曲妥、帕妥、T-DM1失败后新希望

　　美国东部时间2019年2月6日，总部位于马里兰州罗克维尔的临床阶段生物制药公司宏基因（MacroGenics，NASDAQ：MGNX）宣布III期非盲随机对照临床研究SOPHIA取得初步阳性结果：马吉妥昔单抗（margetuximab）与曲妥珠单抗相比，联合化疗对于曲妥珠单抗、帕妥珠单抗、曲妥珠单抗恩坦辛（T-DM1）治疗失败的HER2阳性转移性乳腺癌患者，无进展生存获得显著改善，预计将于2019年下半年向同样位于马里兰州罗克维尔的美国食品药品管理局（FDA）提交生物制剂上市许可申请。

　　马吉妥昔单抗与利妥昔单抗（美罗华）同属人鼠嵌合型单克隆抗体，两者分别嵌合了人类细胞表面抗原CD20和CD16A（FcγRIIIa）受体。马吉妥昔单抗与人源化单克隆抗体曲妥珠单抗、帕妥珠单抗均为HER2靶向药物。

　　该III期国际多中心非盲随机对照临床研究SOPHIA（NCT02492711）自2015年7月从北美、欧洲和亚洲214个研究机构入组曲妥珠单抗和帕妥珠单抗治疗失败的转移性HER2阳性乳腺癌患者536例（其中T-DM1治疗失败患者大约占90%）随机分组接受马吉妥昔单抗或曲妥珠单抗，并且联合四种化疗药物之一（卡培他滨、艾日布林、吉西他滨或长春瑞滨）治疗。主要研究终点为数据安全监测委员会放射科医师复核的无进展生存（预计随访至2018年12月）、总生存（预计随访至2020年3月）和注射相关≥3级不良反应。

　　结果发现，马吉妥昔单抗组患者与曲妥珠单抗组患者相比，复发死亡风险显著减少24%（风险比：0.76，P=0.033）。值得注意的是，其中大约85%的患者携带CD16A（FcγR IIIa）158F等位基因，该等位基因与曲妥珠单抗等其他抗体的临床效果不佳相关。预设该等位基因携带者亚组分析表明，马吉妥昔单抗组患者与曲妥珠单抗组患者相比，复发死亡风险显著减少32%（风险比：0.68，P=0.005）。马吉妥昔单抗＋化疗与曲妥珠单抗＋化疗相比，安全性和耐受性相似。总生存随访仍在进行。

　　对此，旧金山加利福尼亚大学综合癌症中心乳腺肿瘤和临床研究教育主任 Hope S. Rugo 教授表示：目前尚无获批用于转移性HER2阳性乳腺癌曲妥珠单抗、帕妥珠单抗和T-DM1治疗失败患者的药物。如果根据SOPHIA研究数据批准马吉妥昔单抗，相信该药可能成为对于这些患者很有价值的治疗选择。

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Feb 6, 2019

MacroGenics Announces Positive Results from Pivotal Phase 3 SOPHIA Study of Margetuximab.

• Margetuximab improved progression-free survival (PFS) compared to HERCEPTIN (trastuzumab), when used in combination with chemotherapy in patients with HER2+ metastatic breast cancer.

• BLA submission targeted for second half of 2019

• Company to host conference call today at 8:30 AM (ET).

ROCKVILLE, MD, Feb. 06, 2019 (GLOBE NEWSWIRE) --

MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, today announced positive results from SOPHIA, the Company's Phase 3 clinical study of margetuximab in HER2-positive metastatic breast cancer patients. Margetuximab is an investigational immune-enhancing monoclonal antibody derived from the Company's proprietary Fc Optimization technology platform. The SOPHIA clinical trial met the primary endpoint of prolongation of progression-free survival (PFS) in patients treated with the combination of margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy. Patients in the margetuximab arm experienced a 24% risk reduction in 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 diminished clinical response to HERCEPTIN and other antibodies. In this pre-specified subpopulation, patients in the margetuximab arm experienced a 32% risk reduction 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 for publication and presentation later this year at a major scientific conference. Follow-up for determination of the impact of therapy on the sequential primary endpoint of overall survival (OS) is ongoing, as pre-specified in the study protocol and recommended by the trial's independent Data Safety Monitoring Committee. MacroGenics anticipates submitting a Biologics License Application (BLA) to the U.S. Food and Drug Administration in the second half of 2019.

