Fam-trastuzumab deruxtecan-NXKI

- Clinical development for both the investigational CD47-inhibitor evorpacept and the novel EGFR-targeted antibody-drug conjugate ALX2004 remains on track following strong 2025 execution; company anticipates multiple meaningful data sets and milestones in the coming 12 to 18 months - - Evorpacept biomarker strategy validated by data from both the Phase 2 ASPEN-06 gastric cancer trial and the Phase 1b/2 breast cancer trial, independently suggesting CD47 overexpression is predictive of evorpacept activity and drives durable benefit in HER2-positive cancers - - Full biomarker analysis from Phase 1b/2 evorpacept-zanidatamab combination trial accepted for poster presentation at ESMO Breast Cancer 2026 Annual Congress - - Phase 2 ASPEN-09 breast cancer trial is currently enrolling patients and will evaluate evorpacept efficacy by CD47 expression levels, with topline data anticipated mid-2027 - - Phase 1 trial evaluating ALX2004 continues to enroll patients in the third dose cohort; safety data from dose-escalation phase expected in 2H 2026 - - Company completed a $150 million registered offering of common stock and pre-funded warrants, extending cash runway through 1H 2028 inclusive of key clinical program milestones for evorpacept and ALX2004 - - Barbara Klencke, M.D., appointed to Chief Medical Officer on a permanent basis - - Company to host webcast on Friday, February 27, at 5:30 a.m. PT / 8:30 a.m. ET - SOUTH SAN FRANCISCO, Calif., Feb. 27, 2026 (GLOBE NEWSWIRE) -- ALX Oncology Holdings Inc. (“ALX Oncology”; Nasdaq: ALXO), a clinical-stage biotechnology company advancing a pipeline of novel therapies designed to treat cancer and extend patients’ lives, today reported financial results for the fourth quarter and full year 2025, and provided a corporate update. “Through strong execution of our targeted clinical development strategy in 2025, we have positioned ourselves to achieve multiple significant catalysts in the clinical programs for evorpacept and ALX2004, two potentially best- and first-in-class agents, in the coming 12 to 18 months,” said Jason Lettmann, Chief Executive Officer at ALX Oncology. “We are particularly pleased that recent topline biomarker data from the Phase 1b/2 trial evaluating evorpacept with zanidatamab in advanced HER2-positive breast cancer reinforce findings from the ASPEN-06 HER2-positive gastric cancer trial, suggesting that CD47 is a predictive biomarker for evorpacept response. These findings strengthen our confidence in the ongoing Phase 2 ASPEN-09-Breast trial, where we will evaluate patient responses by CD47 level to further define the predictive potential of this biomarker among patients with HER2-positive disease that has progressed following ENHERTU. “Additionally, we are pleased with the clinical progress of ALX2004, which has successfully cleared the first two dose cohorts in the ongoing Phase 1 trial. The potential of these two novel therapies, coupled with our substantial progress on their respective clinical programs, contributed to the successful completion of our recent financing. With our