Labetuzumab govitecan

Results Show Encouraging Activity of Trodelvy in Combination with KEYTRUDA in 1L Metastatic NSCLC Across all PD-L1 Subgroups and Histologies Studied Results Support Further Investigation of Trodelvy in Combination with KEYTRUDA in 1L Metastatic NSCLC FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced promising early data from the global, open-label, Phase 2 EVOKE-02 study evaluating Trodelvy® (sacituzumab govitecan-hziy) in combination with Merck’s anti-PD-1 therapy KEYTRUDA® (pembrolizumab) with or without platinum agents in patients with previously untreated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations. The results are being presented today at the IASLC 2023 World Conference on Lung Cancer (#WCLC23) hosted by the International Association for the Study of Lung Cancer. The preliminary analysis of the EVOKE-02 study includes results of two cohorts: Trodelvy in combination with KEYTRUDA in first-line advanced or metastatic squamous/non-squamous NSCLC with PD-L1 tumor proportion score (TPS) ≥ 50% (Cohort A) and TPS < 50% (Cohort B). In Cohort A (n=29), confirmed and unconfirmed objective response rate (ORR) was 69%, and disease control rate (DCR) was 86%. In Cohort B (n=32), confirmed and unconfirmed ORR was 44%, and DCR was 78%. Across both cohorts, the ORR was 56%, and DCR was 82%. Median duration of response (DoR) was not reached at the time of data cut-off, and DoR rate at six months was 88% in both cohorts. “Patients with metastatic NSCLC continue to need novel treatment options. The data from the EVOKE-02 study gives us confidence in the clinical activity of sacituzumab govitecan in combination with pembrolizumab in first-line metastatic NSCLC patients,” said Byoung Chul Cho, MD, PhD, Professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine. “The positive response rates and duration of response across patients treated with the combination shows promise compared with historical responses to anti-PD1 monotherapy in this setting. These data support further investigation of sacituzumab govitecan as a potential IO-combination option in first-line metastatic NSCLC.” “The EVOKE-02 trial is the first data presented from several Gilead studies dedicated to exploring Trodelvy’s potential in lung cancer,” said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. “These data are very encouraging and confirms our approach for the ongoing Phase 3 EVOKE-03 