for adverse reactions in eight percent of the 682 patients receiving KEYTRUDA (pembrolizumab) across both doses. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA (pembrolizumab) occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most frequent adverse reactions (reported in at least 10% of KEYTRUDA patients and occurring at the same or higher incidence than in the docetaxel arm) were decreased appetite (25% for KEYTRUDA vs. 23% for docetaxel), dyspnea (23% vs. 20%), nausea (20% vs. 18%), cough (19% vs. 14%), rash (17% vs. 8%), constipation (15% vs. 12%), vomiting (13% vs. 10%), arthralgia (11% vs. 9%), back pain (11% vs. 8%), and pruritus (11% vs. 3%). Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%), and pyrexia (11%).
PD-L1 Companion Diagnostic for Patients with Metastatic NSCLC
The PD-L1 IHC 22C3 PharmDx™ kit made by Dako North America, Inc., an Agilent Technologies Company, was approved in 2015 by the FDA for use in detecting PD-L1, an immune-related biomarker expressed on some tumor cells. The diagnostic is intended to aid in identifying appropriate patients for treatment with KEYTRUDA, including previously treated patients whose tumors have any level of PD-L1 expression (TPS of one percent or more) and previously untreated patients whose tumors have high levels of PD-L1 expression (TPS of 50 percent or more). Tumors with a TPS of less than one percent are considered to have no PD-L1 expression.
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