Bedard Philippe L, Jhaveri Komal L, Accordino Melissa K, Cervantes Prof Andrés, Gambardella Valentina, Hamilton Erika, Italiano Prof Antoine, Kalinsky Prof Kevin, Krop Prof Ian E, Oliveira Mafalda, Schmid Prof Peter, Saura Cristina, Turner Prof Nicholas, Varga Andrea, Cheeti Sravanthi, Dey Anwesha, Hilz Stephanie, Hutchinson Katherine E, Jin Yanling, Royer-Joo Stephanie, Peters Ubong, Shankar Noopur, Schutzman Jennifer L, Aimi Junko, Song Kyung, Juric Dejan
Princess Margaret Cancer Centre - University Health Network, University of Toronto, Toronto, ON, Canada.
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
Eur J Cancer. 2025 May 15;221:115397. doi: 10.1016/j.ejca.2025.115397. Epub 2025 Mar 30.
A variety of treatment options continue to be explored in the post-cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) setting for hormone receptor (HR)-positive, HER2-negative locally advanced/metastatic breast cancer (LA/mBC), and optimal sequencing of therapies remains to be determined. This phase 1/1b study examined inavolisib, a potent and selective PI3Kα inhibitor that promotes mutated p110α degradation, alone and in combination with endocrine therapy (ET) ± palbociclib, in PIK3CA-mutated, HR-positive, HER2-negative LA/mBC. We report data on inavolisib plus ET, including in patients who had previously received a CDK4/6i.
Women age ≥ 18 years received inavolisib (6 mg/9 mg orally once daily [PO QD]) plus letrozole (2·5 mg PO QD), or inavolisib (9 mg PO QD) plus fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1 then every 4 weeks), until unacceptable toxicity/disease progression.
safety and tolerability.
Thirty-seven and 60 patients were enrolled in the inavolisib plus letrozole and inavolisib plus fulvestrant arms, respectively. Overall, treatment-related adverse events (mostly low grade) occurred in 94·6 % and 93·3 % of patients, respectively; the most frequent (≥10 % of patients in either arm) were hyperglycaemia, stomatitis, nausea, and diarrhoea. Confirmed objective response rates in patients with measurable disease were 9·7 % and 25·9 %, respectively; median progression-free survival was 3·7 and 7·3 months. Among patients with previous CDK4/6i therapy (29/37 and 58/60 patients, respectively), confirmed objective response rates were 13·0 % and 25·0 %; median progression-free survival was 3·7 and 7·1 months. No drug-drug interactions were observed for any study treatment. Paired baseline and Cycle 1 Day 15 tumour biopsies and circulating tumour DNA analyses demonstrated the impact of study treatment on pharmacodynamic/pathophysiologic biomarkers of response.
Inavolisib plus ET demonstrated a manageable safety profile and encouraging preliminary anti-tumour activity in patients with PIK3CA-mutated, HR-positive, HER2-negative LA/mBC, including those in the post-CDK4/6i setting.
在细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）治疗后的激素受体（HR）阳性、人表皮生长因子受体2阴性局部晚期/转移性乳腺癌（LA/mBC）患者中，仍在探索多种治疗方案，治疗的最佳顺序尚待确定。这项1/1b期研究在PIK3CA突变、HR阳性、HER2阴性的LA/mBC患者中，单独或联合内分泌治疗（ET）±哌柏西利，研究了强效选择性PI3Kα抑制剂艾纳沃利西布，后者可促进突变型p110α的降解。我们报告了艾纳沃利西布联合ET的数据，包括之前接受过CDK4/6i治疗的患者的数据。
年龄≥18岁的女性接受艾纳沃利西布（6 mg/9 mg口服，每日一次[PO QD]）联合来曲唑（2.5 mg PO QD），或艾纳沃利西布（9 mg PO QD）联合氟维司群（第1周期第1天和第15天各500 mg肌肉注射，之后每4周一次），直至出现不可接受的毒性或疾病进展。
安全性和耐受性。
分别有37例和60例患者入组艾纳沃利西布联合来曲唑组和艾纳沃利西布联合氟维司群组。总体而言，治疗相关不良事件（大多为低级别）分别发生在94.6%和93.3%的患者中；最常见的（任何一组中≥10%的患者）是高血糖、口腔炎、恶心和腹泻。可测量疾病患者的确认客观缓解率分别为9.7%和25.9%；中位无进展生存期分别为3.7个月和7.3个月。在之前接受过CDK4/6i治疗的患者中（分别为29/37例和58/60例患者），确认客观缓解率分别为13.0%和25.0%；中位无进展生存期分别为3.7个月和7.1个月。未观察到任何研究治疗存在药物相互作用。配对的基线和第1周期第15天肿瘤活检以及循环肿瘤DNA分析证明了研究治疗对反应的药效学/病理生理学生物标志物的影响。
艾纳沃利西布联合ET在PIK3CA突变、HR阳性、HER2阴性的LA/mBC患者中显示出可控的安全性和令人鼓舞的初步抗肿瘤活性，包括那些处于CDK4/6i治疗后的患者。
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