newly strengthened balance sheet, we now have the opportunity to deliver more robust and meaningful data readouts in both of our ongoing clinical programs, as reflected in our milestone updates,” said Lettmann. ALX Oncology Q4 and Full Year 2025 Highlights and Recent Developments Evorpacept Data from a pre-planned exploratory analysis of the Phase 2 ASPEN-06 clinical trial in gastric cancer showed that CD47 overexpression is a key predictive biomarker for evorpacept response and durable benefit in patients whose tumors have retained HER2 expression. Retained HER2 expression is defined as tumors that are HER2-positive following HER2-targeted treatment, as assessed by either a repeat tumor biopsy or HER2 gene amplification in circulating tumor DNA (ctDNA). These data were highlighted as part of a poster presentation at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in November 2025. In patients with retained HER2-positive and CD47-high gastric cancer (n=43), evorpacept + HERCEPTIN® (trastuzumab), CYRAMZA® (ramucirumab) and paclitaxel (TRP) generated a 65.0% objective response rate (ORR) versus 26.1% ORR for TRP alone.The duration of response (DOR) was three times longer in the evorpacept + TRP arm relative to TRP alone in these patients. Evorpacept + TRP generated a median DOR (mDOR) of 25.5 months versus 8.4 months mDOR for TRP alone. Progression-free survival (PFS) and overall survival (OS) data were also evaluated in these patients. Treatment with evorpacept + TRP resulted in a median PFS (mPFS) of 18.4 months versus 7.0 months for TRP alone, with a hazard ratio (HR) of 0.39. Treatment with evorpacept + TRP resulted in a median OS of 17 months versus 9.9 months for TRP alone, with an HR of 0.70. Consistent with the results from the ASPEN-06 trial, topline data from an exploratory analysis in the Phase 1b/2 trial of evorpacept with investigational zanidatamab in advanced HER2-positive breast cancer suggest that CD47 expression level helps predict therapeutic response. Researchers had previously reported primary trial results showing a 56% (5/9) confirmed objective response rate (cORR) and an mPFS of 7.4 months in the nine patients with centrally confirmed HER2-positive breast cancer who received the investigational combination (2024 San Antonio Breast Cancer Symposium).In January 2026, ALX Oncology announced topline data from the exploratory analysis conducted to identify biomarkers of response to the evorpacept/zanidatamab combination. These findings show that among patients with centrally confirmed HER2-positive breast cancer, responses were largely restricted to patients with higher CD47 expression.The full Phase 1b/2 trial biomarker analysis has been accepted for poster presentation at the European Society for Medical Oncology (ESMO) Breast Cancer 2026 Annual Congress on May 7, 2026, in Berlin. The Phase 2 ASPEN-09-Breast trial evaluating evorpacept plus trastuzumab and physician’s choice of chemotherapy in patients with HER2-positive breast cancer previously treated with ENHERTU® (fam-trastuzumab deruxtecan-nxki) began enrollment in January 2026, and site