Amcenestrant

Pivotal Phase 3 VERITAC-2 clinical trial results presented at ASCO demonstrate 2.9-month improvement in median progression-free survival when compared to fulvestrant in second line-plus patients with an estrogen receptor 1 mutation Vepdegestrant was generally well tolerated, with few discontinuations and low rates of gastrointestinal-related adverse events Vepdegestrant is the first and only PROteolysis TArgeting Chimera (PROTAC) evaluated in a Phase 3 clinical trial and the first to show benefit in patients with breast cancer Data to be featured in a late-breaking oral presentation at ASCO and simultaneously published in the New England Journal of Medicine Arvinas will host a conference call to discuss these results on Monday, June 2, at 8:00 a.m. ET NEW HAVEN, Conn. and NEW YORK, May 31, 2025 – Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) today announced detailed results from the Phase 3 VERITAC-2 clinical trial (NCT05654623) evaluating vepdegestrant monotherapy versus fulvestrant in adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer (MBC) whose disease progressed following prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy. These data, which were highlighted in the American Society of Clinical Oncology (ASCO®) press briefing and selected for Best of ASCO, will be presented today in a late-breaking oral presentation (Abstract LBA1000) and have been simultaneously published in the New England Journal of Medicine. In the trial, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) among patients with an estrogen receptor 1 (ESR1) mutation, reducing the risk of disease progression or death by 43% compared to fulvestrant [Hazard Ratio (HR)=0.57 (95% CI 0.42–0.77); 2-sided P<0.001]. The median PFS, as assessed by blinded independent central review (BICR), was 5.0 months with vepdegestrant versus 2.1 months with fulvestrant. Investigator-assessed PFS was consistent with the BICR-assessed PFS. In patients with ESR1 mutations, vepdegestrant demonstrated a consistent PFS benefit over fulvestrant across all pre-specified subgroups. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population, with a median PFS of 3.7 months for vepdegestrant versus 3.6 for fulvestrant [HR=0.83 (95% CI 0.68–1.02); 2-sided P=0.07]. “Many patients with ER+/HER2- metastatic breast cancer who progress on endocrine therapy have tumors with ESR1 mutations, which drive resistance to standard treatments,” said Erika P. Hamilton, M.D., Director, Breast Cancer Research, Sarah Cannon Research Institute, and a principal investigator of the VERITAC-2 trial. “The VERITAC-2 results are promising and suggest that vepdegestrant could offer a much-needed treatment option for these patients, with a low incidence of burdensome GI effects that can meaningfully affect daily life.” Vepdegestrant was generally well tolerated in the trial, with a safety profile consistent with what has been observed in previous studies, and mostly low-grade treatment-emergent adverse events (TEAEs). Rates and severity of gastrointestinal adverse events were low with vepdegestrant (nausea, 13.5%; vomiting, 6.4%; diarrhea, 6.4%). Grade 4 TEAEs were reported in 5 patients (1.6%) in the vepdegestrant arm versus 9 patients (2.9%) in the