study of Trodelvy in combination with KEYTRUDA vs. KEYTRUDA monotherapy for patients in first-line PD-L1-high metastatic NSCLC. We look forward to potentially bringing a new treatment option to previously untreated metastatic NSCLC patients.” The safety pro Trodelvy in combination with KEYTRUDA in the EVOKE-02 study was consistent with the known safety of each agent. The most common any-grade TEAEs were diarrhea (54%), anemia (48%), and asthenia (38%). Known key safety events for Trodelvy were not increased with the addition of KEYTRUDA. The immune related adverse events were consistent with the known safety pro KEYTRUDA. Discontinuation rates due to adverse events were 18%. One treatment related death was observed due to sepsis. Gilead entered into two clinical trial collaboration and supply agreements with Merck (known as MSD outside of the United States and Canada) in January 2022 to evaluate the combination of Trodelvy and Merck’s KEYTRUDA in the Phase 2 EVOKE-02 signal-seeking study and the ongoing Phase 3 EVOKE-03 study in first-line NSCLC. The use of Trodelvy for the treatment of NSCLC and the use of Trodelvy in combination with KEYTRUDA for any use is investigational, and the safety and efficacy for these uses have not been established or approved by any regulatory agency globally. Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information. About Metastatic Non-Small Cell Lung Cancer Worldwide, more than two million people were diagnosed with lung cancer in 2020. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for up to 85% of diagnoses. It is a cancer with high Trop-2 expression (89 – 100%) and about half of NSCLC cases are diagnosed at the metastatic stage (57%), when treatment is especially difficult. Even in patients whose disease is caught early, half will eventually progress to the metastatic stage within five years. Newly diagnosed patients have several treatment options including platinum-based therapy, checkpoint inhibitors and targeted therapies. About the EVOKE-02 Study The EVOKE-02 study is an open-label, global, multi-center, multi-cohort, Phase 2 study evaluating Trodelvy in combination with KEYTRUDA with or without chemotherapy regardless of PD-L1 expression in patients with advanced or metastatic NSCLC without actionable genomic alterations. Patients were assigned to cohorts according to disease status or PD-L1 expression. Patients were assigned to Cohorts A or B