activation remains on track globally. ALX Oncology has updated the primary objective of this trial to assess the overall response rate in patients whose tumors overexpress CD47. The company now plans to expand the number of patients enrolled in ASPEN-09-Breast – from 80 to up to 120 -- to increase the number of patients whose cancer overexpresses this biomarker. The company expects to provide topline data for 80 patients in mid-2027.The Sanofi-partnered, randomized Phase 1/2 UMBRELLA study evaluating evorpacept with SARCLISA® (isatuximab-irfc) and dexamethasone in patients with previously treated multiple myeloma continues to enroll patients in the dose-optimization portion of the trial.Data presented at the American Society of Hematology (ASH) Annual Meeting 2025 from a Phase 2 investigator-sponsored trial (IST) of evorpacept in combination with standard-of-care rituximab and lenalidomide for patients with previously untreated, indolent B-cell non-Hodgkin lymphoma (iNHL) demonstrated a 100% ORR and 92% complete response (CR) rate (with historical control around 50%), and a one-year PFS rate of 91%. While longer follow-up matures, minimal residual disease (MRD) eradication rate with this novel regimen will be evaluated. ALX2004 The Phase 1 trial of ALX2004, a novel antibody-drug conjugate (ADC) for the treatment of epidermal growth factor receptor (EGFR)-expressing solid tumors, began enrolling patients in the third dose cohort at 4mg/kg in January 2026, after no dose-limiting toxicities were observed in the prior two dose cohorts. ALX Oncology plans to share safety data from the dose-escalation phase of this trial in 2H 2026. The ongoing ALX2004 Phase 1 dose-escalation portion of the trial is enrolling patients with previously treated advanced or metastatic non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC), and colorectal cancer (CRC).ALX2004 preclinical data presented at the World ADC 2026 Conference and at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer demonstrated potent preclinical anti-tumor activity in EGFR-expressing in vivo tumor models across multiple tumor types with differing levels of EGFR expression and varied mutational status across the EGFR signaling pathway. A favorable preclinical safety profile, including no skin toxicity or interstitial lung disease, was observed in pre-clinical toxicology studies at clinically relevant doses of ALX2004. Corporate Update In February 2026, the company completed a registered equity offering, selling 76,979,112 shares of common stock at $1.57 per share and pre-funded warrants to purchase 18,574,120 shares of common stock at $1.569 per underlying share. Gross proceeds from the offering were $150 million. Net proceeds of the offering were $140.4 million, after deducting the underwriting discount and other offering expenses.After serving as Chief Medical Officer in an interim capacity since September 2025, Barbara Klencke, M.D., has been appointed to the position permanently. Dr. Klencke was instrumental in ALX Oncology’s clinical development progress over the past five months. Upcoming Clinical Milestones