fulvestrant arm. The three most common TEAEs observed with vepdegestrant were fatigue (26.6%), increased alanine transaminase (ALT) (14.4%) and increased aspartate aminotransferase (AST) (14.4%). TEAEs leading to treatment discontinuation occurred in 2.9% of patients taking vepdegestrant versus 0.7% of patients taking fulvestrant. “Based on these strong data from VERITAC-2, we believe that vepdegestrant has the potential to be a best-in-class monotherapy treatment for patients in the second-line ESR1-mutant setting,” said John Houston, Ph.D., Chairperson, Chief Executive Officer and President at Arvinas. “We are excited to engage with regulatory authorities on next steps to potentially bring vepdegestrant to healthcare providers and their patients as swiftly as possible.” Overall survival (OS), the key secondary endpoint in VERITAC-2, was immature at the time of the analysis, with less than a quarter of the required number of events having occurred. Additional secondary endpoints include clinical benefit rate (CBR) and objective response rate (ORR) and duration of response by BICR. In patients with an ESR1 mutation, CBR was 42.1% with vepdegestrant versus 20.2% with fulvestrant [odds ratio 2.88 (95% CI: 1.57–5.39); nominal P<0.001] and ORR was 18.6% with vepdegestrant versus 4.0% with fulvestrant [odds ratio 5.45 (95% CI: 1.69–22.73); nominal P=0.001]. The median duration of response was not reached. “Patients whose tumors harbor ESR1 mutations can face a poor prognosis, often experiencing rapid disease progression on endocrine therapy,” said Johanna Bendell, M.D., Chief Oncology Development Officer, Pfizer. “These results highlight the important role vepdegestrant may play in combating ESR1 mutation treatment resistance for these patients.” Approximately 2.3 million new breast cancer diagnoses were reported globally in 2022, and it is estimated there will be nearly 320,000 new diagnoses in the United States in 2025. ER+/HER2- breast cancer accounts for approximately 70% of all cases. Nearly 30% of women initially diagnosed with early-stage breast cancer will ultimately develop metastatic disease,1 with resistance to current standard-of-care treatments often emerging during first-line therapy, leading to disease progression. ESR1 mutations are a common cause of acquired resistance and are found in approximately 40% of patients in the second-line setting.2,3,4 Vepdegestrant, an investigational oral PROTAC ER degrader for ER+/HER2- breast cancer being jointly developed by Arvinas and Pfizer, is designed to harness the body’s natural protein disposal system to specifically target and degrade the ER. These detailed results follow the March 2025 announcement of the topline results from VERITAC-2. The companies plan to submit a New Drug Application (NDA) for vepdegestrant to the U.S. Food & Drug Administration (FDA) in the second half of 2025. ASCO Presentation Details "Vepdegestrant, a PROTAC Estrogen Receptor Degrader, vs Fulvestrant in ER-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results of the Global, Randomized, Phase 3 VERITAC-2 Study" will be presented by Dr. Erika Hamilton, MD, Sarah Cannon Research Institute, in the Oral Abstract Session, Breast Cancer—Metastatic on Saturday, May 31, 