Alpelisib

点击上方蓝字 关注我们 编者按：在HR+/HER2-晚期乳腺癌的治疗版图中，内分泌治疗联合细胞周期蛋白依赖性激酶（CDK）4/6抑制剂已确立了其不可撼动的基石地位。然而，随着临床实践的深入，耐药问题逐渐成为制约患者长期生存的瓶颈。如何精准定义耐药模式、剖析分子机制并制定个体化的后线策略，是当前乳腺癌领域亟待破解的临床难题。在“第一届乳腺癌治愈力年会”上，来自香港仁康医疗乳腺综合诊治中心的医疗总监周永昌教授，围绕“乳腺癌耐药问题及潜在解决方案”进行了深度专题报告。周教授通过对典型临床病例的复盘，系统梳理了原发性与继发性内分泌耐药的应对路径，并展望了抗体偶联药物（ADC）、新型CDK抑制剂及磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR，PAM）通路靶向药物的临床应用。本文特将精华内容整理如下，以飨读者。 拨雾寻踪 内分泌耐药的定义与原发性耐药的挑战 内分泌耐药是HR+晚期乳腺癌治疗中最为复杂的生物学现象之一。周永昌教授首先明确了内分泌耐药的两大核心定义：原发性内分泌耐药（Primary Endocrine Resistance）和继发性内分泌耐药（Secondary Endocrine Resistance）。前者表现为肿瘤对起始内分泌治疗基本无反应，在极短时间内即出现疾病进展或术后早期复发；后者则指患者最初对内分泌治疗有明确获益，但在持续用药后逐渐演变为耐药。这种分类对于指导临床选择靶向药物及判断预后具有至关重要的作用。 在原发性耐药的临床应对中，周教授分享了一例绝经后高危Luminal B型患者的治疗经历。该患者在接受新辅助内分泌治疗联合CDK4/6抑制剂（哌柏西利）的过程中，结果显示淋巴结有所缩小，但未达到理想的临床缓解。周教授认为，这一发现与RIBOLARIS等研究的数据相互印证——即便是在强效CDK4/6抑制剂联合内分泌治疗的背景下，仍有相当比例的高危患者存在原发性耐药。对于这部分人群，单一的内分泌强化方案往往难以奏效。 周教授指出，原发性耐药患者的肿瘤生物学行为更具侵袭性。在该病例中，患者在手术后经历了辅助化疗及多种方案尝试，但短期内即出现肝转移。通过基因检测（NGS）发现，患者不仅携带BRCA1突变，且呈现HER2-low表达。此时，传统的内分泌跨线治疗已非首选，治疗重心应转向更具杀伤力的靶向化疗手段。 近年来，以德曲妥珠单抗（T-DXd）、芦康沙妥珠单抗（SKB264）为代表的ADC药物在HR+晚期乳腺癌中展现出突破性的疗效。针对内分泌耐药患者，T-DXd适用于HER2低表达人群，而SKB264在ESMO发表的研究中显示出对原发性内分泌耐药亚组的显著获益。无论是靶向HER2的T-DXd还是靶向TROP-2的SKB264，这两种不同靶点的ADC均表现出良好的抗肿瘤活性。周教授结合前述病例强调，在原发性耐药阶段，一旦发现有用的靶向药物，应坚持持续治疗，避免非医疗因素导致的中断，因为治疗中断极易诱导更具耐药性的克隆演进。 基因导向 耐药中的ESR1突变与PAM通路靶向治疗 与原发性耐药不同，继发性耐药往往伴随着明确的基因演化。周教授通过另外的病案详述了继发性耐药的演进过程。该患者在内分泌治疗联合CDK4/6抑制剂获益两年后出现肌肉及肝脏转移。循环肿瘤DNA（ctDNA）检测结果显示，患者出现了ESR1突变。 ESR1突变是HR+乳腺癌获得性耐药的典型分子标志物：初治患者突变率仅3.5%，而扩散患者中可达13%-17%。针对这一靶点，新型口服选择性雌激素受体降解剂（SERD）药物展现出明显优势：EMERALD研究指出，在CDK4/6抑制剂使用时间较长（反映肿瘤仍具内分泌敏感性）且存在ESR1突变的患者中，艾拉司群能带来更显著的存活获益；SERENA-6研究也进一步证实，camizestrant在继发性耐药亚组中的效果明显优于原发性耐药。 除ER通路外，PAM通路的异常激活也是继发性耐药的重要机制。周教授指出，AKT突变或PIK3CA突变在晚期患者中广泛存在。CAPItello-291研究确立了AKT抑制剂卡匹色替联合氟维司群的治疗地位，阿培利司、伊那利塞等PI3K抑制剂也显示出一定效果。周教授特别提醒，在继发性耐药阶段，由于癌细胞仍具有一定的内分泌敏感性，化疗并非首选，应优先选择靶向药物联合内分泌方案。 未来视野 肿瘤微环境、类器官与免疫治疗的探索 在报告的最后，周教授对未来HR+乳腺癌耐药的研究方向进行了前瞻性展望。他认为，当前的治疗视角过多聚焦于癌细胞本身，而忽视了肿瘤微环境（Tumor Microenvironment）在耐药形成中的作用。肿瘤浸润淋巴细胞（TILs）的状态直接影响治疗反应，通过某些药物干预，将“冷”肿瘤转化为“热”肿瘤，可能会为免疫治疗在HR+乳腺癌中的应用开启大门。例如，已有研究探索PD-L1抑制剂联合内分泌治疗在绝经前妇女中的应用，初步结果显示出了一定的临床获益。 此外，类器官（Organoids）技术的发展为个体化药敏筛选提供了强大工具，通过采集患者肿瘤样本进行类器官培养，可以在体外模拟肿瘤对不同药物（如他莫昔芬、CDK抑制剂或化疗药）的反应。周教授展示其团队的研究成果，指出类器官测试能够直观观察到某些药物是属于细胞杀伤（Cell kill）还是仅为细胞抑制（Cytostatic），这对于临床制定精准减毒增效方案具有指导意义。 编者总结 HR+/HER2-晚期乳腺癌的内分泌耐药是一个多因素、动态演化的过程。周永昌教授强调，临床诊疗的核心在于早期精准识别耐药类型与全程开展分子监测，以此为基础制定个体化的治疗策略。对于原发性内分泌耐药患者，应积极选用ADC药物等靶向化疗手段，通过强效的靶向治疗实现疾病控制；对于继发性内分泌耐药患者，需深挖ESR1突变及PAM通路异常等核心靶点，优先选择对应的SERD药物或通路抑制剂联合内分泌治疗，而非盲目采用化疗，在有效控瘤的同时兼顾患者的生存质量。 