Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer.

IF 96.2 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL New England Journal of Medicine Pub Date : 2024-10-31 DOI:10.1056/NEJMoa2404625
Nicholas C Turner, Seock-Ah Im, Cristina Saura, Dejan Juric, Sibylle Loibl, Kevin Kalinsky, Peter Schmid, Sherene Loi, Patrapim Sunpaweravong, Antonino Musolino, Huiping Li, Qingyuan Zhang, Zbigniew Nowecki, Roland Leung, Eirini Thanopoulou, Noopur Shankar, Guiyuan Lei, Thomas J Stout, Katherine E Hutchinson, Jennifer L Schutzman, Chunyan Song, Komal L Jhaveri
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Abstract

Background: Inavolisib is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA) that also promotes the degradation of mutated p110α. Inavolisib plus palbociclib-fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials.

Methods: In a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib-fulvestrant (inavolisib group) with placebo plus palbociclib-fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator.

Results: A total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group.

Conclusions: In patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).

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基于 Inavolisib 的 PIK3CA 突变晚期乳腺癌疗法
背景Inavolisib是磷脂酰肌醇3-激酶复合物(由PIK3CA编码)p110催化亚基α异构体的高效选择性抑制剂,它还能促进突变p110α的降解。Inavolisib 加 palbociclib-fulvestrant 已在临床前模型中显示出协同活性,并在早期试验中显示出良好的抗肿瘤活性:在一项3期双盲随机试验中,我们比较了一线inavolisib(口服剂量为9毫克,每天一次)加palbociclib-fulvestrant(inavolisib组)和安慰剂加palbociclib-fulvestrant(安慰剂组)治疗PIK3CA突变、激素受体阳性的白血病患者、激素受体阳性、人表皮生长因子受体 2 (HER2) 阴性的局部晚期或转移性乳腺癌患者,且在辅助内分泌治疗期间或治疗结束后 12 个月内复发者。主要终点是由研究者评估的无进展生存期:共有161名患者被分配到依那韦利昔组,164名患者被分配到安慰剂组;中位随访时间分别为21.3个月和21.5个月。inavolisib组的中位无进展生存期为15.0个月(95%置信区间[CI]为11.3至20.5),安慰剂组为7.3个月(95%置信区间[CI]为5.6至9.3)(疾病进展或死亡的危险比为0.43;95%置信区间[CI]为0.32至0.59;PConclusions:在PIK3CA突变、激素受体阳性、HER2阴性的局部晚期或转移性乳腺癌患者中,inavolisib联合palbociclib-fulvestrant的无进展生存期明显长于安慰剂联合palbociclib-fulvestrant,但毒性反应发生率更高。因不良反应而停用任何试验药物的患者比例较低。(由 F. Hoffmann-La Roche 公司资助;INAVO120 临床试验项目编号:NCT04191499)。
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来源期刊
New England Journal of Medicine
New England Journal of Medicine 医学-医学:内科
CiteScore
145.40
自引率
0.60%
发文量
1839
审稿时长
1 months
期刊介绍: The New England Journal of Medicine (NEJM) stands as the foremost medical journal and website worldwide. With an impressive history spanning over two centuries, NEJM boasts a consistent publication of superb, peer-reviewed research and engaging clinical content. Our primary objective revolves around delivering high-caliber information and findings at the juncture of biomedical science and clinical practice. We strive to present this knowledge in formats that are not only comprehensible but also hold practical value, effectively influencing healthcare practices and ultimately enhancing patient outcomes.
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