[ASCO2016]PI3K抑制剂联合氟维司群用于HER-/HR+晚期乳腺癌
2016年美国临床肿瘤学会（ASCO）年会将于6月3日至7日在美国芝加哥举行。会上将公布一项关于PI3K抑制剂taselisib（GDC-0032）联合氟维司群用于HER2阴性、激素受体（HR）阳性的晚期乳腺癌患者的II期研究（摘要号520)。研究详情如下：
在HR阳性乳腺癌中，PI3K通路是激活的，这通常是经由40%左右的HR阳性乳腺癌中发生的PIK3CA功能突变导致的。Taselisib一种有效的选择性PI3K抑制剂，与野生型PI3Kα相比，对PI3Kα突变亚型具有更高的选择性。Ib期研究初步显示taselisib联合氟维司群对HR阳性乳腺癌具有有效性，且耐受性良好。
这项II期、开放标签的单臂研究招募了发生疾病进展或在辅i助治疗或转移性疾病治疗阶段对1种及以上内分泌治疗没有应答的绝经后的、HER阴性、HR阳性、局部晚期或转移性乳腺癌患者。在该研究中，患者每天口服6mg的taselisib，并在第一个疗程的第一天、第15天肌注500mg的氟维司群，之后在每个疗程的第一天注射。4周为一个疗程。用药直至疾病进展或出现不可接受毒性。
研究人员对存档的肿瘤组织集中进行cobas PIK3CA突变检测，以回顾性验证PIK3CA突变状态。研究的首要终点为所有患者及PIK3CA突变患者的客观缓解率（RECIST版 1.1）和临床获益率（CBR；验证的CR和PR，或疾病稳定超过180天）。次要终点包括安全性、有效性和药代动力学。
研究共招募了60位患者。其中17例具有PIK3CA突变，27例为PIK3CA野生型，16例患者的PIK3CA状态未知。在基线疾病可测的患者中，PIK3CA突变患者的验证缓解率为41.7%（n = 12），PIK3CA野生型为14.3%（n = 21），突变状态未知的患者为9.1%（n = 11）。所有验证的缓解均为局部缓解。PIK3CA突变患者的CBR为41.7%，PIK3CA野生型患者为23.8%，突变状态未知的患者为27.3%。
3级及以上常见不良事件（AE）为结肠炎（13.3%），腹泻（11.7%），高血糖症（6.7%）和肺炎（5%）。18.3%的患者由于不良事件没有继续taselisib治疗。
Taselisib联合氟维司群对于HER2阴性、HR阳性的晚期乳腺癌患者具有可接受的副反应和临床获益。与PIK3CA野生型患者相比，PIK3CA突变的患者具有更高的缓解率和CBR。目前检测Taselisib联用氟维司群疗效的III期研究正在进行中。
摘要原文
A phase II study of the PI3K inhibitor taselisib (GDC-0032) combined with fulvestrant (F) in patients (pts) with HER2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (BC).Abstract No:520
Background: The PI3K pathway is activated in HR+ BC, often via gain-of-function mutations in PIK3CA that occur in ~40% of HR+ BC. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant PI3Kα isoforms than wild type (WT) PI3Kα. Phase Ib data demonstrated good tolerability and preliminary efficacy for taselisib + F in HR+ BC.
Methods: This Phase II, open-label, single-arm study enrolled post-menopausal pts with HER2-, HR+ locally advanced or metastatic BC (mBC) who had progression or non-response to ≥ 1 prior endocrine therapy in adjuvant or mBC settings. Pts received taselisib (6 mg capsule PO qd) plus F (500 mg IM on Cycle 1 Day 1, Cycle 1 Day 15, then q4w Day 1 of each cycle) until progressive disease or unacceptable toxicity. PIK3CA mutation status was centrally confirmed retrospectively on archival tumor tissue by 'cobas'PIK3CA Mutation Test. Primary endpoints were objective response rate (RECIST version 1.1) and clinical benefit rate (CBR; confirmed CR and PR, or stable disease for > 180 days) in all pts and pts with PIK3CA mutations. Secondary endpoints include additional measures of safety, efficacy and pharmacokinetics.
Results: 60 pts were enrolled; 17 had PIK3CA mutations, 27 had WT PIK3CA and 16 had unknown PIK3CA mutation status. Among pts with baseline measurable disease, confirmed response rates were: PIK3CA mutations (n = 12) 41.7%, WT (n = 21) 14.3%, unknown (n = 11) 9.1%; all confirmed responses were PRs. CBRs were: PIK3CA mutations 41.7%, WT 23.8%, unknown 27.3%. Common Grade ≥ 3 adverse events (AE) were colitis (13.3%), diarrhoea (11.7%), hyperglycaemia (6.7%), and pneumonia (5%). 18.3% of patients discontinued taselisib treatment due to an AE. More detailed safety and efficacy data will be presented.
Conclusions: The combination of taselisib plus F had an acceptable side effect profile and clinical activity in pts with HER2-, HR+ advanced BC, with a numerically higher response and CBR in patients with PIK3CA mutations compared with WT pts. Taselisib is currently being tested with F in a randomized Phase III study (SANDPIPER, NCT02340221). Clinical trial information: NCT02340221