Granulocyte colony-stimulating factor(Shire Pharmaceuticals Services Ltd.)

FOSTER CITY, Calif.--( BUSINESS WIRE )--Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to Trodelvy ® (sacituzumab govitecan-hziy) for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has progressed on or after platinum-based chemotherapy. The Breakthrough Therapy Designation is based on results from the global Phase 2 TROPiCS-03 study ES-SCLC cohort, which showed encouraging results with Trodelvy as a second-line treatment for ES-SCLC. As recently presented at the IASLC 2024 World Conference on Lung Cancer, Trodelvy demonstrated promising antitumor activity in both platinum-resistant (PR) and platinum-sensitive (PS) disease, and the safety profile was consistent with previous Trodelvy studies. These data support further investigation of Trodelvy in ES-SCLC and Gilead plans to initiate a Phase 3 clinical trial in this patient population. Lung cancer is the second most diagnosed cancer in the U.S., and the leading cause of cancer-related deaths. Approximately 15% of lung cancer cases are SCLC, with nearly 70% of patients with SCLC diagnosed at extensive-stage, which occurs when the cancer has spread to both lungs or beyond the lungs to lymph nodes or other organs. For people with ES-SCLC whose disease does not respond to current first-line standard of care (platinum-based chemotherapy or immunotherapy), the prognosis is often poor, and treatment options are limited. There is an urgent need for new and more effective approaches to care that can improve survival and slow the progression of the disease. Breakthrough Therapy Designation is designed to expedite the development and regulatory review of investigational treatments for serious or life-threatening conditions that, based on preliminary clinical evidence, have the potential to substantially improve clinical outcomes compared with available therapy. This is the second Breakthrough Therapy Designation for Trodelvy. Trodelvy is the first and only approved Trop-2-directed antibody-drug conjugate (ADC) that has demonstrated meaningful survival advantages in two different types of metastatic breast cancers. Across Phase 3 trials, we are exploring Trodelvy alone or in combination with other agents across many diverse tumor types and stages of disease. This includes collaborations with partners in academia, industry and the global cancer community. About Trodelvy Trodelvy ® (sacituzumab govitecan-hziy) is a first-in-class Trop-2-directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and lung cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the tumor microenvironment through a bystander effect. Trodelvy is currently approved in more than 50 countries for second-line or later metastatic triple-negative breast cancer (TNBC) patients and in more than 40 countries for certain patients with pre-treated HR+/HER2- metastatic breast cancer. Trodelvy is being investigated for use in other TNBC and HR+/HER2- breast cancer populations, as well as a range of tumor types where Trop-2 is highly expressed, including small cell lung cancer and first-line metastatic non-small cell lung cancer where Trodelvy has shown clinical activity through the TROPiCS-03 proof-of-concept study and the EVOKE-02 proof-of-concept study, respectively. Trodelvy is also being studied in head and neck cancer and gynecological cancers. U.S. Indications for Trodelvy In the United States, Trodelvy is indicated for the treatment of adult patients with: Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. Unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting. U.S. Important Safety Information for Trodelvy BOXED WARNING: NEUTROPENIA AND DIARRHEA Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm 3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay. Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold Trodelvy until resolved to ≤Grade 1 and reduce subsequent doses. CONTRAINDICATIONS Severe hypersensitivity reaction to Trodelvy. WARNINGS AND PRECAUTIONS Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 64% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%. Withhold Trodelvy for absolute neutrophil count below 1500/mm 3 on Day 1 of any cycle or neutrophil count below 1000/mm 3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever. Administer G-CSF as clinically indicated or indicated in Table 1 of USPI. Diarrhea: Diarrhea occurred in 64% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 11% of patients. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments. Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.2%. The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions. Nausea and Vomiting: Nausea occurred in 64% of all patients treated with Trodelvy and Grade 3-4 nausea occurred in 3% of these patients. Vomiting occurred in 35% of patients and Grade 3-4 vomiting occurred in 2% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK 1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤1 . Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting. Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 58% in patients homozygous for the UGT1A1*28, 49% in patients heterozygous for the UGT1A1*28 allele, and 43% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 21% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 9% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function. Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose. ADVERSE REACTIONS In the pooled safety population, the most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (84%), decreased neutrophil count (75%), decreased hemoglobin (69%), diarrhea (64%), nausea (64%), decreased lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation (37%), increased glucose (37%), decreased albumin (35%), vomiting (35%), decreased appetite (30%), decreased creatinine clearance (28%), increased alkaline phosphatase (28%), decreased magnesium (27%), decreased potassium (26%), and decreased sodium (26%). In the ASCENT study (locally advanced or metastatic triple-negative breast cancer), the most common adverse reactions (incidence ≥25%) were fatigue, diarrhea, nausea, alopecia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes. In the TROPiCS-02 study (locally advanced or metastatic HR-positive, HER2-negative breast cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, alopecia, and constipation. The most frequent serious adverse reactions (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR were reported in 28% of patients, and 6% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes. DRUG INTERACTIONS UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy. UGT1A1 Inducers: Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy. Please see full Prescribing Information , including BOXED WARNING. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer, and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, Calif. Forward-Looking Statement This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials or studies, including those involving Trodelvy (such as TROPiCS-03); uncertainties relating to regulatory applications and related filing and approval timelines, including potential applications for programs and/or indications currently under evaluation; the possibility that Gilead may make a strategic decision to discontinue development of these programs and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Trodelvy, Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies. U.S. Prescribing Information for Trodelvy, including BOXED WARNING , is available at www.gilead.com . For more information about Gilead, please visit the company’s website at www.gilead.com , follow Gilead on X/Twitter (@GileadSciences) and LinkedIn (@Gilead-Sciences).

