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默沙东公布免疫检查点药物pembrolizumab Ib期研究新数据

  1. Pembrolizumab
  2. 免疫检查点
  3. 抗PD-1单抗
  4. 黑色素瘤
  5. 默沙东

来源:生物谷 2014-06-04 09:18

默沙东公布免疫检查点药物pembrolizumab大型Ib期研究新数据。该药是一种实验性抗PD-1单抗,目前正接受FDA的审查,FDA将于今年10月作出审查决定。

2014年6月4日讯 /生物谷BIOON/ --默沙东(Merck & Co)6月2日公布了实验性单抗药物pembrolizumab(MK-3475)大型Ib期研究(KEYNOTE-001)的新数据。pembrolizumab是一种实验性抗PD-1单抗,该项研究调查了pembrolizumab作为一种单药疗法用于晚期黑色素瘤患者(n=411)的治疗。经pembrolizumab治疗后,预计所有患者的一年期生存率为69%,目前,平均总生存期(OS)数据尚未获得。

KEYNOTE-001是一项多中心、单组、开放标签研究,调查了pembrolizumab单药疗法用于超过1000例多种不同晚期癌症(转移癌)(主要为肺癌和黑色素瘤)的治疗。研究中,评价了pembrolizumab 3种剂量方案(10mg/kg每2周,10mg/kg每3周,2mg/kg每3周)。主要终点是总缓解率(ORR)和安全性,次要终点为无进展生存期(PFS)和总生存期(OS)及响应时间。

Pembrolizumab(MK-3475)是一种实验性、选择性、人源化抗PD-1单克隆抗体,旨在阻断T细胞表面PD-1与其配体PD-L1和PD-L2的相互作用,以重新激活抗肿瘤免疫。

目前,默沙东正调查pembrolizumab用于超过30多种癌症的治疗。

此前,FDA已授予pembrolizumab生物制品许可申请(BLA)优先审查资格并已指定PDUFA目标日期为2014年10月28日。此外,FDA也已授予pembrolizumab治疗晚期黑色素瘤的突破性疗法认定。如果获批,MK-3475将成为新一类免疫检查点调节剂中的首个抗PD-1抗体。

英文原文:Data on Merck’s Pembrolizumab from Largest Study to Date of Investigational Anti-PD-1 Antibody in Advanced Melanoma Highlighted at ASCO 2014

embrolizumab as Monotherapy Shows Estimated Overall Survival Rate of 69 Percent at One Year Across 411 Advanced Melanoma Patients with Varying Stages of Disease and Prior Therapy

Durable Responses and Consistent Tolerability Profile Observed Across Doses, Including Patients With or Without Prior Ipilimumab Therapy

Phase 3 Trials Ongoing or Planned Across Lines of Therapy, Including Adjuvant Treatment

CHICAGO--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced new data from the company’s large ongoing Phase 1b study (KEYNOTE-001) evaluating pembrolizumab (MK-3475), Merck’s investigational anti-PD-1 antibody, as a single agent (monotherapy) in 411 patients with advanced melanoma. Following treatment with pembrolizumab, the estimated overall survival (OS) rate at one year was 69 percent across all patients studied, including 74 percent in patients without prior ipilimumab therapy (current standard therapy) and 65 percent in patients who had progressive disease on or following ipilimumab. At 18 months, the estimated OS was 62 percent. The median OS has not been reached, with some patients receiving treatment with pembrolizumab as monotherapy for more than two years.

These new data will be presented today in an oral session by Dr. Antoni Ribas, professor, Hematology/Oncology and Surgery, and director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO 2014) in Chicago (Abstract #LBA9000; 3:00 PM CDT; Location – E Arie Crown Theater).

“The data presented today provide further evidence of durable anti-tumor activity stimulated by pembrolizumab as a single agent in patients suffering from malignant melanoma,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “While we await further confirmation through controlled clinical trials, the survival rates seen with pembrolizumab therapy, including in patients with advanced disease who have failed other therapies, support the use of immune manipulation in cancer care.”

New Data for Pembrolizumab in Advanced Melanoma

These data from 411 patients with advanced melanoma enrolled in multiple cohorts from KEYNOTE-001, the largest Phase 1b study to date of an anti-PD-1 antibody, will be highlighted as part of the ASCO 2014 Press Program. KEYNOTE-001 involved seven advanced melanoma cohorts including patients with varying stages of disease and prior lines of therapy. At baseline, 56 percent of patients had the most advanced stage of disease (M1c) (n=232) and 77 percent of patients had received at least one prior systemic therapy (n=316). Interim data from a single cohort of 135 patients from KEYNOTE-001 were first presented at ASCO 2013 and published concurrently in the New England Journal of Medicine. More recently, updated findings from this cohort were reported at the 10th International Congress of the Society for Melanoma Research (November 2013).

At the time of analysis, 88 percent of reported responses in evaluable patients were ongoing and the median duration of response, by RECIST criteria, had not been reached (n=115/130) (range 6+ weeks to 76+ weeks). The median progression-free survival (PFS), by RECIST criteria, was 5.5 months overall (95% CI, 3.8-6.2), including 5.6 months in patients with no prior ipilimumab therapy (95% CI, 3.7-11) and 5.4 months in patients who had progressive disease on or following ipilimumab therapy (95% CI, 3.2-5.6). Anti-tumor activity was observed across all doses studied, regardless of the type and number of previous treatments (including prior ipilimumab therapy), performance status, Lactate Dehydrogenase (LDH) levels, BRAF mutation status, tumor size at baseline, and anatomical site of metastatic disease. An analysis of patient subgroups indicates that lower tumor burden at baseline is a strong predictor of response to pembrolizumab.