1:15 – 4:15 p.m. CDT in Hall B1. Abstract LBA1000. Investor Call and Webcast Details Arvinas will host a conference call and webcast on June 2, 2025, at 8:00 a.m. ET to review these data. Participants are invited to listen by going to the Events and Presentation section under the Investors page on the Arvinas website at www.arvinas.com. A replay of the webcast will be available on the Arvinas website following the completion of the event and will be archived for up to 30 days. About the VERITAC-2 Clinical Trial The Phase 3 VERITAC-2 clinical trial (NCT05654623) is a global randomized trial evaluating the efficacy and safety of vepdegestrant (ARV-471) as a monotherapy compared to fulvestrant in patients with ER+/HER2- advanced or metastatic breast cancer. The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy. Patients were randomized 1:1 to receive either vepdegestrant once daily, orally on a 28-day continuous dosing schedule, or fulvestrant, administered intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each 28-day cycle starting from Day 1 of Cycle 2. In the trial, 43% of patients (n=270) had ESR1 mutations detected. The primary endpoint was progression-free survival (PFS) in the ESR1-mutation and intent-to-treat populations as determined by blinded independent central review. Overall survival is the key secondary endpoint. About Vepdegestrant Vepdegestrant is an investigational, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER-positive (ER+)/human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) breast cancer. Vepdegestrant is being developed as a potential monotherapy for ER+/HER2- advanced or metastatic breast cancer with estrogen receptor 1 (ESR1) mutations in the second line-plus setting. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits. The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy in the treatment of adults with ER+/HER2- advanced or metastatic breast cancer previously treated with endocrine-based therapy. About Arvinas Arvinas (Nasdaq: ARVN) is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its PROTAC protein degrader platform, Arvinas is pioneering the development of protein degradation therapies designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; and ARV-102, targeting LRRK2 for neurodegenerative disorders. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit www.arvinas.com and connect on LinkedIn and X. About Pfizer Oncology At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on X at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer. Arvinas Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding: vepdegestrant’s development as a potential monotherapy for patients with estrogen receptor positive (“ER+”), human epidermal growth factor receptor 2 negative (“HER2-”), metastatic breast cancer with estrogen receptor 1 (“ESR1”) mutations in the second-line plus setting; vepdegestrant’s potential as a treatment option for patients with a low incidence of burdensome gastrointestinal effects; vepdegestrant’s potential to be a best-in-class monotherapy treatment for patients with ER+/HER2- metastatic breast cancer in the second-line ESR1-mutant setting; and Arvinas’ and Pfizer’s plans to engage with regulatory authorities on next steps