编者按：HR+/HER2-乳腺癌的新辅助治疗药物仍以内分泌治疗和化疗为主，但整体的疗效并不满意，远期获益并不明确。近年来，靶向于HER2的新型抗体偶联药物（ADC）在晚期HR+/HER2低表达乳腺癌已被证实有确切的疗效和安全性，其在早期治疗中的探索仍十分有限。在第47届圣安东尼奥乳腺癌研讨会（2024 SABCS）上，河南省肿瘤医院刘真真教授团队一项II期研究入选亮点壁报环节，该研究探讨了国产原研的新型HER2 ADC药物SHR-A1811用于HR+/HER2低表达乳腺癌新辅助治疗的疗效和安全性。《肿瘤瞭望》特邀刘真真教授介绍如下。 研究题目 SHR-A1811用于HR+/HER2低表达乳腺癌患者新辅助治疗：一项开放标签、单臂、两阶段、II期临床试验的第一阶段结果（摘要号：PS3-07）[1] 研究背景 激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性乳腺癌患者在新辅助化疗或内分泌治疗中达到病理完全缓解（pCR）的比例较低，pCR率分别为10%和5%。HER2低表达在HR阳性乳腺癌中较为常见，但HER2低表达患者的pCR显著低于HER2 0表达患者。抗HER2 ADC药物T-DXd在DESTINY-Breast 06研究中证实对HR+/HER2低表达晚期乳腺癌具有抗肿瘤活性。 SHR-A1811是一种新型HER2 ADC，也在HER2低表达晚期乳腺癌中显示出活性。我们开展的这项临床试验，旨在探讨SHR-A1811用于HR+/HER2-L乳腺癌患者新辅助治疗的疗效和安全性。 研究方法 这是一项基于Simon两阶段设计的开放标签、单臂II期临床试验。共需招募66例患者，第一阶段入组35例患者。如果有18例或更多患者有治疗反应，试验将进入第二阶段，额外招募31例患者。主要入组标准包括：年龄18-70岁，未接受过治疗，组织学确诊的浸润性乳腺癌，临床分期T2-3/N0-2M0，HR+/HER2低表达和Ki-67＞14%。符合条件的患者接受SHR-A1811（6.4 mg/kg静脉注射，每21天）共8个周期的治疗。主要研究终点是客观缓解率（ORR）；次要研究终点包括安全性、残余肿瘤负荷(RCB)0-1、pCR、无事件生存(EFS)。 △研究设计 研究结果 截至2024年6月17日，第一阶段的35例患者中有34例成功接受了研究方案并按计划完成了手术。所有入组人群中，74.3%（26/35）的患者为淋巴结阳性，85.7%（30/35）的患者为IIA/IIB期，14.3%（5/35）的患者为IIIA期，74.3%（26/35）的患者基线HER2表达为IHC 2+，25.7%（9/35）为IHC 1+。 △患者基线特征 研究达到了第一阶段的主要终点，ORR达74.3%（26/35），包括26例部分缓解（PR）和9例疾病稳定（SD）。34例手术患者中无患者达到病理完全缓解（pCR）。所有35例患者都报告了治疗相关不良事件（TRAEs），≥3级治疗相关不良事件（TRAEs）的发生率为65.7%（23/35），最常见的≥3级TRAEs包括中性粒细胞减少（48.6%，17/35）、白细胞减少（28.6%，10/35）、贫血（22.9%，8/35）、腹泻和血小板计数减少（各11.4%，4/35）。对13例患者进行了以G-CSF为主的支持治疗后，未发生≥3级的中性粒细胞减少AE，无间质性肺病（ILD）及治疗相关死亡报道。 △疗效汇总和疗效瀑布图 △常见（≥20%）的TRAEs 研究结论 SHR-A1811在HR+/HER2-L乳腺癌患者新辅助治疗中显示出良好的抗肿瘤活性和可控的安全性。研究的第二阶段正在进行中。 研究者说 在乳腺癌患者中，约有55%存在HER2低表达，而且相较于HR-乳腺癌，HR+乳腺癌的HER2低表达比例更高（55.2% vs 28.1%），具有更低的Ki-67指数和更小的肿瘤直径[2-3]。目前，HR+/HER2-早期乳腺癌的新辅助治疗以化疗和内分泌治疗为主，但总体的病理完全缓解（pCR）较低，仅为5%～10%；而且HER2低表达患者的pCR率低于HER2零表达患者[4]。此外，有关pCR能否作为EFS、RFS替代终点的问题仍有争议，临床研究也评价了ORR、RCB等其他指标作为新辅助治疗替代终点，并且使用Ki-67增殖指数、术前内分泌预后指数（PEPI）等标志物来选择对新辅助治疗反应更好的患者。 DB-04研究[5]证实了T-DXd在HER2低表达乳腺癌中的疗效，开启了临床对HER2低表达分类治疗的关注。SHR-A1811是我国自主研发的新型HER2 ADC，由一种人源化HER2靶向单克隆抗体（曲妥珠单抗），通过新型可裂解的四肽连接子与DNA拓扑异构酶 I 抑制剂(SHR169265)偶联而成，尤其是载荷SHR169265加入了手性环丙基，优化结构，使其具有更好的稳定性和膜透性，从而增强“旁观者效应"[6]。2024年发表于JCO的I期临床试验显示，SHR-A1811在多种既往多线治疗失败的晚期实体瘤中均展现了显著的抗肿瘤活性，其诱导的肿瘤反应不仅强烈且持久[7]。 我们这项研究将SHR-A1811用于HR+/HER2低表达早期乳腺癌的新辅助治疗，显示了较高的疗效，ORR达74.3%，尽管没有患者达到pCR。再者，SHR-A1811的安全性可控，常见的≥3级TRAEs以血液学毒性为主，此类不良事件的临床管理经验成熟；该研究中没有发现间质性肺病（ILD）事件。