【假装在Munich】04-KEYNOTE-048
简单介绍下，因为图实在不全或者说最后一天都去小酒馆浪了，所以结合着默大网站上的PRESS RELEASE来，反正说的是一个东西嘛，英文原文见最后。
一言概之：1）K药单药组的 ORR 和 PFS实际上比标准治疗组更差 ，即便在PD-L1高表达组也是如此；2）可能是持续缓解是时间更长，使得单药组PD-L1高表达群体OS获益
看官方口径：相比较标准疗法，Merck的KEYTRUDA在单药和联合化疗在复发或转移性头颈部肿瘤患者的一线治疗中，显著提升总生存：1）在KEYTRUDA单药组的PD-L1 CPS≥20、CPS≥1以及KEYTRUDA联合化疗组的总人群中发现生存获益；2)KEYTRUDA成为首个被证明在复发或转移性头颈部肿瘤的一线治疗中存在生存获益的抗PD-1疗法
关于头颈部肿瘤：头颈部肿瘤是一系列发生在咽、喉、鼻、鼻窦和口部级或周围的不同肿瘤的统称，绝大多数（~90%）属于鳞状细胞癌，通常起源于形成头颈部结构表层的鳞状细胞。最主要的诱因是吸烟和酗酒，另外就是特定的HPV感染。预计2018年全球新诊断头颈部肿瘤人数83.5万，死亡43.1万。在美国2017年新诊断6.3万例。目前的一线标准治疗是EXTREME方案：包括西妥昔单抗+铂类（卡铂或顺铂）+5-FU。目前nivo和pembro已经获批二线。
关于试验设计
KEYNOTE-048是一项随机、开放标签的三期研究，旨在于882名复发或转移头颈部肿瘤患者中评估KEYTRUDA单药、KEYTRUDA联合化疗（卡铂/顺铂+5-FU）对比EXTREME一线治疗的效果。主要终点OS和PFS，次要终点6个月和12个月时的PFS、ORR、生活质量恶化时间，另外作为预先指定的探索性分析也要评估DoR。主要次要临床终点和探索性分析需要分别在PD-L1 CPS≥20、CPS≥1以及不考虑PD-L1表达的总人群中进行评估。截止至数据分析，单药组、联合组及EXTREME组的中位随访时间分别11.7 mos、13.0 mos和10.7 mos。
这是官方描述
因为图实在不全，所以综合图及各方面信息总结如下：
生存和缓解率数据
安全性数据
下面可能是讨论环节的图，大家有兴趣可以参考
Merck’s KEYTRUDA (pembrolizumab) Significantly Improved Overall Survival Compared to Standard of Care, as Monotherapy and in Combination with Chemotherapy, as First-Line Treatment for Patients with Recurrent or Metastatic Head and Neck Cancer
OCTOBER 22, 2018
Survival Benefit Observed with KEYTRUDA Monotherapy in Patients Whose Tumors Expressed PD-L1 with CPS≥20 and CPS≥1 and in Total Patient Population for KEYTRUDA in Combination with Chemotherapy
KEYTRUDA is the First Anti-PD-1 Therapy to Demonstrate a Survival Benefit as First-Line Therapy for Head and Neck Cancer that has Recurred or Metastasized
Results from Pivotal Phase 3 KEYNOTE-048 Trial Presented Today at the ESMO 2018 Congress during the Presidential Symposium
KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the first presentation of interim data from the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as both monotherapy and in combination with chemotherapy, for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). These interim results are being presented today during the Presidential Symposium at the ESMO 2018 Congress (Abstract # LBA8_PR) and are included in the official Press Program.
Interim data from KEYNOTE-048 showed KEYTRUDA monotherapy improved overall survival (OS), a primary endpoint of the study, by 39 percent (HR 0.61 [95% CI, 0.45-0.83]; p=0.0007) in patients whose tumors expressed PD-L1 with Combined Positive Score (CPS) ≥20, and by 22 percent (HR 0.78 [95% CI, 0.64-0.96]; p=0.0086) in patients with CPS≥1, compared to the EXTREME regimen (cetuximab with carboplatin or cisplatin plus 5-fluorouracil (5-FU), the current standard of care. In addition, KEYTRUDA in combination with chemotherapy (carboplatin or cisplatin plus 5-FU) (KEYTRUDA combination) demonstrated improved OS compared to the EXTREME regimen by 23 percent (HR 0.77 [95% CI, 0.63-0.93]; p=0.0034), regardless of PD-L1 expression. At the final analysis, superiority for OS will be evaluated for KEYTRUDA monotherapy in the total population and KEYTRUDA combination in patients whose tumors express PD-L1 at CPS≥20 and CPS≥1; at this interim analysis, based upon the prespecified testing algorithm, non-inferiority for KEYTRUDA monotherapy in the total population was demonstrated and statistical significance was not achieved for the KEYTRUDA combination in the subset of patients whose tumors expressed PD-L1 at CPS ≥20 or ≥1. Additionally, at this time point there was no difference in progression-free-survival (PFS), a dual primary endpoint of the study, in any of the groups studied. There were no new safety concerns identified with the use of KEYTRUDA in KEYNOTE-048.