内分泌耐药的治疗是一场持久战，CDK抑制剂在HR+乳腺癌内分泌耐药治疗中已占据重要临床地位，其中CDK4/6抑制剂更是临床常用的核心治疗选择，而除了这类已广泛应用的药物外，国产创新研发的CDK2/4/6抑制剂库莫西利也于近期获批，该药物通过同时靶向CDK2、CDK4和CDK6多个靶点封堵细胞周期通路，在既往内分泌经治的HR+/HER2-晚期乳腺癌患者中展现出良好的疾病控制效果，为内分泌耐药患者的治疗增添了新的方向。如今，伴随ADC、SERD类精准药物的不断丰富，加之各类新型CDK抑制剂的迭代发展，临床正从单一治疗方案逐步走向“因人而异、因时而异”的精准治疗序列，为不同耐药类型、不同分子特征的患者提供更具针对性的治疗选择。 未来，随着类器官药敏测试技术的成熟、肿瘤微环境重塑研究的深入，以及更多新型靶向药物的临床转化，临床医生将能更精准地捕捉肿瘤生物学特征的动态变化，及时调整治疗策略，同时规避有效药物的非医疗性中断，减少耐药克隆的产生。相信在精准诊疗理念的指引下，HR+晚期乳腺癌患者的生存期与生活质量将迎来更进一步的跨越式提升。 （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。

Pfizer (NYSE: PFE) reported Phase II results for atirmociclib in HR-positive, HER2-negative metastatic breast cancer, with the FOURLIGHT-1 trial meeting its primary endpoint by demonstrating a 40% reduction in the risk of disease progression or death compared to standard-of-care options. The data mark the first randomized Phase II readout for a selective CDK4 inhibitor in patients whose disease has progressed on prior CDK4/6 inhibitor therapy, a population with limited treatment options and no established targeted retreatment strategy. Trial specifics FOURLIGHT-1 is an open-label, randomized, multicenter Phase II study that enrolled 264 patients across 14 countries with HR-positive, HER2-negative advanced or metastatic breast cancer who had progressed after CDK4/6 inhibitor-based treatment. Patients were randomized to atirmociclib plus fulvestrant versus physician’s choice of fulvestrant alone or everolimus plus exemestane. The primary endpoint was investigator-assessed progression-free survival. Atirmociclib plus fulvestrant reduced the risk of progression or death by 40% versus control, with a hazard ratio of 0.60 (95% CI: 0.440–0.825; p=0.0007). The benefit was consistent across prespecified subgroups, including patients with visceral disease, those with prior CDK4/6 inhibitor treatment lasting less than or more than 12 months, and regardless of which CDK4/6 inhibitor was previously received. More than 90% of enrolled patients initiated atirmociclib within three months of their last CDK4/6 inhibitor treatment, indicating a population with recent disease progression rather than a prolonged treatment-free interval. Overall survival data were not mature, with approximately 20% of participants having had an event at the time of analysis. The safety profile was consistent with prior studies of atirmociclib. Discontinuation due to treatment-emergent adverse events occurred in 6.4% of patients on the atirmociclib arm, and no new safety signals were identified, according to the company. Detailed safety data were