to potentially bring vepdegestrant to healthcare providers and patients, and the companies’ plans to submit a New Drug Application to the U.S. Food and Drug Administration, and the timing thereof. All statements, other than statements of historical fact, contained in this press release, including statements regarding Arvinas’ strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “target,” “goal,” “potential,” “will,” “would,” “could,” “should,” “look forward,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Arvinas may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on such forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements Arvinas makes as a result of various risks and uncertainties, including but not limited to: whether Arvinas and Pfizer will successfully perform their respective obligations under the collaboration between Arvinas and Pfizer; whether Arvinas and Pfizer will be able to successfully conduct and complete clinical development for vepdegestrant as a monotherapy; whether Arvinas will be able to successfully conduct and complete development for its other product candidates, including ARV-393 and ARV-102; whether Arvinas and Pfizer, as appropriate, will be able to obtain marketing approval for and commercialize vepdegestrant and other product candidates on current timelines or at all; Arvinas’ ability to protect its intellectual property portfolio; Arvinas’ reliance on third parties; whether Arvinas will be able to raise capital when needed; whether Arvinas’ cash and cash equivalents will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; and other important factors discussed in the “Risk Factors” section of Arvinas’ Annual Report on Form 10-K for the year ended December 31, 2024 and subsequent other reports on file with the U.S. Securities and Exchange Commission. The forward-looking statements contained in this press release reflect Arvinas’ current views with respect to future events, and Arvinas assumes no obligation to update any forward-looking statements, except as required by applicable law. These forward-looking statements should not be relied upon as representing Arvinas’ views as of any date subsequent to the date of this release. Pfizer Disclosure Notice: The information contained in this release is as of May 31, 2025. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about Pfizer Oncology and vepdegestrant, including its potential benefits, detailed results from the Phase 3 VERITAC-2 clinical trial evaluating vepdegestrant monotherapy versus fulvestrant in adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer whose disease progressed following prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy and plans to submit a New Drug Application for vepdegestrant to the FDA in the second half of 2025 that involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; whether the VERITAC-2 trial will meet the secondary endpoint for overall survival; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for any potential indication for vepdegestrant; whether and when any such applications that may be filed for vepdegestrant may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy, and, if approved, whether vepdegestrant will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of