伊沙匹隆为基础的疗法治疗 - 突变型晚期乳腺癌。
Inavolisib-Based Therapy in -Mutated Advanced Breast Cancer.
机构信息
From the Royal Marsden Hospital and Institute of Cancer Research (N.C.T.) and the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London (P. Schmid), London, and Roche, Welwyn Garden City (E.T., G.L.) - all in the United Kingdom; Seoul National University Hospital, Seoul National University College of Medicine, Cancer Research Institute, Seoul National University, Seoul, South Korea (S.-A.I.); Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (C. Saura); Mass General Cancer Center, Department of Medicine, Harvard Medical School, Boston (D.J.); Winship Cancer Institute at Emory University, Atlanta (K.K.); Genentech, San Francisco (N.S., T.J.S., K.E.H., J.L.S., C. Song); the Breast and Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College - both in New York (K.L.J.); the German Breast Group, Neu-Isenburg, and the Center for Hematology and Oncology Bethanien, Goethe University, Frankfurt - both in Germany (S. Loibl); the Division of Cancer Research and Clinical Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, and the Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, VIC - both in Australia (S. Loi); the Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand (P. Sunpaweravong); the Department of Medicine, University of Parma, Parma, and the Medical Oncology and Breast Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori," Meldola - both in Italy (A.M.); the Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing (H.L.), Harbin Medical University, Harbin (Q.Z.), and the University Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (R.L.) - all in China; and Maria Skłodowska-Curie Institute of Oncology, Warsaw, Poland (Z.N.).
出版信息
N Engl J Med. 2024 Oct 31;391(17):1584-1596. doi: 10.1056/NEJMoa2404625.
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 ) 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 -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 -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.).
背景
Inavolisib 是一种高度有效的选择性抑制剂，可抑制磷脂酰肌醇 3-激酶复合物的 alpha 同工型（由编码），还可促进突变型 p110α的降解。Inavolisib 联合 palbociclib-fulvestrant 在临床前模型中显示出协同活性，并在早期试验中显示出有希望的抗肿瘤活性。
方法
在一项 3 期、双盲、随机试验中，我们比较了一线治疗中 inavolisib（口服剂量为 9mg 每日一次）联合 palbociclib-fulvestrant（inavolisib 组）与安慰剂联合 palbociclib-fulvestrant（安慰剂组）在接受过辅助内分泌治疗后复发的 -突变、激素受体阳性、HER2 阴性局部晚期或转移性乳腺癌患者中的疗效。主要终点为研究者评估的无进展生存期。
结果
共有 161 名患者被分配至 inavolisib 组，164 名患者被分配至安慰剂组；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]，11.3 至 20.5），安慰剂组为 7.3 个月（95%CI，5.6 至 9.3）（疾病进展或死亡的风险比，0.43；95%CI，0.32 至 0.59；P<0.001）。inavolisib 组客观缓解率为 58.4%，安慰剂组为 25.0%。inavolisib 组 80.2%的患者发生 3 级或 4 级中性粒细胞减少症，安慰剂组为 78.4%；3 级或 4 级高血糖症，分别为 5.6%和 0%；3 级或 4 级口腔炎或黏膜炎症，分别为 5.6%和 0%；3 级或 4 级腹泻，分别为 3.7%和 0%。未观察到 3 级或 4 级皮疹。inavolisib 组因不良事件停止任何试验药物治疗的患者比例为 6.8%，安慰剂组为 0.6%。
结论
在 -突变、激素受体阳性、HER2 阴性局部晚期或转移性乳腺癌患者中，inavolisib 联合 palbociclib-fulvestrant 可显著延长无进展生存期，优于安慰剂联合 palbociclib-fulvestrant，但毒性作用发生率更高。因不良事件停止任何试验药物治疗的患者比例较低。（由 F. Hoffmann-La Roche 资助；INAVO120 ClinicalTrials.gov 编号，NCT04191499.）
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