not disclosed and are expected at a future medical meeting. Development context Atirmociclib is an oral, selective inhibitor of cyclin-dependent kinase 4 (CDK4), a protein that drives the transition from G1 to S phase of the cell cycle. Unlike currently approved CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib, which inhibit both CDK4 and CDK6, atirmociclib targets CDK4 alone. The rationale for selective CDK4 inhibition centers on the hypothesis that sparing CDK6 may reduce hematologic toxicity, particularly neutropenia, which is the dose-limiting side effect of dual CDK4/6 inhibitors. Whether CDK4 selectivity translates into a clinically distinct efficacy or tolerability profile remains to be established in larger trials. The post-CDK4/6 inhibitor treatment landscape in HR-positive, HER2-negative metastatic breast cancer lacks a consensus targeted retreatment approach. Current options after progression on a CDK4/6 inhibitor include fulvestrant monotherapy, everolimus combined with exemestane, and more recently, agents such as elacestrant, an oral selective estrogen receptor degrader approved by the US FDA in 2023 for patients with ESR1-mutated tumors. The PI3K inhibitor alpelisib combined with fulvestrant is approved for PIK3CA-mutated disease. Capivasertib, an AKT inhibitor, received US FDA approval in 2023 in combination with fulvestrant for patients with PIK3CA/AKT1/PTEN-altered tumors. None of these therapies directly address the question of whether continued cell cycle inhibition through a next-generation mechanism can extend disease control after CDK4/6 inhibitor failure. Pfizer stated that a Phase III registrational study for atirmociclib in the first-line metastatic setting is ongoing, and results from a Phase II neoadjuvant study in early breast cancer will be presented at a future medical meeting. The company did not disclose a timeline for regulatory filing based on the FOURLIGHT-1 data or whether the Phase II results alone would support an accelerated approval pathway. The broader competitive context for next-generation CDK4 inhibitors includes programs from other companies, though atirmociclib is the first to report randomized Phase II data in the post-CDK4/6 inhibitor setting. Pfizer’s decision to advance atirmociclib into first-line and early-stage disease reflects a strategy to position the molecule as a potential replacement for, rather than a successor to, existing CDK4/6 inhibitors across treatment lines. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website