【回乡偶记】MGAH22在SOPHIA研究达到主要终点
MacroGenics Announces Positive Results from Pivotal Phase 3 SOPHIA Study of Margetuximab
Margetuximab improved progression-freesurvival (PFS) compared to HERCEPTIN® (trastuzumab), when used in combinationwith chemotherapy in patients with HER2+ metastatic breast cancer
BLA submission targeted for second half of 2019
1 主要新闻
MacroGenics宣布旨在评估margetuximab（也就是MGAH22）治疗HER2+ mBC的临床3期SOPHIA研究的阳性结果。Margetuximab是基于MacroGenics公司旗下Fc优化技术平台开发的一款增强免疫效果的单克隆抗体。SOPHIA研究结果显示Margetuximab相比赫赛汀联合化疗显著提升共同主要终点PFS，降低24%的疾病进展风险（HR=0.76, p=0.033）。需要指出的是研究中85名患者携带了CD16A (FcγRIIIa)158F等位基因，先前数据显示这部分患者对赫赛汀或其它单抗的临床缓解减弱。根据预先设定的亚组分析，margetuximab组相比赫赛汀组降低了32%的疾病进展风险(HR=0.68, p=0.005)。该结果会在将来的学术会议（ASCO？AACR应该来不及了）上发表，对另一个主要终点OS的随访将继续，预计19H2 BLA。
2 SOPHIA研究
SOPHIA研究在北美、欧洲和亚洲的200个中心招募了536名患者，患者随机分配到接受margetuximab或赫赛汀联合化疗（卡培他滨、艾瑞布林、吉西他滨或长春西滨这四类方案任选一），所有的患者先前接受过曲妥珠和帕妥珠单抗治疗，90%接受过T-DM1。安全性方面，margetuximab联合化疗相比赫赛汀联合化疗有着可以接受的安全性和毒性数据。
所以可以看出这并不是一线治疗，是主流的抗HER2治疗失败后的新方案探索。
不管是CT上的描述：
https://clinicaltrials.gov/ct2/show/NCT02492711 ，
Have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the metastatic setting. In either case, patients must have received prior treatment with pertuzumab, in the (neo)adjuvant or metastatic setting. Prior radiotherapy, hormonal therapies, and other anti-HER2 therapies are allowed.
Prior treatment with at least one, and no more than three, lines of therapy overall in the metastatic setting. Patients must have progressed on or following, the most recent line of therapy.
还是之前的摘要：
http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.TPS630
SOPHIA is a randomized, prospective study testing the hypothesis that m plus CTX is more effective than T plus CTX in patients previously treated for HER2+ MBC.
所以和mBC的1L治疗是完全不同的研究。
3 研究背景
这看下为什么3-4L治疗要这么搞这么大动静，篇幅有限，只做描述，无法给出判断。
一个是HER2+ mBC的3-4L缺少好的标准方案，另外就是日本研究者1999年发表的研究《Relevance of FcγRIIIa-158V-F polymorphism to recurrence of adult periodontitis in Japanese patients》：The immunoglobulin receptor FcγRIIIa (CD16) is distributed on natural killer (NK) cells, macrophages, and γδ T cells, and is polymorphic. FcγRIIIa-158V has a higher affinity for both monomeric and immune complexed IgG1, IgG3, and IgG4 than IIIa-158F. We determined FcγRIIIa-158V/F genotypes of Japanese patients with adult periodontitis. A significant over-representation of FcγRIIIa-158F was found in patients with recurrence, compared with patients without recurrence, making FcγRIIIA a candidate gene for recurrence risk of adult periodontitis.
之前的体外研究数据显示：The engineered Fc domain of margetuximab confers increased affinity in vitro for all allotypes of activating CD16A Fcγ receptors on NK cells and decreased affinity for inhibitory CD32B Fcγ receptors, compared to trastuzumab
这里插句题外话，个人对 ITT群体 OS的结果不是特别看好，纯粹直觉，赌个10块钱
4 Presentation
链接 ：
http://ir.macrogenics.com/static-files/c73fd3d3-6a17-4f04-95d9-3d6c39eb7411
5 新闻原文
MacroGenics Announces Positive Results from Pivotal Phase 3 SOPHIA Studyof Margetuximab
ROCKVILLE, MD, Feb. 06, 2019 (GLOBE NEWSWIRE) -- MacroGenics,Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused ondiscovering and developing innovative monoclonal antibody-based therapeuticsfor the treatment of cancer, today announced positive results from SOPHIA, theCompany’s Phase 3 clinical study of margetuximab in HER2-positive metastaticbreast cancer patients. Margetuximab is an investigational immune-enhancingmonoclonal antibody derived from the Company’s proprietary Fc Optimizationtechnology platform. The SOPHIA clinical trial met the primary endpoint ofprolongation of progression-free survival (PFS) in patients treated with thecombination of margetuximab plus chemotherapy compared to trastuzumab pluschemotherapy. Patients in the margetuximab arm experienced a 24% risk reductionin PFS compared to patients in the trastuzumab arm (HR=0.76, p=0.033). Notably,approximately 85% of patients in the study were carriers of the CD16A(FcγRIIIa) 158F allele, which has been previously associated with diminishedclinical response to HERCEPTIN and other antibodies. In this pre-specifiedsubpopulation, patients in the margetuximab arm experienced a 32% riskreduction in PFS compared to patients in the trastuzumab arm (HR=0.68,p=0.005). Results of the SOPHIA study are being prepared for submission forpublication and presentation later this year at a major scientific conference.Follow-up for determination of the impact of therapy on the sequential primaryendpoint of overall survival (OS) is ongoing, as pre-specified in the studyprotocol and recommended by the trial’s independent Data Safety MonitoringCommittee. MacroGenics anticipates submitting a Biologics LicenseApplication (BLA) to the U.S. Food and Drug Administration in thesecond half of 2019.
The SOPHIA study enrolled 536 patients at approximately 200 trial sitesacross North America, Europe and Asia. Patients weretreated with either margetuximab or trastuzumab in combination with one of fourchemotherapy agents (capecitabine, eribulin, gemcitabine or vinorelbine). Allstudy patients had previously received trastuzumab and pertuzumab, andapproximately 90% had previously received ado-trastuzumab emtansine. Thecombination of margetuximab and chemotherapy demonstrated acceptable safety andtolerability, comparable overall to that of trastuzumab and chemotherapy.
“There are currently no approved agents for the treatment of patients withmetastatic HER2+ breast cancer who have previously received trastuzumab,pertuzumab and ado-trastuzumab emtansine. If margetuximab is approved, based onSOPHIA data, I believe that this agent could become a valuable treatment optionfor these patients,” said Hope S. Rugo, M.D., Director, Breast Oncologyand Clinical Trials Education, University of California San FranciscoComprehensive Cancer Center.
“We are pleased with the SOPHIA clinical results and are especiallygrateful to the patients, their caregivers, trial investigators and sitepersonnel who participated in the study. I would also like to thank theentire MacroGenics team and our business partners who workeddiligently to bring margetuximab to the clinic and execute the SOPHIA study,”said Scott Koenig, M.D., Ph.D., MacroGenics’ President and CEO. “Our Fc-engineered,immune-enhanced molecule has demonstrated a superior outcome in a head-to-headstudy against HERCEPTIN. We look forward to additional opportunities to developmargetuximab in other HER2-positive breast and gastric cancer populations.”