The SOPHIA study enrolled 536 patients at approximately 200 trial sites across North America, Europe and Asia. Patients were treated with either margetuximab or trastuzumab in combination with one of four chemotherapy agents (capecitabine, eribulin, gemcitabine or vinorelbine). All study patients had previously received trastuzumab and pertuzumab, and approximately 90% had previously received ado-trastuzumab emtansine. The combination of margetuximab and chemotherapy demonstrated acceptable safety and tolerability, comparable overall to that of trastuzumab and chemotherapy.

"There are currently no approved agents for the treatment of patients with metastatic HER2+ breast cancer who have previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine. If margetuximab is approved, based on SOPHIA data, I believe that this agent could become a valuable treatment option for these patients," said Hope S. Rugo, M.D., Director, Breast Oncology and Clinical Trials Education, University of California San Francisco Comprehensive Cancer Center.

"We are pleased with the SOPHIA clinical results and are especially grateful to the patients, their caregivers, trial investigators and site personnel who participated in the study. I would also like to thank the entire MacroGenics team and our business partners who worked diligently 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-head study against HERCEPTIN. We look forward to additional opportunities to develop margetuximab in other HER2-positive breast and gastric cancer populations."

About Margetuximab

Margetuximab is an investigational monoclonal antibody that targets the human epidermal growth factor receptor 2, or HER2 oncoprotein. HER2 is expressed by tumor cells in breast, gastroesophageal and other solid tumors. Margetuximab was designed to provide HER2 blockade and has been engineered with an Fc domain to enhance the engagement of the immune system. In addition to studying margetuximab in breast cancer, MacroGenics is developing the antibody in combination with anti-PD-1 therapy to engage both innate and adaptive immunity for the treatment of patients with gastroesophageal cancer.

About MacroGenics' Fc Optimization Technology

MacroGenics' Fc Optimization platform is designed to modulate an antibody's interaction with immune effector cells. The Fc region of certain antibodies binds activating and inhibitory receptors, referred to as FcγRs, on immune cells found within the innate immune system. Such interactions affect killing of cancer cells through antibody dependent cellular cytotoxicity (ADCC), among other Fc-dependent functions.

Activating FcγRs occur in two variants, or alleles, with high (158V) or low (158F) affinity for the Fc domain of IgG1. A majority (approximately 85%) of the population carries the 158F allele, either in the homozygous or heterozygous form with 158V. Patients that carry the 158F allele have been reported to show diminished clinical responses to certain therapeutic antibodies, including HERCEPTIN.

MacroGenics' optimized Fc region binds with increased affinity to the activating FcγRs, including the 158F low-affinity allele, and, unique to MacroGenics' technology, with reduced affinity to the inhibitory FcγR, resulting in improved effector functions, such as ADCC. To date, MacroGenics has successfully incorporated its proprietary Fc Optimization technology in margetuximab, as well as enoblituzumab, an anti-B7-H3 monoclonal antibody currently in development in combination with anti-PD-1 therapy for cancer treatment.

About MacroGenics, Inc.

MacroGenics is a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer. The Company generates its pipeline of product candidates primarily from its proprietary suite of next-generation antibody-based technology platforms, which have applicability across broad therapeutic domains. The combination of MacroGenics' technology platforms and protein engineering expertise has allowed the Company to generate promising product candidates and enter into several strategic collaborations with global pharmaceutical and biotechnology companies. For more information, please see the Company's website at www.macrogenics.com. MacroGenics and the MacroGenics logo are trademarks or registered trademarks of MacroGenics, Inc.

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