Phase 1b/2 trial evaluating evorpacept in combination with investigational zanidatamab in advanced HER2-positive breast cancer: Full biomarker analysis to be presented in a poster session on May 7, 2026, at the ESMO Breast Cancer 2026 Annual Congress.Phase 2 ASPEN-09 breast cancer trial: Topline data readout for 80 patients anticipated in mid-2027.Phase 1 ALX2004 trial: Safety data from the dose-escalation phase of trial anticipated in 2H 2026. Fourth Quarter and Full Year 2025 Webcast Information To access the conference call, please dial +1-877-407-0752 or +1-201-389-0912 and ask to be joined into the ALX Oncology Fourth Quarter and Full Year 2025 Financial Results Conference Call. Another option for instant telephone access to the event is to use the Call me™ link below: https://callme.viavid.com/viavid/?callme=true&passcode=13755276&h=true&info=company&r=true&B=6 A live audio webcast of the call, along with accompanying slides, will be available under "Events & Presentations" in the Investor section of the company's website, www.alxoncology.com. An archived webcast will be available on the company's website after the event. Date & Time: Friday, February 27, 2026, 5:30 a.m. PT / 8:30 a.m. ET Webcast Access: https://viavid.webcasts.com/starthere.jsp?ei=1753123&tp_key=d6cfaba210 Fourth Quarter and Full Year 2025 Financial Results Cash, Cash Equivalents and Investments: ALX held $48.3 million in cash, cash equivalents and investments as of December 31, 2025. Along with the $140.4 million in net proceeds from the February 2026 financing, the cash, cash equivalents and investments on hand are expected to be sufficient to fund ALX’s operating expenses through the first half of 2028.Research and Development (“R&D”) Expenses: R&D expenses consist primarily of preclinical, clinical and development costs related to the development of the company’s current product candidates, evorpacept and ALX2004, and R&D personnel-related expenses, including stock-based compensation. R&D expenses for the three months ended December 31, 2025 were $17.6 million compared to $23.5 million for the prior-year period, or a decrease of $5.9 million. This decrease was primarily attributable to a decrease of $2.7 million in stock-based compensation expense, a decrease of $2.5 million in personnel and related costs, and a decrease of $1.5 million in preclinical costs due to pipeline prioritization strategy. These decreases were partially offset by an increase of $0.6 million in clinical and development costs to support active clinical trials for ALX product candidates, evorpacept and ALX2004. R&D expenses for the year ended December 31, 2025, were $77.0 million compared to $116.4 million for the prior-year period.General and Administrative (“G&A”) Expenses: G&A expenses consist primarily of administrative personnel-related expenses, including stock-based compensation and other costs such as legal and other professional fees, patent filing and maintenance fees, and insurance. G&A expenses for the three months ended December 31, 2025 were $5.4 million compared to $7.1 million for the prior year