奥拉帕利＋艾日布林→三阴乳腺癌
奥拉帕利为全球首个多腺苷二磷酸核糖聚合酶（PARP）抑制剂，2018年1月获美国批准用于化疗失败的乳腺癌易感基因（BRCA）突变型HER2阴性转移性乳腺癌。艾日布林为全球首个细胞有丝分裂微管动力抑制剂，2010年11月15日获美国批准用于至少两个化疗方案失败的转移性乳腺癌。
2019年1月28日，欧洲癌症治疗研究组织、欧洲癌症组织、欧洲乳腺癌专科医师学会《欧洲癌症杂志》在线发表日本国家癌症中心、大阪国立医院、四国癌症中心、北海道癌症中心、国家癌症中心东院、神奈川癌症中心、千叶癌症中心、东京圣卢克国际医院、熊本医疗中心、东京大学、北里大学的研究报告，探讨了奥拉帕利＋艾日布林治疗晚期或转移性三阴性乳腺癌日本患者的推荐剂量（I期研究）、有效性和安全性（II期研究）。
该多中心研究（UMIN00009498）分为I期和II期。I期研究的奥拉帕利剂量为每天两次口服25～300毫克，艾日布林剂量为第1、8天每平方米体表面积1.4毫克。II期研究患者接受I期研究推荐的II期研究剂量治疗以评定缓解率（独立复核）。计划样本量为24例，临界值为10%。
结果，参加I期研究的24例患者仅出现1例剂量受限毒性反应，故推荐II期研究剂量为奥拉帕利每天两次300毫克，艾日布林每平方米体表面积1.4毫克。
参加II期研究的24例患者给药疗程中位5.5（范围：1～28）。≥3级不良事件包括中性粒细胞减少、白细胞减少、贫血、发热性中性粒细胞减少、血栓形成（83.3%、83.3%、41.7%、33.3%、8.3%）。
缓解率为29.2%（7例，独立复核；90%置信区间：14.6～47.9）。中位无进展生存、中位总生存分别为4.2、14.5个月（95%置信区间：3.0～7.4、4.8～22.0）。
种系BRCA突变分别见于I期研究3例患者和II期研究2例患者。奥拉帕利的血药浓度峰值和曲线下面积与剂量成正比，艾日布林和奥拉帕利的这些参数无相互影响。
因此，该研究结果表明，奥拉帕利＋艾日布林的联合疗法对于晚期或转移性三阴性乳腺癌具有抗肿瘤活性，对于蒽环类和紫杉类治疗失败的患者有效，但是需要注意发热性中性粒细胞减少。药物代谢动力学分析未见艾日布林与奥拉帕利之间存在药物相互作用。PARP抑制作用可见于最小剂量的奥拉帕利。
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Eur J Cancer. 2019 Jan 28;109:84-91.
A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes.
Kan Yonemori, Akihiko Shimomura, Hiroyuki Yasojima, Norikazu Masuda, Kenjiro Aogi, Masato Takahashi, Yoichi Naito, Satoru Shimizu, Rikiya Nakamura, Jun Hashimoto, Harukaze Yamamoto, Akihiro Hirakawa, Hirofumi Michimae, Akinobu Hamada, Teruhiko Yoshida, Tamie Sukigara, Kenji Tamura, Yasuhiro Fujiwara.
National Cancer Center, Tokyo, Japan; Osaka National Hospital, Osaka, Japan; Shikoku Cancer Center, Ehime, Japan; Hokkaido Cancer Center, Hokkaido, Japan; National Cancer Center Hospital East, Chiba, Japan; Kanagawa Cancer Center, Kanagawa, Japan; Chiba Cancer Center, Chiba, Japan; St. Luke's International Hospital, Tokyo, Japan; Kumamoto Medical Center, Kumamoto, Japan; The University of Tokyo, Tokyo, Japan; Kitasato University, Tokyo, Japan.
HIGHLIGHTS
Olaparib combined with eribulin showed efficacy in patients previously treated with anthracycline and taxanes.
In pharmacokinetics, no drug interaction between eribulin and olaparib was observed.
Poly(ADP-ribose) polymerase inhibition was observed from the lowest dose of olaparib.
BACKGROUND: We conducted a multicenter phase I/II trial of olaparib plus eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer (TNBC) to determine the recommended phase II dose (RP2D) (phase I) and to examine the efficacy and safety (phase II) (UMIN00009498) of the combined therapy.
PATIENTS AND METHODS: In phase I, olaparib tablet was orally administered twice daily from level 1:25 mg BID to level 7:300 mg BID, with 1.4 mg/m2 of eribulin on days 1 and 8. In phase II, patients were treated with RP2D to assess the response rate (independent review). The planned sample size was 24 with a threshold of 10%.
RESULTS: One of the 24 patients enrolled in phase I experienced dose-limiting toxicity. The RP2D was established as 300 mg twice daily for olaparib and 1.4 mg/m2 for eribulin. Among the 24 patients in phase II, the median number of administered courses was 5.5 (range: 1-28). Grade ≥III adverse events included neutropenia (83.3%), leucopenia (83.3%), anaemia (41.7%), febrile neutropenia (33.3%) and thrombosis (8.3%). The response rate was 29.2% (independent; N = 7/24; 90% confidence interval [CI]; 14.6-47.9). Median progression-free survival and overall survival were 4.2 (95% CI, 3.0-7.4) and 14.5 (95% CI, 4.8-22.0) months, respectively. Germline BRCA1/2 mutation status was observed in three patients in phase I and 2 patients in phase II, respectively. The Cmax and area under the curve for olaparib increased in a dose-dependent manner, and these parameters for eribulin and olaparib were not influenced by each other.
CONCLUSIONS: Combination therapy of olaparib with eribulin shows antitumour activity against advanced or metastatic TNBC, but caution must be exercised in the presence of febrile neutropenia.
KEYWORDS: Eribulin, Olaparib, PARP inhibitor, Triple-negative breast cancer, Metastatic disease
DOI: 10.1016/j.ejca.2018.11.014
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