according to Tumor Proportion Score (TPS) status: Cohort A enrolled patients with squamous/non-squamous NSCLC with TPS ≥ 50%. Cohort B enrolled patients with squamous/non-squamous NSCLC with TPS < 50%. Patients enrolled in Cohorts A or B received the combination of Trodelvy and KEYTRUDA. Following enrolment in a safety run-in cohort, patients will be enrolled in Cohorts C or D according to disease status for carboplatin combinations. Cohort C enrolled patients with non-squamous NSCLC with any PD-L1 expression level. Cohort D enrolled patients with squamous NSCLC with any PD-L1 expression level. Patients enrolled in Cohorts C or D received Trodelvy plus KEYTRUDA plus platinum agent. The primary endpoints are objective response rate (ORR) as assessed by independent review per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and percentage of participants experiencing dose-limiting toxicities (DLTs) per dose level in the safety run-in cohorts. Additional efficacy measures include progression-free survival (PFS), overall survival (OS), duration of response (DoR) and disease control rate (DCR). More information about EVOKE-02 is available at . KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. 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 bladder 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 microenvironment. Trodelvy is approved in almost 50 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. Trodelvy is also approved in the U.S. and the European Union to treat certain patients with pre-treated HR+/HER2- metastatic breast cancer. In the U.S., Trodelvy also has accelerated approval for treatment of certain patients with second-line metastatic urothelial cancer (UC); see below for the full U.S. indication for Trodelvy. Trodelvy is also being developed for potential investigational use in other TNBC, HR+/HER2- and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer. 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. Locally advanced or metastatic urothelial cancer (mUC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 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/mm3 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/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 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 NK1 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. In the TROPHY study (locally advanced or metastatic urothelial cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, any infection, alopecia, decreased appetite, constipation, vomiting, rash, and abdominal pain. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes. 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, and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California. Forward-Looking Statements 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 within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials, including those involving Trodelvy; uncertainties relating to regulatory applications for Trodelvy and related filing and approval timelines, including with respect pending or potential applications for the treatment of metastatic TNBC, HR+/HER2- metastatic breast cancer, metastatic UC, metastatic NSCLC, metastatic SCLC, head and neck cancer, and endometrial cancer, in the currently anticipated timelines or at all; Gilead’s ability to receive regulatory approvals for such indications in a timely manner or at all, and the risk that any such approvals may be subject to significant limitations on use; the possibility that Gilead may make a strategic decision to discontinue development of Trodelvy for such indications and as a result, Trodelvy may never be commercialized for these indications; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2023, 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. U.S. Prescribing Information for Trodelvy including BOXED WARNING, is available at . Trodelvy, Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies. For more information about Gilead, please visit the company’s website at or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. View source version on businesswire.com: Contacts Jacquie Ross, Investors investor_relations@gilead.com Meaghan Smith, Media public_affairs@gilead.com Source: Gilead Sciences, Inc. View this news release online at:

截至目前，关于ADC在实体瘤中的毒副作用及防范措施，已知如下：①ADC的适应症正在迅速扩大，逐渐从晚期阶段转向早期阶段，从单一疗法转向联合策略。②大多数ADC的毒性特征与其有效载荷的细胞毒性相似。③某些ADC也可以观察到非常规和潜在的危及生命的毒性，需要对这些事件有更多的了解，并优化诊断和管理实践。④业界正在寻求多种药理学修饰策略以试图改善ADC的耐受性，包括抗体部分，接头和/或细胞毒性有效载荷的分子改变。⑤在随机试验中探索不同剂量以及研究适应反应的剂量策略可以优化ADC的使用，这可以最大限度地提高其对每种适应症的治疗价值。⑥目前正在进行广泛的努力，以确定接受ADC治疗的患者的毒性生物标志物，并开发能够预测和/或早期发现毒性的诊断工具。  01  已获批实体瘤ADC：结构、主要毒性、原因解读到目前为止，FDA和EMA已批准六种ADC药物用于实体瘤患者。下图描述了每种ADC的组成（就靶向抗原，单克隆抗体类型，有效载荷和接头而言）、目前批准的适应症、每种药物观察到的最常见毒性（如图1和表1）。每个ADC的不良反应特征通常是靶向和脱靶效应的混合，后者通常决定最大耐受剂量。在许多ADC中不同程度地观察到的常见不良反应包括疲劳，脱发，血细胞减少和胃肠道紊乱。 