period, or a decrease of $1.7 million. This decrease was primarily attributable to a decrease in stock-based compensation expense and decreases in legal and corporate costs. G&A expenses for the year ended December 31, 2025 were $23.9 million compared to $26.1 million for the prior-year period.Net loss: GAAP net loss was ($22.8) million for the three months ended December 31, 2025, or ($0.42) per basic and diluted share, as compared to a GAAP net loss of ($29.2) million for the three months ended December 31, 2024, or ($0.55) per basic and diluted share. The lower net loss is primarily attributed to lower R&D expenses. GAAP net loss was ($101.7) million for the year ended December 31, 2025, or ($1.90) per basic and diluted share, as compared to a GAAP net loss of ($134.9) million for the year ended December 31, 2024, or ($2.58) per basic and diluted share. Non-GAAP net loss was ($20.1) million for the three months ended December 31, 2025, as compared to a non-GAAP net loss of ($23.2) million for the three months ended December 31, 2024. Non-GAAP net loss was ($88.8) million for the year ended December 31, 2025, as compared to a non-GAAP net loss of ($107.5) million for the year ended December 31, 2024. A reconciliation of GAAP to non-GAAP financial results can be found at the end of this news release. ALX OncologyALX Oncology (Nasdaq: ALXO) is a clinical-stage biotechnology company advancing a pipeline of novel therapies designed to treat cancer and extend patients’ lives. ALX Oncology’s lead therapeutic candidate, evorpacept, has demonstrated potential to serve as a cornerstone therapy upon which the future of immuno-oncology can be built. Evorpacept is currently being evaluated across multiple ongoing clinical trials in a wide range of cancer indications. ALX Oncology’s second pipeline candidate, ALX2004, is a novel EGFR-targeted antibody-drug conjugate with a differentiated mechanism of action. A Phase 1, dose-escalation trial of ALX2004 is ongoing in patients with EGFR-expressing solid tumors. More information is available at www.alxoncology.com and on LinkedIn @ALX Oncology. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. Forward-looking statements include statements regarding future results of operations and financial position, business strategy, product candidates, planned preclinical studies and clinical trials, results of clinical trials, research and development costs, regulatory approvals, timing and likelihood of success, plans and objectives of management for future operations, as well as statements regarding industry trends. Such forward-looking statements are based on ALX Oncology’s beliefs and assumptions and on information currently available to it on the date of this press release. Forward-looking statements may involve known and unknown risks, uncertainties and other factors that may cause ALX Oncology’s actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements. These and other risks are described more fully in ALX Oncology’s filings with the Securities and Exchange Commission (“SEC”), including ALX Oncology’s Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q