过去20年来，激素受体阳性HER2阴性晚期乳腺癌的治疗方法已经发生巨大变化。过去，通常的治疗方法是先用选择性雌激素受体调节剂他莫昔芬、雌激素合成酶（芳香化酶）抑制剂或雌激素受体拮抗剂氟维司群进行内分泌治疗，直至内分泌耐药，随后转向化疗。耐药可原发于乳腺癌诊断时，或继发于乳腺癌诊断后长期内分泌治疗引起的适者生存。细胞信号传导通路以及体细胞基因突变可将乳腺癌对内分泌敏感转变为耐药，例如细胞周期蛋白依赖性激酶CDK4/6、磷脂酰肌醇3激酶PI3K。PI3K由分子量分别为85千道尔顿的抑制亚基p85和110千道尔顿的催化亚基p110组成，p110又有p110α、p110β、p110γ、p110δ四种异构体，分别由PIK3CA、PIK3CB、PIK3CG、PIK3CD四种基因编码，其中PIK3CA激活突变发生于高达35%至40%的激素受体阳性乳腺癌，属于核心突变，存在于癌症起始细胞，主要引起原发耐药，而其他致癌突变主要引起继发耐药，例如雌激素受体α编码基因ESR1的突变。不过，前几代p110α抑制剂不良反应发生率较高，而且大多用于内分泌耐药二线治疗，联合CDK4/6抑制剂和内分泌治疗均告失败。新一代高效选择性p110α抑制剂伊那利塞（又译：伊纳沃利昔布）既可抑制p110α，又可促进PIK3CA突变基因编码的p110α降解。临床前研究已经证实伊那利塞联合CDK4/6抑制剂哌柏西利以及氟维司群具有协同作用，早期临床研究也发现该联合方案抗肿瘤活性良好。那么，对于PIK3CA突变的内分泌耐药晚期乳腺癌，将该联合方案前移至一线治疗，有效性和安全性效果如何？
2024年10月31日，国际四大医学期刊之一、创刊于1812年的美国麻省医学会《新英格兰医学杂志》在线发表英国罗氏、伦敦大学癌症研究院、皇家马斯登医院、伦敦大学玛丽王后学院巴茨癌症研究所、韩国首尔大学医学院附属医院癌症研究所、西班牙巴塞罗那大学希伯伦河谷医院肿瘤研究所、美国基因泰克、哈佛大学医学院麻省总医院癌症中心、埃默里大学温希普癌症研究院、纽约纪念医院斯隆凯特林癌症中心、康奈尔大学威尔医学院、德国乳腺癌研究协作组、法兰克福大学贝塔尼血液学和肿瘤学中心、澳大利亚墨尔本大学彼得麦卡伦癌症中心、泰国宋卡王子大学、意大利帕尔马大学罗马涅肿瘤研究院、中国北京大学肿瘤医院李惠平、哈尔滨医科大学附属肿瘤医院张清媛、香港大学李嘉诚医学院、波兰居里夫人肿瘤研究院的INAVO 120研究报告，首次比较了哌柏西利＋氟维司群＋伊那利塞或安慰剂一线治疗PIK3CA突变且激素受体阳性HER2阴性乳腺癌局部晚期或远处转移患者的有效性和安全性。
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INAVO120 (NCT04191499): A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer -
OFFICIAL TITLE: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Inavolisib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer
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随访时间：中位21.3个月比21.5个月 -
18个月无进展生存率：46.2%比21.1% -
无进展生存时间：中位15.0个月比7.3个月（95%置信区间：11.3～20.5、5.6～9.3） -
进展或死亡风险：降低57%（风险比：0.43；95%置信区间：0.32～0.59；P<0.001，小于预设0.0098） -
18个月总生存率：73.7%比67.5% -
总死亡风险：降低36%（风险比：0.64；95%置信区间：0.43～0.97；P=0.03，未小于预设0.0098） -
客观缓解率：58.4%比25.0%
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3或4级中性粒细胞减少：80.2%比78.4% -
3或4级高血糖：5.6%比0% -
3或4级口腔炎或黏膜炎：5.6%比0% -
3或4级腹泻：3.7%比0% -
3或4级皮疹：0比0 -
由于不良事件停用任何试验药物：6.8%比0.6%
N Engl J Med. 2024 Oct 31;391(17):1584-1596. IF: 96.2
Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer.
Turner NC, Im SA, Saura C, Juric D, Loibl S, Kalinsky K, Schmid P, Loi S, Sunpaweravong P, Musolino A, Li H, Zhang Q, Nowecki Z, Leung R, Thanopoulou E, Shankar N, Lei G, Stout TJ, Hutchinson KE, Schutzman JL, Song C, Jhaveri KL.
Royal Marsden Hospital, Institute of Cancer Research, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London; Roche, Welwyn Garden City, United Kingdom; Seoul National University Hospital, Seoul National University College of Medicine, Cancer Research Institute, Seoul National University, Seoul, Korea; Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona; Mass General Cancer Center, Harvard Medical School, Boston; Winship Cancer Institute at Emory University, Atlanta; Genentech, San Francisco; Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York; German Breast Group, Neu-Isenburg; Center for Hematology and Oncology Bethanien, Goethe University, Frankfurt, Germany; Peter MacCallum Cancer Centre, Melbourne, VIC; University of Melbourne, Parkville, VIC, Australia; Prince of Songkla University, Songkhla, Thailand; University of Parma, Parma; IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori,” Meldola, Italy; Peking University Cancer Hospital and Institute, Beijing; Harbin Medical University, Harbin; Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China; Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland.
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
PMID: 39476340
DOI: 10.1056/NEJMoa2404625
N Engl J Med. 2024 Oct 31;391(17):1644-1647. IF: 96.2
Improving the Outcome of Bad-Acting Hormone Receptor-Positive Breast Cancer.
Gradishar WJ.
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago.
PMID: 39476346
DOI: 10.1056/NEJMe2411229