图1：目前获批于实体瘤的ADC结构和主要毒性（图注：CINV，化疗引起的恶心和呕吐；GGFG，Gly-Gly-Phe-Gly；DAR，药物与抗体的比例；DXd，deruxtecan；ILD，间质性肺病；MCC，马来酰亚胺甲基环己烷-1-羧酸酯；MMAE，单甲基auristatin E；TOPO1，拓扑异构酶1；Trop2，滋养层细胞表面抗原2；VCit，缬氨酸瓜氨酸。）表1 ：FDA批准的ADC在实体瘤患者中的毒性（表注：ADC，抗体-药物偶联物；AE，不良事件；ALT，丙氨酸氨基转移酶；AST，天冬氨酸转氨酶；DXd，deruxtecan；FRα，叶酸受体-α；GGFG，Gly-Gly-Phe-Gly；HR，激素受体；ILD，间质性肺病；MCC，马来酰亚胺甲基环己烷-1-羧酸酯；MMAE，单甲基auristatin E；NSCLC，非小细胞肺癌；TNBC，三阴性乳腺癌；Trop2，滋养层细胞表面抗原2。a仅批准。b包括三例与治疗相关的死亡。c. Data仅在会议摘要中提供。）鉴于分子量较大，ADC通常通过静脉注射给药。体内实验的数据表明，这种给药途径可能与某些ADC的活性降低和严重的皮肤毒性有关。注射后，理想地ADC应当在循环中保持完整，并且仅在靶向肿瘤细胞内或附近释放其细胞毒性有效载荷。ADC结构的微小改变通常会导致药物的药代动力学和/或药效学特征发生巨大变化（表2）。注射后，ADC通常作为完整ADC（>组成的90%），未结合药物（或药物接头）和解离抗体的动态混合物在血流中循环。从循环中，ADC逐渐扩散到身体组织的间质空间，最终到达靶向肿瘤细胞，估计实体瘤的比例约为0.1%。一旦ADC到达肿瘤微环境（TME），通常认为它会结合癌细胞表面表达的靶抗原，在内体内发生内化，并通过溶酶体中的化学或酶促裂解释放有效载荷，最终导致坏死或凋亡，这取决于有效载荷的作用机制和靶位点达到的浓度。更疏水的有效载荷（例如单甲基auristatin E（MMAE）和exatecan衍生物）能够在细胞内与抗体解偶联后扩散到靶细胞之外，从而对抗原阴性细胞产生“旁观者杀伤”作用，可以增强某些ADC的抗肿瘤活性。这种效应也构成毒性的决定因素：释放的有效载荷也可以通过被动扩散或转运蛋白介导的摄取进入相邻的非恶性细胞，可能导致脱靶细胞毒性。除了传统上公认的肿瘤细胞内靶向有效载荷释放机制之外，某些ADC不需要抗原参与和内化就能释放细胞毒性有效载荷。例如，sacituzumab-govitecan被证明可以在TME内细胞外释放其SN-38有效载荷，这种机制可能解释了这种和其他ADC的活性和毒性。表2 ：ADC毒性的药理学决定因素如上所述，ADC的大多数部分不到达肿瘤细胞，并且通过特异性和非特异性机制的组合逐渐降解，然后消除，包括靶介导的清除，Fcγ受体（FcγR）介导的摄取和/或位于各种组织中的巨噬细胞的胞饮作用。重要的是，在进行降解和排泄之前，利用巯基马来酰亚胺化学物质（占大多数批准的ADC）从ADC释放的有效载荷-连接子复合物可以与血清白蛋白的游离半胱氨酸残基反应，从而产生长寿命的白蛋白-连接子-有效载荷加合物。  02  谈一谈ADC的毒性（从结构入手）ADC具有模块化的结构，对其任何关键组件的微小修改都可能导致临床特征的重大变化（图2）。在本节中将剖析每个ADC成分的相对贡献，以及患者特征在所观察到的毒性类型和严重程度中的作用。 图2:ADC毒性的决定因素（图注：Cit，瓜氨酸；谷胱甘肽；MMAE，单甲基auristatin E；MMAF，单甲基auristatin F；Trop2，滋养层细胞表面抗原2。高度稳定的接头与某些不良反应的发生率增加有关，包括眼部毒性，神经毒性或肝毒性，具体取决于特定的药物。）2.1 有效载荷根据ADC开发背后的基本原理，预期靶向抗原将确定药物的毒性特征。但是临床经验表明，与ADC相关的大多数不良事件在频谱、发生率和严重程度上与有效载荷主干相似，并且共享相同有效载荷的不同ADC通常具有相似的毒性特征，而不管目标抗原的差异如何。这些毒性可以大致分为与抗体靶向的抗原无关的脱靶，脱瘤效应，以及由抗体与位于非恶性组织中的同源抗原结合产生的靶向，脱瘤效应。脱靶，肿瘤外毒性在大多数ADC的毒性特征中占主导地位，通常导致类似有效载荷的不良反应特征。ADC的脱靶，肿瘤外毒性的关键机制被认为至少部分与体循环中有效载荷的过早解偶联有关，这导致游离细胞毒性有效载荷扩散到肿瘤外区室。这种有效载荷通常是亲脂性分子，能够渗透质膜并进入非靶向非恶性细胞。如前所述，部分有效载荷也可能与血清白蛋白和其他含有巯基的循环血浆蛋白结合，这可以增加有效载荷-接头复合物的半衰期，并可能导致有效载荷沉积在非恶性组织中。除了荷载从ADC中解离的机制外，还有其他机制被认为介导非恶性细胞对细胞毒性荷载的暴露，包括非特异性内吞作用，在非恶性细胞内完整ADC的内吞作用；以及靶外、受体介导的摄取作用，这是由抗体骨干的Fc区与免疫细胞表达的Fc受体相互作用引起的。后一种机制可能与高度稳定的ADC更相关，这些ADC与荷载的过早解离和释放进入循环有限相关，因此更有可能将完整的ADC遇到非恶性组织。无论机制如何，非恶性细胞对有效载荷的脱靶暴露程度最终决定了药剂的耐受性，使得有效载荷的选择成为任何ADC设计中的关键决策。2.2 链接子如上所述，在接受ADC的患者中导致脱靶毒性的主要机制可能与从缀合物释放有效载荷的时间和定位有关。这些特征在很大程度上取决于接头的稳定性和药理结构，因此可能对ADC的毒性特征产生重大影响。理想的接头足够稳定以将有效载荷递送至预期部位，但也足够不稳定以在肿瘤内或肿瘤附近释放有效量的有效载荷。一般来说，不太稳定的接头导致游离有效载荷较早释放到循环中，细胞毒素峰值浓度较高，典型的化疗相关毒性（如血细胞减少症，脱发和/或胃肠道毒性）增加。更稳定的接头可以导致完整ADC的长时间循环，有效载荷稍后释放。