and other documents ALX Oncology files with the SEC from time to time. Except to the extent required by law, ALX Oncology undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. ALX ONCOLOGY HOLDINGS INC.Consolidated Statements of Operations(unaudited)(in thousands, except share and per share amounts) Three Months Ended Year Ended December 31, December 31, 2025 2024 2025 2024 Operating expenses: Research and development $17,645 $23,532 $76,996 $116,373 General and administrative 5,376 7,081 23,850 26,094 Impairment charge — — 3,175 — Total operating expenses 23,021 30,613 104,021 142,467 Loss from operations (23,021) (30,613) (104,021) (142,467)Interest income 573 1,878 3,964 9,366 Interest expense (383) (427) (1,602) (1,729)Other (expense) income, net (17) (1) (36) (20)Net loss $(22,848) $(29,163) $(101,695) $(134,850)Net loss per share, basic and diluted $(0.42) $(0.55) $(1.90) $(2.58)Weighted-average shares of common stock used to compute net loss per shares, basic and diluted 54,283,507 52,802,409 53,658,399 52,174,904 Consolidated Balance Sheet Data(unaudited)(in thousands) December 31, December 31, 2025 2024 Cash, cash equivalents and investments $48,284 $131,281 Total assets $59,046 $147,775 Total liabilities $33,065 $34,157 Accumulated deficit $(722,817) $(621,122)Total stockholders’ equity $25,981 $113,618 GAAP to Non-GAAP Reconciliation(unaudited)(in thousands) Three Months Ended Year Ended December 31, December 31, 2025 2024 2025 2024 GAAP net loss, as reported $(22,848) $(29,163) $(101,695) $(134,850)Adjustments: Stock-based compensation expense 2,706 5,858 12,579 27,093 Accretion of term loan discount and issuance costs 72 69 280 265 Total adjustments 2,778 5,927 12,859 27,358 Non-GAAP net loss $(20,070) $(23,236) $(88,836) $(107,492) Use of Non-GAAP Financial Measures We supplement our consolidated financial statements presented on a GAAP basis by providing additional measures which may be considered “non-GAAP” financial measures under applicable SEC rules. We believe that the disclosure of these non-GAAP financial measures provides our investors with additional information that reflects the amounts and financial basis upon which our management assesses and operates our business. These non-GAAP financial measures are not in accordance with generally accepted accounting principles and should not be viewed in isolation or as a substitute for reported, or GAAP, net loss, and are not a substitute for, or superior to, measures of financial performance performed in conformity with GAAP. “Non-GAAP net loss” is not based on any standardized methodology prescribed by GAAP and represents GAAP net loss adjusted to exclude stock-based compensation expense and accretion of term loan discount and issuance costs. Non-GAAP financial measures used by ALX Oncology may be calculated differently from, and therefore may not be comparable to, non-GAAP measures used by other companies. Investor Relations Contact: Elhan Webb, CFA, IR Consultantewebb@alxoncology.com Media Contact: Michele Parisi, SparkPoint Healthcare Communicationsmparisi@sparkpointpr.com(925) 864-5028