vepdegestrant; whether the collaboration between Pfizer and Arvinas will be successful; risks and uncertainties related to issued or future executive orders or other new, or changes in, laws or regulations; uncertainties regarding the impact of COVID-19 on our business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2024, and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov  1 Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med. 2013;274(2):113-126. doi:10.1111/joim.12084.2 Bidard F-C, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Journal of Clinical Oncology. 2022 May https://doi.org/10.1200/JCO.22.00338. 3 Kalinsky, K. Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial. Journal of Clinical Oncology. 2024 Dec. https://doi.org/10.1200/JCO-24-0208.4 Tolaney, S. et al. AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer. Journal of Clinical Oncology. https://ascopubs.org/doi/full/10.1200/JCO.22.02746. Pfizer Media Contact: +1 (212) 733-1225 PfizerMediaRelations@Pfizer.com Pfizer Investor Contact: +1 (212) 733-4848 IR@Pfizer.com Arvinas Media Contact: Kirsten Owens +1 (203) 584-0307 Kirsten.Owens@Arvinas.com Arvinas Investor Contact: Jeff Boyle +1 (347) 247-5089 Jeff.Boyle@Arvinas.com

100+创始人齐聚海南，对话“先行先试”政策机会，共探 CGT全产业发展之路，欢迎报名！从2020年开始，乳腺癌发病率超过了肺癌发病率，成为全球第一大恶性肿瘤，是药企必争之地。罗氏曾凭借HER2单抗——曲妥珠单抗、帕妥珠单抗、HER2 ADC药物T-DM1（恩美曲妥珠单抗）等，使乳腺癌患者的生存获益显著提高，自己也成为该领域的主导者。不过花无百日红，随着核心产品迎来专利悬崖，T-DM1被DS-8201头对头击败，罗氏在乳腺癌领域的辉煌逐渐成为过去式。在后续一众虎视眈眈的围猎者中，第一三共和阿斯利康是其中的佼佼者。1DS-8201横空出世，重塑乳腺癌治疗体系作为日本百年药企，第一三共独有的DXd ADC技术平台已成为ADC新药开发的一面旗帜。其首款重磅ADC药物Enhertu（德曲妥珠单抗，DS-8201）的横空出世，更是重新点燃了全球ADC药物的研发热情。德曲妥珠单抗是一款靶向HER2的抗体偶联药物（ADC），由第一三共研发，并由第一三共和阿斯利康共同开发和商业化。HER2是一种酪氨酸激酶受体促生长蛋白，在多种肿瘤细胞表面均有表达。作为一款HER2靶向ADC，德曲妥珠单抗采用第一三共独有的DXd ADC技术设计，由靶向HER2的人源化单克隆抗体通过四肽可裂解连接子与拓扑异构酶1抑制剂（喜树碱类衍生物，DXd）有效载荷连接组成。自2019年获FDA批准上市以来（用于治疗接受过2种或以上抗HER2疗法的治疗的无法切除或转移性HER2阳性乳腺癌患者），德曲妥珠单抗就不断书写它的传奇，并一步步重塑乳腺癌治疗格局。首次惊艳业界的是与恩美曲妥珠单抗的头对头随机对照研究。DESTINY-Breast03是首个头对头比较德曲妥珠单抗和恩美曲妥珠单抗在 HER2 阳性晚期乳腺癌二线治疗中疗效的 Ⅲ 期临床研究。在2022 年圣安东尼奥国际乳腺癌研讨会（SABCS）上公布的研究结果显示，德曲妥珠单抗组无进展生存期（PFS）获益明显（28.8 个月 vs 6.8 个月），约为恩美曲妥珠单抗组的 4 倍，并且降低患者疾病进展或死亡风险67%。2022年5月，德曲妥珠单抗扩展适应症获美FDA批准，用于治疗无法切除或转移性HER2+乳腺癌患者，这些患者曾经接受过一种抗HER2靶向疗法的治疗。德曲妥珠单抗重塑了HER2+乳腺癌的二线治疗标准。随后的DESTINY-Breast04研究则更进一步，将HER2低表达（IHC 1+或2+/ISH阴性）乳腺癌确立为新的治疗亚型，开创了HER2低表达晚期乳腺癌治疗的新时代。研究结果显示，在激素受体（HR）阳性/HER2低表达乳腺癌患者中，德曲妥珠单抗组的中位PFS绝对值较化疗组延长了近5个月（10.1个月 vs 5.4个月，HR=0.51，95%CI：0.40-0.64）；中位总生存期（OS）也显著延长（23.9个月 vs 17.5个月，HR=0.64，95%CI：0.48-0.86）；德曲妥珠单抗组客观缓解率（ORR）达52.6%，而化疗组仅为16.3%。基于DESTINY-Breast04研究的出色结果，德曲妥珠单抗获得了国内外权威指南的一致推荐。美国NCCN乳腺癌指南（2022.V4版）将“HER2低表达乳腺癌（IHC 1+或IHC 2+/ISH-）”作为一种全新的治疗分型，将德曲妥珠单抗作为伴有内脏危象/内分泌难治HER2低表达乳腺癌的二线治疗方案。随后德曲妥珠单抗获批HER2低表达转移性乳腺癌适应症，使得乳腺癌治疗从传统的非阴即阳二分法时代迈入更加精准的三分法时代（阳性/低表达/阴性），不仅将受益人群扩大至60%-70%，更是推动整个抗HER2乳腺癌治疗模式的革新。据第一三共2024财年业绩，德曲妥珠单抗在HER2阳性乳腺癌二线治疗和HER2低表达乳腺癌适应症上，都实现了两位数的增长（德曲妥珠单抗2024全球销售额约34.77亿美元）。DESTINY-Breast系列研究还在继续。今年1月27日，FDA批准德曲妥珠单抗用于治疗不可切除或转移性、激素受体（HR）阳性且HER2低表达（IHC 1+或IHC 2+/ISH-）或超低表达（IHC 0但具有膜染色）的乳腺癌患者。这一批准基于DESTINY-Breast06研究，结果显示，在总人群中，德曲妥珠单抗相比标准治疗组，将中位PFS显著延长了5.1月（13.2个月 vs 8.1个月，HR=0.63，P<0.0001）；在HER2低表达患者亚组中，德曲妥珠单抗相比标准治疗组，中位PFS显著延长（13.2个月 vs 8.1个月，HR=0.62，P<0.0001），OS达到12个月的比例更高（87.6% vs 81.7%，HR=0.83）；在HER2超低表达患者亚组中，德曲妥珠单抗展现出与HER2低表达亚组相似的获益趋势，相比标准治疗组，中位PFS显著延长（13.2个月 vs 8.3个月，HR=0.78），OS达到12个月的比例更高（84.0% vs 78.7%，HR=0.75）。