新型ADC用于新辅助治疗已有研究报道。例如2022年SABCS大会报道的TALENT研究[8]，T-DXd用于HR+/HER2低表达乳腺癌新辅助治疗的ORR为75%，仅有1/17例患者达到pCR。这两项研究均显示相当水平的ORR和pCR率。未来我们会进一步报道次要终点RCB、EFS等相关数据。另外值得注意的是，本次SABCS大会还报道了SHR-A1811单药或联合小分子TKI吡咯替尼HER2+早期乳腺癌新辅助治疗的Ⅱ期FASCINATE-N研究[9]，结果显示二者的pCR率分别为63.2%和62.5%，与标准方案PCbHP（白蛋白结合型紫杉醇+卡铂+曲妥珠单抗+帕妥珠单抗64.4%）疗效相当。 总之，SHR-A1811作为一种新型的HER2 ADC，在本项研究用于HR+/HER2低表达乳腺癌患者新辅助治疗中，表现了积极的抗肿瘤活性和可控的安全性，是此类患者一种潜在的新辅助治疗策略。 研究sub焦得闯教授现场参会 参考文献 上下滑动查看更多内容 [1]Zhenzhen Liu,et al.SHR-A1811 as Neoadjuvant Treatment in Patients with HR-Positive, HER2- low Breast Cancer: The first-stage results from an open-label, single-arm, two-stage, phase II clinical triall.SABCD 2024;PS3-07 [2]Prat A, Bardia A, Curigliano G, et al. An Overview of Clinical Development of Agents for Metastatic or Advanced Breast Cancer Without ERBB2 Amplification (HER2-Low). JAMA Oncol. Published online September 15, 2022. doi:10.1001/jamaoncol.2022.4175 [3]Tarantino P, Hamilton E, Tolaney SM, et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape. J Clin Oncol. 2020;38(17):1951-1962. doi:10.1200/JCO.19.02488 [4]Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021;22(8):1151-1161. doi:10.1016/S1470-2045(21)00301-6 [5]Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690 [6]Herui Yao, et al. Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 (a HER2-targeting ADC) in HER2-expressing/mutated advanced solid tumors: a global phase 1, multi-center, first-in-human study. 2023 AACR, CT175. [7]Yao H, Yan M, Tong Z, et al. Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial. J Clin Oncol. 2024;42(29):3453-3465. doi:10.1200/JCO.23.02044 [8]San Antonio Breast Cancer Symposium 2022：TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan (T-DXd) with or without anastrozole for HER2-low, HR+ early-stage breast cancer [9]Junjie Li,et al.HER2-Directed Antibody-Drug Conjugate SHR-A1811 in the Neoadjuvant Treatment of HER2-positive Early Breast Cancer: a Prospective, Randomized, Open label, Phase 2 Trial.SABCD 2024;GS1-04 刘真真 教授 河南省肿瘤医院 乳腺科主任，主任医师 河南省乳腺癌诊疗中心主任 国家肿瘤质控中心乳腺癌专业委员会委员 河南省肿瘤诊疗质量控制中心乳腺癌专家委员会主任委员 河南省临床肿瘤学会（HSCO）乳腺癌专业委员会主任委员 中国抗癌协会乳腺癌专业委员会常务委员 中华医学会肿瘤学分会乳腺癌学组委员 中华医学会外科分会乳腺外科学组委员 中国临床肿瘤学会乳腺癌专家委员会常委 中国医师协会外科分会乳腺外科医师委员会委员 河南省医学会乳腺病学分会候任主任委员 （来源：《肿瘤瞭望》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。