引言： 细胞周期依赖性激酶4/6抑制剂（CDK4/6i）的问世，显著改善了HR+晚期乳腺癌患者的生存预后。目前，内分泌治疗+CDK4/6i已成为HR+/HER2-晚期乳腺癌一线治疗的标准方案1。然而，随着该治疗方案的广泛应用，耐药问题逐渐凸显，许多患者在治疗后仍会面临疾病进展的困境，且这些患者当前尚缺乏标准的后续治疗方案。因此，深入剖析CDK4/6i的耐药机制，并探索有效的应对策略，成为当前临床研究的关键课题。本文将系统梳理相关研究成果，为临床实践提供参考。 耐药溯源：CDK4/6i耐药机制 CDK4/6i经治后进展的耐药机制复杂，涉及多个分子通路的异常调控，主要包括：PI3K/AKT信号通路过度激活；RB1分子改变；细胞周期蛋白失调；FGFR通路分子改变；抑癌基因非典型钙粘蛋白1（FAT1）缺失、Hippo通路失活及CDK6过表达；TP53通路改变，包括TP53功能缺失突变和MDM2扩增；极光激酶A（AURKA）上调；RAS/MAPK通路过度激活；致病性胚系突变等2。 破局利器：CDK4/6i耐药后的治疗方案 面对CDK4/6i耐药的临床挑战，国内外研究者开展了大量探索，形成了多种潜在的后续治疗策略，包括CDK4/6i跨线治疗、靶向PI3K/AKT/mTOR通路抑制剂、口服选择性雌激素受体降解剂（SERD）、抗体偶联药物（ADC）等，为患者提供了新的治疗方向。 ►CDK4/6i跨线治疗再思考：循证之下的审慎施策 CDK4/6i一线治疗能显著延长HR+/HER2-晚期乳腺癌患者的无进展生存期（PFS），但对于治疗进展后再次使用CDK4/6i进行跨线治疗的疗效，不同研究的结果尚未统一。 部分研究显示出积极结果：II期MAINTAIN研究中，既往接受瑞波西利联合内分泌治疗进展的患者，继续使用瑞波西利联合内分泌治疗的中位PFS为5.29个月，显著优于安慰剂联合内分泌治疗的2.76个月（HR=0.57，P=0.006）3；III期postMONARCH研究表明，阿贝西利+氟维司群治疗既往CDK4/6i经治患者的中位PFS为6.0个月，优于安慰剂+氟维司群的5.3个月（HR=0.73，P=0.017）4；另一项III期EMBER-3研究也表明，相较于Imlunestrant单药组，Imlunestrant联合阿贝西利可以显著改善既往CDK4/6i经治患者的中位PFS（10.9个月 vs 5.5个月，HR=0.59，P＜0.0001)5。 但也有研究未能证实跨线治疗的优势：PALMIRA研究结果显示，哌柏西利联合内分泌治疗的中位PFS为4.9个月，与单独内分泌治疗的3.6个月相比，未达到显著统计学差异（HR=0.84，P=0.149）6。 因此，综合现有研究，CDK4/6i跨线治疗的确切疗效尚存争议，其在临床中的应用仍需进行审慎评估与个体化决策。在第八版晚期乳腺癌国际共识指南（ABC8）专家投票中，90%以上专家认为在CDK4/6i治疗后出现进展的情况下继续使用CDK4/6i通常并非优选方案，除非无其他可联合内分泌治疗的靶向药物可用，且前期CDK4/6i治疗持续时间超过12个月。若确需使用，建议同时更换CDK4/6i和内分泌治疗药物7。 ► 靶向PI3K/AKT通路抑制剂：基因检测指导的耐药攻坚 中国HR+晚期乳腺癌患者约有60%存在PIK3CA/AKT1/PTEN基因改变，这类基因异常与患者预后不良密切相关8,9。国内外指南均建议在首次复发时或疾病进展时进行PIK3CA/AKT1/PTEN等基因检测，对于存在基因改变的患者，靶向PI3K/AKT通路抑制剂联合内分泌治疗成为重要选择1,10。  AKT抑制剂 卡匹色替是一种口服生物利用度高的小分子抑制剂，可抑制3种同工型AKT1/2/3及下游mTOR蛋白11。CAPItello-291研究纳入了708例既往接受过芳香化酶抑制剂（AI）治疗的HR+/HER2-晚期乳腺癌患者，其中，69.1%患者接受过CDK4/6i治疗，40.8%患者存在PIK3CA/AKT1/PTEN基因改变，旨在评估卡匹色替联合氟维司群在该人群中的疗效及安全性。结果显示，在PIK3CA/AKT1/PTEN任一基因改变的患者中，与安慰剂+氟维司群相比，卡匹色替联合氟维司群可显著改善患者的中位PFS（7.3个月 vs. 3.1个月, HR=0.5, P<0.001）11;在PIK3CA突变、AKT1突变及PTEN突变人群中观察到一致获益，HR分别为0.51、0.51和0.4312。 PI3Kα抑制剂 伊那利塞是一种新型选择性PI3Kα抑制剂，Ⅲ期INAVO120研究表明，在辅助内分泌治疗期间或治疗结束后12个月内疾病进展或复发且伴PIK3CA突变的晚期一线患者中，伊那利塞+氟维司群+哌柏西利组的中位PFS为15个月，显著优于安慰剂+氟维司群+哌柏西利组的7.3个月（HR=0.42，P<0.001）13。需注意的是，该研究中经CDK4/6i治疗的患者比例仅为1.2%13。 mTOR抑制剂 mTOR位于PI3K/AKT通路下游，依维莫司是一种mTOR抑制剂，在Ⅲ期BOLERO-2研究中，依维莫司联合依西美坦二线治疗显著改善了HR+/HER2-晚期乳腺癌患者的中位PFS（7.8个月 vs 3.2个月，HR=0.45，P＜0.001），值得注意的是，由于开展时间较早，该研究未纳入CDK4/6i经治的患者14。 ► 口服SERD药物：ESR1突变人群的治疗新章节 晚期乳腺癌患者中，ESR1突变频率达30%~40%，传统SERD药物氟维司群受剂型和药代动力学限制，临床使用便利性不足，而新型口服SERD药物凭借较高的生物利用度，为ESR1突变患者带来了新的治疗选择9。 Elacestrant是首个美国食品药品监督管理局（FDA）获批的口服SERD药物9，Ⅲ期EMERALD研究纳入了既往接受CDK4/6i联合AI或氟维司群治疗进展的ER+/HER2-晚期乳腺癌患者，结果显示，在ESR1突变患者中，Elacestrant组的中位PFS显著优于标准内分泌治疗组（3.8个月 vs 1.9个月，HR=0.55，P=0.0005），疾病进展风险降低45%；其中既往接受内分泌+CDK4/6i治疗≥12个月的患者，Elacestrant单药治疗的中位PFS为8.6个月，同样优于标准内分泌治疗组的1.9个月（HR=0.41）15。 Imlunestrant是新一代具有脑渗透性的口服SERD药物，EMBER-3研究纳入了既往接受AI±CDK4/6i后出现复发或进展的ER+/HER2-晚期乳腺癌患者，Imlunestrant单药组中，59.8%患者既往接受过CDK4/6i治疗16。结果显示，在ESR1突变患者中，Imlunestrant单药组的中位PFS为5.5个月，显著优于标准治疗组的3.8个月（(HR=0.62，P=0.0007）5。在总生存期（OS）方面，Imlunestrant单药组的中位OS为34.5个月，标准治疗组为23.1个月，两组间HR为0.60，p=0.0043，未达到预设的统计学显著性界值5。 Giredestrant也是新一代口服SERD药物，evERA研究评估了Giredestrant联合依维莫司在CDK4/6i经治ER+/HER2-晚期乳腺癌患者中的疗效。结果显示，在ESR1突变患者中，与标准内分泌治疗联合依维莫司组相比，Giredestrant联合依维莫司组的中位PFS显著延长（9.99个月 vs 5.45个月，HR=0.38，p<0.0001）17。 ►ADC药物：靶向治疗的新探索 近年来，ADC药物同样在HR+/HER2-晚期乳腺癌治疗中取得了突破性进展，凭借其独特的作用机制为CDK4/6i经治、无最佳内分泌治疗选择的人群带来了显著临床获益。 德曲妥珠单抗（T-DXd）是一种由抗HER2单克隆抗体曲妥珠单抗、可裂解的四肽连接子及拓扑异构酶Ⅰ抑制剂共同构成的HER2 ADC药物18。DESTINY-Breast04研究纳入了既往接受过1-2线化疗且内分泌难治的HER2低表达晚期乳腺癌患者，旨在评估T-DXd对比医生选择的治疗方案（TPC）在该人群中的疗效和安全性19。该研究中，约70%的HR+患者既往接受过CDK4/6i治疗。结果显示，在HR+患者中，T-DXd组的中位PFS较TPC组显著延长（10.1个月 vs. 5.4个月，HR=0.51，p<0.001）；总生存期（OS）也显著优于TPC组（23.9个月 vs. 17.5个月，HR=0.64，p=0.003）19。DESTINY-Breast06研究则探索了T-DXd对比研究者选择的化疗在内分泌±CDK4/6i经治的HR+/HER2（超）低表达患者中的疗效。结果显示，在HR+/HER2低表达人群中，T-DXd组较研究者选择的化疗组获得了具有统计学意义和临床意义的中位PFS延长（13.2个月 vs 8.1个月，HR=0.62，P＜0.0001）；在HER2超低表达患者亚组中，T-DXd同样带来了一致的PFS获益（13.2个月 vs 8.3个月；HR=0.78）20。 德达博妥单抗（Dato-DXd）是一种由靶向TROP2的人源化单抗MAAP-9001a抗体与拓扑异构酶Ⅰ抑制剂DXd通过GGFG四肽连接子连接而成的TROP2 ADC药物21。TROPION-Breast01研究纳入了既往在不可手术/转移阶段接受过1-2线化疗且存在内分泌治疗耐药或不适合接受内分泌治疗的HR+/HER2-乳腺癌患者，80%以上的患者既往接受过CDK4/6i治疗，旨在评估Dato-DXd对比研究者选择的化疗（ICC）在该人群中的疗效和安全性。结果显示，与ICC相比，Dato-DXd使疾病进展或死亡风险降低37%（HR=0.63，P<0.0001），Dato-DXd组和ICC组的中位PFS分别为6.9个月和4.9个月22。 戈沙妥珠单抗（SG）是由人源化抗Trop-2单克隆抗体hRS7和拓扑异构酶I抑制剂伊立替康的活性代谢产物SN-38通过可水解的pH敏感连接子CL2A组成的TROP2 ADC药物23。TROPiCS-02研究纳入既往接受过至少一种内分泌治疗和CDK4/6i治疗，且接受过2-4线晚期化疗的HR+/HER2-晚期乳腺癌患者，旨在评估SG对比化疗在该人群中的疗效和安全性。初步分析显示，与化疗相比，SG组的mPFS显著改善，使疾病进展或死亡风险降低34%（5.5个月 vs. 4.0个月；HR=0.66，p=0.0003）24。 总结 CDK4/6i的出现为HR+晚期乳腺癌患者带来了显著的生存获益，但耐药问题仍是临床治疗中不可回避的挑战。目前，针对CDK4/6i耐药的治疗策略正处于多维度探索阶段，尚无标准方案，其中部分方案已在临床研究中取得显著进展，为患者提供了更多治疗选择。未来，随着对CDK4/6i耐药机制研究的不断深入，以及精准医疗技术的持续发展，有望实现基于患者个体分子特征的个体化治疗，进一步优化治疗方案，延长患者生存时间，改善生活质量。同时，更多新型药物和联合治疗策略的研发与探索，将为HR+晚期乳腺癌CDK4/6i耐药患者带来新的希望，推动临床治疗水平迈向新的高度。 参考文献 1. 2025年CSCO BC诊疗指南 2. da Silva JL, et al. Ther Adv Med Oncol. 2025;17:17588359251353623. 3. Kalinsky K, et al. J Clin Oncol. 2023 Aug 20;41(24):4004-4013. 4. Kalinsky K, et al. J Clin Oncol. 2025;43(9):1101-1112. 5. Jhaveri KL, et al. Ann Oncol. Published online December 12, 2025. 6. Llombart-Cussac A, et al. J Clin Oncol. 2025 Jun 20;43(18)2084-2093. 7. https://www.abc-lisbon.org/ 8. Ziang Li, et al. 2024 SABCS. P3-10-13. 9. 李彬,等. 中国癌症杂志,2025,35(3):273-282. 10. NCCN Guidelines 2025.v4 Invasive Breast Cancer. 11. Turner NC, et al. N Engl J Med. 2023;388(22):2058-2070. 12. Sacha J. Howell, et al. 2023 SABCS PS17-03. 13. Turner NC, et al. N Engl J Med. 2024;391(17):1584-1596. 14. Yardley DA, et al. Adv Ther. 2013;30(10):870-884. 15. Bardia A, et al. Clin Cancer Res. 2024;30(19):4299-4309. 16. Jhaveri KL, et al.N Engl J Med. 2025;392(12):1189-1202. 17. H. S. Rugo,et al.GS3-09, SABCS 2025 18. 刘炜,等.肿瘤药学,2025,15(4):455-461. 19. Modi S, et al. N Engl J Med. 2022 Jul 7;387(1):9-20. 20. CURIGLIANO G, et al. J Clin Oncol, 2024, ASCO:LBA1000. 21. Okajima D, et al. Mol Cancer Ther. 2021;20(12):2329-2340. 22. Bardia A, et al. J Clin Oncol. 2025 Jan 20;43(3):285-296. 23. Rossi V, et al. Front Immunol. 2024;15:1447280. Published 2024 Aug 15. 24. Rugo HS, et al. Lancet. 2023 Oct 21;402(10411):1423-1433. 审批编号：CN-178598 有效期至：2027-02-08 本文由阿斯利康提供，仅供医疗卫生专业人士参考，不可用于推广目的 编辑：ICEY 审校：ICEY 排版：Ben 执行：Zelda 本平台旨在为医疗卫生专业人士传递更多医学信息。本平台发布的内容，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。如该等信息被用于了解医学信息以外的目的，本平台不承担相关责任。本平台对发布的内容，并不代表同意其描述和观点。若涉及版权问题，烦请权利人与我们联系，我们将尽快处理。