至此，德曲妥珠单抗从HER2阳性到HER2低表达、超低表达，都已积累了循证医学证据，重新塑造了乳腺癌治疗格局。2阿斯利康不语，只一味卷自己在乳腺癌治疗领域，阿斯利康是不能被忽视的存在。阿斯利康瞄准HR+乳腺癌患者这一大群体，陆续推出了他莫昔芬、戈舍瑞林、阿那曲唑和氟维司群四款内分泌治疗基石药物，并不断在此基础上超越自己。以经典药物氟维司群（fulvestrant）为例，这是一款选择性雌激素受体降解剂（SERD），其通过与癌细胞表面的ER相结合，降低ER的稳定性，诱导它们被细胞正常的蛋白降解机制降解，从而降低雌激素受体水平，抑制癌细胞的生长。其优势在于能够更全面地抑制雌激素受体的功能，并且可能解决雌激素受体突变产生的耐药性。2002年4月，Faslodex（氟维司群）获FDA批准上市，用于雌激素治疗（如他莫昔芬）后疾病进展的绝经后乳腺癌患者。作为全球首款SERD药物，氟维司群可将达到总生存期5年的晚期乳腺癌患者的比例，由22.5%提升至50%。在二十年的时间中，氟维司群独占SERD市场，销售峰值达到10.28亿美元。不足的是，氟维司群只能肌肉注射给药，生物利用度低且可及性欠佳。所以业界开始追求效果更强、可及性更好、极具替代潜力的SERD口服药，不过，这一路走来并不顺利。2022年，赛诺菲的SERD口服药Amcenestrant在用于局部晚期或转移性HR+/HER2-乳腺癌患者的II期临床研究，以及联合CDK4/6抑制剂哌柏西利用于HR+/HER2-晚期乳腺癌的III期研究均失败。赛诺菲遂终止Amcenestrant项目的所有临床试验。同一年，罗氏宣布其SERD口服药Giredestrant在II期研究中未能达到PFS主要终点，OS尚不成熟。2023年，在经历14年临床开发后，美纳里尼集团旗下子公司美纳里尼集团的ORSERDU（Elacestrant，艾拉司群）获FDA批准上市，用于治疗局部晚期或转移性乳腺癌的绝经后女性或者成年男性，患者具有HR+/HER2-和ESR1突变，并且接受了至少一种内分泌治疗后病情出现进展。艾拉司群成为首个成功上市的SERD口服药物。看来，SERD口服药的研发远不如想象般容易。幸运的是，阿斯利康近日也传来好消息。2月26日，阿斯利康宣布，其SERD口服药物camizestrant在治疗HR+局部进展或转移性乳腺癌患者的III期SERENA-6临床研究中达到主要终点。即camizestrant 联合CDK4/6抑制剂在PFS的主要终点方面显示出具有统计学意义和临床意义的改善。该试验新颖之处在于，利用ctDNA监测来识别患者的内分泌耐药性早期迹象和ESR1突变的出现。ESR1基因突变是内分泌耐药的关键驱动因素，大约30%的内分泌敏感HR+疾病患者在一线治疗期间出现ESR1突变。SERENA-6研究表明，在检测到ESR1突变（尚无疾病进展）后，从芳香化酶抑制剂（阿那曲唑或来曲唑）转换为camizestrant联合CDK4/6抑制剂，可以延缓疾病进展并延长一线治疗的益处。至此，Camizestrant成为了首个证明与CDK4/6抑制剂联用时具有一线治疗获益的新一代SERD口服药物。在内分泌治疗领域，阿斯利康还率先推出了AKT抑制剂Capivasertib，该药于2023年11月，获FDA批准用于治疗HR+/HER2-局部晚期或转移性乳腺癌患者，这些患者在接受内分泌基础方案治疗过程中或之后疾病复发或进展。除在内分泌治疗不断进行自我迭代外，阿斯利康还推出了全球首款PARP抑制剂——奥拉帕利，也是首个利用DNA损伤修复通路缺陷来杀死癌细胞的靶向治疗药物。目前，在乳腺癌领域，奥拉帕利获批用于辅助治疗BRCA生殖系突变（gBRCAm）的HER2阴性高危早期乳腺癌患者，这是首款也是唯一一款获得批准治疗BRCA突变早期乳腺癌患者的疗法。在乳腺癌领域，阿斯利康产品已覆盖从早期到晚期、从绝经前到绝经后的HR+乳腺癌患者。3深耕技术平台 vs 多元合作创新，都有“美好的未来”第一三共在乳腺癌领域的异军突起，来自于对平台技术数十年磨一剑的专注。其ADC研发最早可追溯至20世纪80年代，经过40年迭代，其通过靶点选择及连接子、细胞毒药物的技术优化等，打造了独特的DXd-ADC技术平台，以实现精准靶向、高效低毒的技术优势。依托该平台，第一三共改良的DXd以10倍药物活性与极强的渗透细胞膜的能力，能够更好地发挥“旁观者效应”，这也是德曲妥珠单抗对于HER2低表达乳腺癌有优异疗效的关键因素。除德曲妥珠单抗之外，第一三共还布局了6款ADC药物，包括Dato-DXd（靶向TROP2 ADC），HER3-DXd（靶向HER3 ADC）， I-DXd（B7H3 ADC）和 R-DXd（CDH6 ADC） 等。其中Dato-DXd 由第一三共研发，第一三共和阿斯利康共同开发和商业化，是一款新型TROP2 ADC，具有抗肿瘤旁观者效应，且药物安全性更高。目前Dato-DXd已被日本药品与医疗器械管理局（PMDA）、FDA批准用于治疗既往接受过化疗和内分泌治疗的不可切除或转移性HR+/HER2阴性（IHC 0、IHC 1+或IHC 2+/ISH-）乳腺癌成人患者（商品名：Datroway）。此外，Dato-DXd的研究布局还拓展至三阴性乳腺癌（TNBC）的早期和晚期治疗领域。这类乳腺癌为雌激素受体（ER）阴性、孕激素受体（PR）阴性、以及HER2阴性，由于缺乏有效治疗靶点，且预后差，素有“乳腺癌之王”之称。对于TNBC，寻找新的有效疗法刻不容缓。第一三共和阿斯利康已经启动多项III期临床研究评估Dato-DXd单药或联合疗法治疗TNBC的潜力。第一三共凭借独有的DXd-ADC技术平台，在乳腺癌治疗领域后来居上，用创新实力重新定义疾病分类，重塑了乳腺癌治疗体系。阿斯利康则通过自研和外部合作，在乳腺癌领域成功搭建出了一个有规模有层次的产品管线。从他莫昔芬到氟维司群，从奥拉帕利到Capivasertib，再从氟维司群到Camizestrant，阿斯利康的产品覆盖多个前沿靶点，同时在现有药物基础上不断改良升级，占领创新高地，实现治疗场景全覆盖。对比第一三共和阿斯利康，两家药企虽然模式不同，但都心系研发，最终印证了创新突破与商业的共振逻辑。大浪淘沙，乳腺癌药物市场虽大，最终也只能奖赏专注研发、不断自我超越的真创新药企。参考文献：1.Latest global cancer data: Cancer burden rises to 19.3 million new cases and 10.0 million cancer deaths in 2020. Retrieved Nov 16 ,2020,fromhttps://www.iarc.who.int/faq/latest-global-cancer-data-2020-qa/.2.Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. The New England Journal of Medicine. 2022; 387(1):9-20.3.Curigliano G, Hu XC, Dent R, et al. Trastuzumab deruxtecan (T-DXd) vs physicians choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). 2024 ASCO. LBA1000.4.https://www.daiichisankyo.com/files/news/pressrelease/pdf/202412/20241227_E.pdf.