默沙东牵手卫材深度挖掘PD-1免疫疗法Keytruda临床潜力

目前，PD-1/PD-L1免疫竞赛激烈程度无法想象，其市场峰值高达350亿美元，默沙东（Merck）、百时美施贵宝（BMS）、阿斯利康（AZN）、罗氏（Roche）均在火速推进各自的临床项目，同时广泛合作深度挖掘各自免疫疗法的临床潜力。就在近日，百时美与Bavarian Nordic签署高达10亿美元协议，合作开发癌症免疫鸡尾酒；而今儿一大早，更是爆出其PD-1免疫疗法Opdivo获FDA批准肺癌适应症，从开始受理到批准仅4个工作日！相对黑色素瘤，肺癌是更加有利可图的广阔市场，元宵节当天拿到肺癌批文，百时美无疑是这个春节最大的赢家。

而其他各方也没闲着。默沙东近日就与日本药企卫材（Eisai）宣布了一项战略合作开展多个临床试验，评估其PD-1免疫疗法Keytruda（pembrolizumab）与卫材肿瘤学药物Lenvima（lenvatinib）和Halaven（eribulin）组合疗法的疗效和安全性。双方已计划开展的研究包括：一项Ib/II研究将调查Keytruda+Lenvima组合疗法用于特定实体瘤；一项Ib/II研究评估Keytruda+Halaven用于三阴乳腺癌（TNBC）。这些研究预计将从2015年第二季度开展，相关财务细节尚未披露。

Lenvima是卫材自主研发的新型抗癌药，于今年2月获FDA批准用于放射性碘难治性分化型甲状腺癌（RR-DTC），该药是一种口服多受体酪氨酸激酶（RTK）抑制剂，具有新颖的结合模式，除抑制参与肿瘤增殖的其他促血管生成和致癌信号通路相关RTK外，还能够选择性抑制血管内皮生长因子（VEGF）受体的激酶活性。目前，卫材也正在评估lenvatinib用于其他类型肿瘤的治疗，包括肝细胞癌癌、肾细胞癌、非小细胞肺癌等。Halaven则是卫材自主研发的一种新型海洋抗癌药物，该药是一种微管动力学抑制剂，具有一种全新的作用机制，能够抑制生长期微管导致细胞周期阻断最终导致细胞凋亡。目前，Halaven已获全球60个国家批准作用于转移性乳腺癌。

Keytruda则属于当前备受瞩目的PD-1/PD-L1免疫疗法，该类药物旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，在临床试验中针对多种类型肿瘤均表现出强大的疗效。根据此前公布的数据，罗氏MPDL3280A和默沙东Keytruda针对三阴乳腺癌（TNBC）均表现出积极的疗效。

英文原文：Eisai and Merck Enter Collaboration to Explore Novel Combination Regimens of Anti-PD-1 Therapy with Multi-targeting RTK Inhibitor and Microtubule Dynamics Inhibitor in Multiple Types of Cancer

Combination clinical studies of lenvatinib, eribulin and pembrolizumab to be explored

TOKYO & KENILWORTH, N.J.--(BUSINESS WIRE)--Eisai Co., Ltd. and Merck (NYSE:MRK), known as MSD outside the U.S. and Canada, through a subsidiary, announced today a clinical trial collaboration to evaluate the safety, tolerability and efficacy of Merck’s anti-PD-1 therapy, pembrolizumab (marketed in the U.S. under the brand name KEYTRUDA®), in combination with Eisai oncology compounds lenvatinib mesylate (a multi-targeting RTK inhibitor marketed in the U.S. under the brand name LENVIMA™, “lenvatinib”) and eribulin mesylate (a microtubule dynamics inhibitor marketed in nearly 60 countries including Japan, the U.S., and Europe under the brand name HALAVEN®, “eribulin”) in multiple clinical trials.

The planned studies include a multicenter, open-label Phase 1b/2 study of lenvatinib plus pembrolizumab in select solid tumors and an open-label, single-arm, multicenter Phase 1b/2 study to evaluate the efficacy and safety of eribulin in combination with pembrolizumab in metastatic triple-negative breast cancer. Eisai and Merck will establish a Joint Development Committee to oversee clinical development activities. The studies are expected to begin in the second half of 2015. Financial terms of the agreement were not disclosed.

“This collaboration could be a major step in the direction of developing combination regimens in different types of cancer, potentially maximizing the value of eribulin and lenvatinib,” said Kenichi Nomoto, PhD, president, oncology product creation unit, Eisai Product Creation Systems. “Together, Eisai and Merck seek to explore combination regimens that have the potential to create synergistic effects between lenvatinib and pembrolizumab as well as between eribulin and pembrolizumab. Our hope is that we will bring treatments to market that make a difference in the lives of people battling cancer.”

“Cancer is a complex disease that often requires different approaches to help patients achieve the best possible outcome,” said Dr. Eric Rubin, therapeutic area head, oncology early-stage development, Merck Research Laboratories. “The collaboration with Eisai exemplifies Merck’s focus on advancing breakthrough science in immuno-oncology. We look forward to evaluating pembrolizumab in combination with eribulin and also with lenvatinib in different tumor types.”

The combinations of lenvatinib and pembrolizumab, and eribulin and pembrolizumab, are investigational. The efficacy and safety of these combinations have not been established.

About LENVIMA™ (lenvatinib mesylate)

LENVIMA, discovered and developed by Eisai, is an oral molecular targeted agent that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4)), and fibroblast growth factor (FGF) receptors FGFR1, 2, 3 and 4 in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation. In particular, LENVIMA possesses a new binding mode (Type V) to VEGFR2, as confirmed through X-ray crystal structural analysis, and exhibits rapid and potent inhibition of kinase activity, according to kinetic analysis.

LENVIMA was approved on February 13, 2015 and launched on February 26, 2015 for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer in the United States, and is currently undergoing regulatory review for this indication in Japan, the EU, Switzerland, South Korea, Canada, Singapore, Russia, Australia and Brazil. Meanwhile, Eisai is currently conducting studies clinical studies of LENVIMA in several types of cancer including hepatocellular carcinoma (Phase III), renal cell carcinoma (Phase II), non-small cell lung cancer (Phase II) and endometrial cancer (Phase II). Furthermore, lenvatinib has been granted Orphan Drug Designation in Japan (for thyroid cancer), the United States (for the treatment of follicular, medullary, anaplastic, and metastatic or locally advanced papillary thyroid cancer), and Europe (for follicular and papillary thyroid cancer).

About HALAVEN® (eribulin mesylate)

HALAVEN, a halichondrin class microtubule dynamics inhibitor with a novel mechanism of action, belongs to a class of antineoplastic agents, the halichondrins, which are natural products isolated from the marine sponge Halichondria okadai. It is believed to work by inhibiting the growth phase of microtubule dynamics without affecting the shortening phase and sequestering tubulin into nonproductive aggregates.

HALAVEN was first approved as a treatment for metastatic breast cancer in the United States in November 2010, and is now approved in nearly 60 countries worldwide, including Japan and countries in the Americas, Europe and Asia. In the United States, HALAVEN Injection is indicated for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic breast cancer. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. In Japan, HALAVEN has been approved to treat inoperable or recurrent breast cancer and was launched in the country in July 2011. Since June 2014, Eisai has been obtaining approval in countries in Europe and Asia for the indication expansion of HALAVEN to contribute to earlier treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments. In addition, HALAVEN has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

About KEYTRUDA® (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 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.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 70 clinical trials – across more than 30 tumor types and over 8,000 patients – both as a monotherapy and in combination with other therapies.