“In this study, KEYTRUDA showed the potential to significantly prolong survival when used as first-line therapy for patients whose head and neck cancer had recurred or spread,” said Dr. Barbara Burtness, lead investigator for KEYNOTE-048, professor of medicine at Yale School of Medicine and co-director, Development Therapeutics Research Program, Yale Cancer Center. ”This is a devastating cancer when it recurs, and there has not been any advance in first-line treatment for over a decade. It is thrilling to see these new data, which have the potential to alter the standard of care in the first-line treatment of head and neck cancer.”
“KEYTRUDA is the first anti-PD-1 therapy to show superior overall survival as first-line treatment compared to the EXTREME regimen, the current standard of care in patients with recurrent or metastatic head and neck cancer,” said Dr. Roy Baynes, senior vice president and head of Global Clinical Development, chief medical officer, Merck Research Laboratories. “Recurrent or metastatic head and neck cancer is a very challenging disease. Merck would like to thank the patients and investigators for participating in this important study, which is helping to advance our understanding of the potential for KEYTRUDA and PD-1 inhibition in the first-line setting.”
KEYTRUDA is currently approved in 61 countries for the treatment of second-line recurrent or metastatic HNSCC, including the U.S. and Europe. Merck plans to file a supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration (FDA) for a first-line indication based on KEYNOTE-048 data and will include data from the Phase 3 KEYNOTE-040 trial as supportive data. Based on these results, Merck has withdrawn the sBLA for KEYNOTE-040 for KEYTRUDA as a second-line treatment in patients with recurrent or metastatic HNSCC, which was previously assigned a Prescription Drug User Fee Act (PDUFA) or target action date of Dec. 28, 2018. The results from KEYNOTE-048 will also be submitted to regulatory authorities worldwide.
Study Design and Additional Data from KEYNOTE-048 (Abstract # LBA8_PR)
KEYNOTE-048, a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT02358031), evaluated KEYTRUDA monotherapy or KEYTRUDA combination, compared with the EXTREME regimen, as first-line treatment in 882 patients with recurrent or metastatic HSNCC. The dual primary endpoints were OS and PFS. The secondary endpoints were PFS (at 6 months and 12 months), objective response rate (ORR) and time to deterioration in Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and Safety. Duration of response (DOR) was evaluated as part of a pre-specified exploratory analysis. The primary and secondary endpoints, as well as exploratory DOR analysis, were evaluated in patients whose tumors expressed PD-L1 with CPS ≥20 and CPS ≥1, and in the total population, regardless of PD-L1 expression, based on a fixed sequential testing strategy. At the time of the analysis, the median follow-up was 11.7 months for KEYTRUDA monotherapy, 13.0 months for KEYTRUDA combination and 10.7 months for the EXTREME regimen, respectively.
In the first comparison group, OS in the CPS ≥20 population was significantly longer with KEYTRUDA monotherapy (14.9 months) (n=133) compared to the EXTREME regimen (10.7 months) (n=122) (HR 0.61 [95% CI, 0.45-0.83]; p=0.0007). There was no difference in PFS between the study arms (HR 0.99 [95% CI, 0.75-1.29]; p=0.5). ORR was 23.3 percent for KEYTRUDA monotherapy and 36.1 percent for the EXTREME regimen, respectively. The median DOR was substantially longer with KEYTRUDA monotherapy (20.9 months) compared to the EXTREME regimen (4.2 months).
Similarly, OS in the CPS ≥1 population was significantly longer with KEYTRUDA monotherapy (12.3 months) (n=257) compared to the EXTREME regimen (10.3 months) (n=255) (HR 0.78 [95% CI, 0.64-0.96]; p=0.0086). There was no difference in PFS between the study arms (HR 1.16 [95% CI, 0.96-1.39]). ORR was 19.1 percent for KEYTRUDA monotherapy and 34.9 percent for the EXTREME regimen, respectively. The median DOR was substantially longer with KEYTRUDA (20.9 months) compared to the EXTREME regimen (4.5 months).