这方面可能解释了某些高度稳定的ADC的特殊毒性特征，其中一些已被发现具有有限的化疗相关毒性，但眼部毒性的发生率出乎意料地高。这些发现表明，在试图确定ADC稳定性时应保持平衡，ADC有效载荷的过度释放和保留都可能导致意外的毒性。除了接头稳定性之外，用于将有效载荷与抗体连接的特定化学物质以及药物与抗体的比率（DAR）都可能对ADC的毒性特征产生影响。2.3 抗体ADC的大部分毒性由接头-有效载荷复合物决定，但是尽管是具有相同有效载荷和接头的ADC，由于靶向，非肿瘤毒性，其不良反应也可能有很大差异。这些事件与特定靶标的参与或有效载荷在表达ADC靶标的非恶性组织中的积累有关，因此根据靶抗原而变化很大。在某些情况下，靶向毒性可能主导ADC的安全性：基于EphA2靶向MMAF的ADC MEDI-547就是这种情况，即使在低剂量下，它也与危及生命的出血和凝血事件有关，这可能与EphA2的靶向参与有关，EphA2是一种与新血管生成有关的受体。为了最大程度地降低这种靶向毒性的风险，需要仔细选择ADC靶标，优先推荐肿瘤细胞（理想高表达）和非恶性细胞（理想低表达或不表达）之间表达的抗原。总体而言，尽管抗体相关毒性通常不会主导ADC的不良反应，但已经观察到几种严重的靶向，肿瘤外毒性或抗体Fc部分介导的毒性。这些观察结果突出了这些化合物作用机制的复杂性以及每个ADC组分与耐受性概况的相关性。2.4 患者相关因素除了在各种ADC中观察到的毒性特征的差异之外，在接受相同ADC的不同患者中发生的不良反应的频谱和等级中也存在相关程度的异质性。多种与患者相关的因素可能会影响这些药物的药代动力学和药效学，包括基线器官功能，合并症的存在，参与ADC代谢或其分解代谢的酶的多态性等。最后，已发现种族会影响ADC代谢：例如，与其他国家的患者相比，日本种族患者的平均血清T-DXd浓度增加了20%，这一发现可能解释了在该患者人群中观察到的ILD发生率较高。  03  与联合用药策略相关的不良反应ADC为联合策略提供了多种机会，目的是实现加性或协同抗肿瘤活性。然而，这些组合还存在增加方案毒性的风险，这可能是由于重叠的不良反应或意外的协同作用。在本节中，我们概括了与不同类别的抗癌剂一起施用的ADC组合的可用毒性数据（表3和表4）。3.1 ADC联合化疗结合不同类型的化疗是克服耐药性和提高治疗效果的既定方法。然而，将ADC与化疗相结合会带来一些与重叠毒性相关的挑战。大多数试验的数据似乎表明，当ADC与传统化疗相结合时，毒性增加不可忽略，这可能是由于ADC有效载荷的脱靶、肿瘤外效应导致的重叠毒性。表3 ：ADC联合化疗在实体瘤患者中的毒性观察（表注：5-FU，5-氟尿嘧啶；ADC，抗体-药物偶联物；ALT，丙氨酸氨基转移酶；AST，天冬氨酸转氨酶；Dato DXd，datopotamab deruxtecan；DLT，剂量限制性毒性；ILD，间质性肺病；LABC，局部晚期乳腺癌；MBC，转移性乳腺癌；NSCLC，非小细胞肺癌；NR，未报告；T-DM1， ematansine；T-DXd，曲妥珠单抗-德鲁替康。）3.2 ADC联合内分泌治疗内分泌治疗是一种常见的治疗策略，其总体目标是通过阻断激素产生或激素促进肿瘤细胞生长的能力来抑制激素依赖性癌症的生长。这种药剂通常耐受性良好，并且频繁给药于患有乳腺癌或前列腺癌的患者。总的来说，ADC与内分泌治疗相联合似乎与毒性增加无关。3.3 ADC与免疫疗法相结合ADC与化疗具有引发免疫原性细胞死亡的潜力，同时还通过抗体的Fc结构域具有潜在的免疫刺激功能，从而为与免疫检查点抑制剂（ICI）的组合提供了思路。迄今为止，还没有观察到ICI和T-DXd、Dato-DXd或sacituzumab-govitecan的组合具有协同毒性的相关信号。该领域的进一步数据预计来自正在进行的随机III期试验（NCT05629585、NCT05382286和NCT05633654），这些试验有望澄清除T-DM1外将ICI与ADC结合的方案的毒性特征。3.4 ADC与靶向治疗联合在目前批准的ADC中，T-DM1是与靶向制剂联合使用时，具有最多活性和安全性证据的制剂。T-DM1与HER2酪氨酸激酶抑制剂图卡替尼的组合在Ib期试验中进行了测试，发现其是可耐受的，尽管存在频繁的胃肠道和肝脏毒性。HER2CLIMB-02的 Ib期试验中，T-DM1还与CDK4和CDK6抑制联合进行了测试，没有观察到DLT。在一项纳入转移性TNBC患者的Ib期试验中，将西妥珠单抗戈韦替康与PARP抑制剂塔拉佐帕尼联合使用，导致多发性DLT（大多数入选患者患有发热性中性粒细胞减少症）。最后，在涉及铂耐药性卵巢癌患者的Ib期试验中，评估了将抗VEGFA抗体贝伐单抗添加到米韦妥昔单抗-索拉韦坦辛中，产生了与ADC单独的毒性相当的毒性特征。表4 ：ADC联合其他疗法对实体瘤患者的毒性观察（表注：ADC，抗体-药物偶联物；不良事件，不良事件；ALT，丙氨酸氨基转移酶；AST，天冬氨酸转氨酶；ET，内分泌治疗；FRα，叶酸受体-α；HR，激素受体；ILD，间质性肺病；NACT，新辅助化疗；T-DM1，曲妥珠单抗ematansine；T-DXd，曲妥珠单抗-德鲁替康；TNBC，三阴性乳腺癌。）  04  优化ADC安全性的新兴策略在临床实践中，已经采取了几种策略来预防或优化管理与ADC相关的毒性（图3）。 4.1 剂量优化策略考虑到与ADC相关的许多毒性的剂量依赖性，人们相当关注剂量和给药方案的优化，试图提高治疗指数。为此，已经采用了五种经典的剂量优化策略，包括体重剂量上限、治疗持续时间上限、剂量频率优化、反应引导的剂量适应和随机剂量发现研究。4.2 优化ADC设计ADC工程和其他优化策略是最大化制剂的疗效和安全性的重要方法。事实上，每个ADC成分的设计创新可以实现药理学特性的微调，并对耐受性产生潜在影响。