晚期乳腺癌内分泌治疗失败新对策
大约40%的激素受体阳性HER2阴性乳腺癌患者存在PIK3CA突变，对内分泌治疗效果不佳。早期研究结果表明，PI3Kα特异性抑制剂阿尔卑利昔（BYL719、阿吡利塞、阿培利司）对于PIK3CA突变乳腺癌具有抗癌活性。
2019年5月16日，美国麻省医学会《新英格兰医学杂志》发表法国古斯塔夫鲁西研究所、巴黎第十一大学、西部癌症研究所、西班牙马德里大学医院、匈牙利杜纳医疗中心国家肿瘤研究所、德国乳腺癌研究协作组、法兰克福血液学肿瘤学中心、美国旧金山加利福尼亚大学海伦迪勒家族综合癌症中心、范德堡大学、哈佛大学医学院麻省总医院癌症中心、日本爱知癌症中心、神奈川癌症中心、埼玉癌症中心、北海道癌症中心、意大利帕多瓦大学威尼托肿瘤研究所、以色列查姆希巴医疗中心、中国台湾大学医院的SOLAR-1研究报告，比较了氟维司群±阿尔卑利昔对晚期乳腺癌内分泌治疗失败患者的有效性和安全性。
SOLAR-1: A Phase III Randomized Double-blind, Placebo Controlled Study of Alpelisib in Combination With Fulvestrant for Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment (NCT02437318)
该国际多中心安慰剂随机对照三期研究于2015年7月26日～2017年7月21日从34个国家地区198个研究中心入组激素受体阳性HER2阴性晚期乳腺癌芳香酶抑制剂治疗失败患者572例，按1∶1随机分组接受阿尔卑利昔＋氟维司群或安慰剂＋氟维司群。根据肿瘤组织PIK3CA突变状态（其中确认肿瘤组织PIK3CA突变341例）进行亚组分析。主要终点为研究者评定的无进展生存，次要终点包括总缓解率和安全性。
结果，阿尔卑利昔与安慰剂相比：
对于PIK3CA突变患者，中位随访20个月时
中位无进展生存期：11.0比5.7个月（95%置信区间：7.5～14.5、3.7～7.4）
一年无进展生存率：46.3%比32.9%
进展＋死亡风险比：0.65（95%置信区间：0.50～0.85，P<0.001）
完全＋部分缓解率：26.6%比12.8%
对于PIK3CA未变患者，中位随访7.4个月时
中位无进展生存期：7.4比5.6个月（95%置信区间：5.4～9.3、3.9～9.1）
一年无进展生存率：28.4%比22.2%
进展＋死亡风险比：0.85（95%置信区间：0.58～1.25，风险比<1.00占79.4%）
阿尔卑利昔与安慰剂相比，不良事件发生率：
3～4级高血糖：36.6%比0.7%
3～4级皮疹：9.9%比0.3%
3级腹泻：6.7%比0.3%
4级腹泻：0比0
不良事件所致停药：25.0%比4.2%
因此，该研究结果表明，对内分泌治疗失败的PIK3CA突变激素受体阳性HER2阴性晚期乳腺癌患者，阿尔卑利昔＋氟维司群可以显著延长无进展生存。
相关阅读
N Engl J Med. 2019 May 16;380(20):1929-1940.
Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.
André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group.
Institut Gustave Roussy, Université Paris-Sud, Villejuif; Institut de Cancérologie de l'Ouest, St. Herblain; Novartis Pharma, Paris, France; Hospital Universitario 12 de Octubre, Madrid; National Institute of Oncology, Duna Medical Center, Budapest, Hungary; German Breast Group, Neu-Isenburg; Center for Hematology and Oncology Bethanien, Frankfurt, Germany; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco; Aichi Cancer Center, Nagoya, Kanagawa Cancer Center, Yokohama, Saitama Cancer Center, Saitama; National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan; Istituto Oncologico Veneto, University of Padua, Padua, Italy; Vanderbilt University, Nashville; Chaim Sheba Medical Center, Tel Hashomer, Israel; National Taiwan University Hospital, Taipei; Novartis Pharma, Basel, Switzerland; Novartis Pharmaceuticals, East Hanover, NJ; Massachusetts General Hospital Cancer Center, Boston.
BACKGROUND: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies.
METHODS: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety.
RESULTS: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively.
CONCLUSIONS: Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously.
Funded by Novartis Pharmaceuticals
SOLAR-1 ClinicalTrials.gov number: NCT02437318
PMID: 31091374
DOI: 10.1056/NEJMoa1813904