In the second comparison group, OS in the total population was significantly longer with the KEYTRUDA combination (13.0 months) (n=281) compared to the EXTREME regimen (10.7 months) (n=278) (HR 0.77 [95% CI, 0.63-0.93]; p=0.0034). There was no difference in PFS between the study arms (HR 0.92; 95% CI, 0.77-1.10). ORR was 35.6 percent for the KEYTRUDA combination and 36.3 percent for the EXTREME regimen, respectively. The median DOR was longer with KEYTRUDA combination (6.7 months) compared to the EXTREME regimen (4.3 months).
There were no new safety concerns identified with the use of KEYTRUDA in KEYNOTE-048. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 16.7 percent, 71.0 percent and 69.0 percent (n=198/287) of patients in the KEYTRUDA monotherapy, KEYTRUDA combination and the EXTREME regimen arms, respectively. TRAEs resulting in discontinuation occurred in 4.7 percent, 22.8 percent and 19.9 percent of patients in the KEYTRUDA monotherapy, KEYTRUDA combination and the EXTREME regimen arms, respectively. There were no TRAEs observed with an incidence of ≥15% in the KEYTRUDA monotherapy arm. The most common TRAEs (occurring in ≥15% of patients) in the KEYTRUDA combination arm included anemia (48.2%), nausea (44.9%), neutropenia (33.0%), fatigue (30.4%), mucosal inflammation (27.9%), thrombocytopenia (27.2%), vomiting (27.2%), stomatitis (24.3%), decreased appetite (22.5%), platelet count decreased (18.5%), diarrhea (17.8%) and neutrophil count decreased (16.7%).
Immune-mediated adverse events in patients receiving KEYTRUDA monotherapy or combination therapy were hypothyroidism (18.0% and 15.2%, respectively), pneumonitis (6.0% and 5.4%, respectively), hyperthyroidism (2.7% and 4.7%, respectively), severe skin reactions (2.7% and 0.7%, respectively), infusion reactions (1.3% and 2.2%, respectively), colitis (1.0% and 2.5%, respectively), nephritis (0.7% in both arms), pancreatitis (0.7% and 0.4%, respectively), hypophysitis (0.3% and 0.4%, respectively); hepatitis (0.7% monotherapy only); myocarditis and thyroiditis (0.4% each, combination only); and adrenal insufficiency, encephalitis and uveitis (0.3% each, monotherapy only). Treatment-related deaths occurred in 3 patients in the KEYTRUDA monotherapy arm [auto-inflammatory disease, disseminated intravascular coagulation, and pneumonitis (n=1 each)]; 10 patients in the KEYTRUDA combination arm [septic shock (n=5), cerebral ischemia, hemorrhage, interstitial lung disease, sepsis, and tumor hemorrhage (n=1 each)]; and 8 patients in the EXTREME regimen arm [pneumonia (n=3), sepsis (n=2), and hypoxia, osteomyelitis, and pulmonary artery thrombosis (n=1 each)].
Additional Information About KEYNOTE-048
KEYNOTE-048 enrolled 882 patients with recurrent or metastatic HSNCC who were randomized to one of three regimens as first-line therapy, as follows:
KEYTRUDA monotherapy (200 mg fixed dosed every three weeks [Q3W]) for up to 24 months (n=301); or
KEYTRUDA (200 mg fixed dose Q3W) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV continuous from Day 1-4 Q3W (maximum six cycles), followed by additional KEYTRUDA monotherapy maintenance therapy until progression of disease, toxicity or until the patient had received a maximum of 24 months total treatment (n=281); or
EXTREME regimen including cetuximab at a loading dose (400 mg/m2 IV) followed by weekly doses (250 mg/m2 IV) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV) continuous from Day 1-4 Q3W (maximum six cycles), followed by additional cetuximab monotherapy maintenance therapy until progression of disease or toxicity (n=300).
About Head and Neck Cancer
Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. The leading modifiable risk factors for head and neck cancer include tobacco and heavy alcohol use. Other risk factors include infection with certain types of HPV, also called human papillomaviruses. Worldwide, an estimated 835,000 new head and neck cancer cases will be diagnosed in 2018, and an estimated 431,000 people will die from the disease this year. In the U.S., there were an estimated 63,000 new cases diagnosed in 2017.