In patients with measurable disease at baseline who had at least one treatment scan, 72 percent (n=227/317) showed tumor shrinkage, including 39 percent (n=123/317) who had tumor shrinkage of greater than 50 percent by RECIST criteria. Based on irRC (central review), 64 percent (n=204/319) of patients showed tumor shrinkage, including 31 percent (n=100/319) who showed tumor shrinkage of greater than 80 percent.

The incidence of adverse events was consistent with previously reported data for pembrolizumab. The most common investigator-assessed, treatment-related adverse events were grade 1/2 and included fatigue (36%), pruritus (24%), rash (20%), diarrhea (16%) and arthralgia (16%), nausea (12%), vitiligo (11%), asthenia (9%) and cough (9%). The most common immune-related adverse events included hypothyroidism (8%) and hyperthyroidism (1%). Twelve (3%) treatment-related cases of pneumonitis were reported including one grade 3/4 event. The most common grade 3/4 treatment-related adverse event reported was fatigue (2%). Overall, 17 patients (4%) discontinued treatment due to investigator assessed, treatment-related adverse events. No treatment-related deaths were reported.

Dosing and Other Advanced Melanoma Data at ASCO 2014

Dosing was analyzed across all evaluable patients with advanced melanoma and a comparison of two pembrolizumab doses will be presented on Tuesday, June 3 in an oral presentation at ASCO 2014 (Abstract #3000; 9:45 AM CDT; Location – S100a). Based on these randomized data, comparing 2 mg/kg and 10 mg/kg every three weeks, and an additional cohort of randomized data comparing 10 mg/kg every two or three weeks, which is planned to be presented at a future congress, the recommended dose proposed for pembrolizumab in advanced melanoma is 2 mg/kg once every three weeks.

Data evaluating pembrolizumab in advanced melanoma is the subject of additional oral presentations and a poster discussion at ASCO 2014. For additional information on pembrolizumab data being presented for advanced melanoma, see the ASCO iPlanner: https://iplanner.asco.org/am2014.

Merck Oncology Briefing Webcast

Merck will hold a webcast in conjunction with ASCO 2014 on June 2 at 6:15 p.m. CDT. Investors and journalists may access a live audio webcast of the event on Merck’s website at www.merck.com. Software needed to listen to the webcast is available on the corporate website and should be downloaded prior to the beginning of the webcast. Institutional investors, analysts and members of the media also can also listen to the event by dialing (866) 486-2604 or (706) 902-0743 and using ID code number 53194490.

About the KEYNOTE-001 Study

The Phase 1b trial (KEYNOTE-001) is an ongoing multi-center, single-arm, open-label study evaluating pembrolizumab monotherapy in more than 1,000 patients with diverse late-stage cancers (metastatic carcinoma) – predominantly lung and melanoma. Three dosing regimens of pembrolizumab were evaluated, including 10mg/kg every two weeks, 10mg/kg every three weeks or 2mg/kg every three weeks. The primary endpoint of the study includes overall response rate (ORR) and safety; the secondary endpoints include progression-free survival (PFS), overall survival (OS) and duration of response. Tumor response in advanced melanoma was assessed every 12 weeks by investigator-assessed, immune-related response criteria (irRC), and by independent, central, blinded radiographic review per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

About Pembrolizumab in Advanced Melanoma

Pembrolizumab (MK-3475) is an investigational selective, humanized monoclonal anti-PD-1 antibody designed to block the interaction of PD-1 on T-cells with its ligands, PD-L1 and PD-L2, to reactivate anti-tumor immunity. Pembrolizumab exerts dual ligand blockade of PD-1 pathway.

Pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. Merck has a broad development program in advanced melanoma evaluating pembrolizumab across multiple stages of disease, lines of therapy and in combination with other anti-cancer agents. The company currently has two Phase 3 studies ongoing (KEYNOTE-002, 006) in advanced melanoma, and one planned for adjuvant treatment in the same indication. For information about Merck’s oncology clinical studies, please visit www.merck.com/clinical-trials.

The Biologics License Application (BLA) for pembrolizumab is under priority review with the U.S. Food and Drug Administration (FDA) for the proposed indication for the treatment of patients with advanced melanoma previously-treated with ipilimumab; the PDUFA date is October 28, 2014. Pembrolizumab has been granted FDA’s Breakthrough Therapy designation for advanced melanoma. If approved by the FDA, pembrolizumab has the potential to be the first PD-1 immune checkpoint modulator approved in this class. The company plans to file a Marketing Authorization Application in Europe for pembrolizumab for advanced melanoma in 2014.

About Advanced Melanoma

Melanoma is the most serious form of skin cancer and is one of the most common types of cancer diagnosed in the U.S. While it accounts for less than two percent of skin cancer cases, melanoma is responsible for the vast majority of skin cancer deaths. In 2014, an estimated 76,100 people are expected to be diagnosed with melanoma and an estimated 9,710 people will die of the disease in the U.S.

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