4.3 抗体部分的创新目前批准和研究的大多数ADC都针对在非恶性组织中不同程度异质表达的靶点。探针-药物偶联物（PDC）的产生提供了一个可能降低靶向、非肿瘤毒性发生率的工程策略的例子。除了掩蔽抗体的结合区之外，目前正在尝试沉默抗体Fc结构域，以减少与免疫细胞Fc介导的ADC摄取相关的脱靶、肿瘤外毒性。另一种改善ADC向肿瘤部位的递送并潜在地降低靶向毒性发生率的策略是将有效载荷与双特异性抗体而不是常规抗体结合。与常规抗体相比，双特异性抗体在肿瘤细胞中具有更高的选择性和更好的内化。4.4 连接子技术的创新目前正在开发多种旨在提高ADC在系统循环中稳定性的策略，以优化安全性。这些方法能够制备具有可预测DAR和有效载荷附着位点的同质ADC，这可能与改善耐受性和更可预测的药代动力学有关。临床前证据表明，这些结合策略可以改善安全性。临床前数据表明，使用该策略开发的ADC保留了活性并改善了药代动力学特性，目前正在进行临床测试。4.5 有效载荷方面的创新为了提高单个有效载荷ADC的治疗指数，已经开发了具有与同一单克隆抗体连接的两种不同类型有效载荷的新构建体。临床前数据已经证实了这种方法的可行性和高抗肿瘤活性，其构建体例如与MMAE和MMAF偶联的HER2靶向抗体和与MMAE及α-鹅膏菌素偶联的FGF2靶向抗体。此外，除了抗微管剂、拓扑异构酶I抑制剂和DNA嵌入剂之外，还正在探索新的有效载荷。这些有效载荷包括其他细胞毒性分子（如拓扑异构酶II抑制剂或抑制转录或翻译的试剂）以及具有非常规有效载荷的ADC，如免疫刺激分子、异源双功能蛋白质降解剂和酪氨酸激酶抑制剂。ADC与有效载荷中和抗体片段的联合给药是另一项旨在提高ADC耐受性的创新。临床前数据表明，当在异种移植物模型中将HER2靶向的基于MMAE的ADC与人源化抗MMAE Fab片段ABC3315联合给药时，化疗相关毒性降低，小鼠模型中体重减轻得到改善，并保留了活性。4.6 药物基因组学识别ADC治疗后发生不良事件风险最大的患者是改善此类患者临床管理的重要一步。总体而言，数据表明，药物基因组参数可能对某些ADC的安全性产生相关影响。随着新型ADC的开发，在设计早期试验时考虑纳入药物基因组图谱可能是一种合理的方法，可以确保安全性不会在特定人群和/或个体间遗传变异中受到过度影响。4.7 诊断工具早期检测和更好地管理ADC诱导的不良事件的另一种潜在方法涉及使用可穿戴生物传感器（WBS）。这些技术的快速发展可能有助于对有风险的患者进行ILD的早期诊断，有助于识别ILD的急性加重，并支持实时临床决策。  总结与展望  ADC在一系列实体瘤中改善了传统化疗方案的活性。尽管它们具有理想的靶向作用机制，但大多数ADC仍然具有频繁且有时危及生命的毒性。鉴于其适应症的迅速扩大，对这些不良反应及其管理的认识以及预防和减轻ADC相关毒性的努力至关重要。这些包括在将ADC与其他抗癌药物联合使用时仔细注意协同或重叠毒性的风险，以及在早期疾病中开发和测试新型ADC时的谨慎，其中每个适应症都需要专门平衡风险和收益。ADC设计，药物基因组学测试和WBS的创新，以及通过专门的前瞻性试验对ADC剂量优化的更多关注，可能有助于利用这类极具前景的抗癌药物的潜力，而这类药物仍远未得到充分探索。 主要参考文献 [1] Tarantino P, Ricciuti B, Pradhan SM, Tolaney SM. Optimizing the safety of antibody-drug conjugates for patients with solid tumours. Nat Rev Clin Oncol. 2023 Aug;20(8):558-576. doi: 10.1038/s41571-023-00783-w. Epub 2023 Jun 9. PMID: 37296177.[2] Jiang, Z. et al. A multiple center, open-label, single-arm, phase II clinical trial of MRG002,an HER2-targeted antibody-drug conjugate, in patients with HER2-low expressing advanced or metastatic breast cancer. J. Clin. Oncol. 40, 1102–1102 (2022).[3] Yamaguchi, K. et al. Trastuzumab deruxtecan in anti–-human epidermal growth factor receptor 2 treatment-naive patients with human epidermal growth factor receptor 2-low gastric or gastroesophageal junction adenocarcinoma: exploratory cohort results in a phase II trial. J. Clin. Oncol. 41, 816–825 (2023).[4] Nguyen, T. D., Bordeau, B. M. & Balthasar, J. P. Mechanisms of ADC toxicity and strategiesto increase ADC tolerability. Cancers 15, 713 (2023).[5] Hasan, M. M., Laws, M., Jin, P. & Rahman, K. M. 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