Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.
Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer.
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DOI：
10.1007/s10549-021-06306-4
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发表时间：
2021-08
影响因子：
3.8
通讯作者：
Kalinsky K
中科院分区：
文献类型：
--
作者：
Kearney M;Franks L;Lee S;Tiersten A;Makower DF;Cigler T;Mundi P;Chi DC;Goel A;Klein P;Andreopoulou E;Sparano J;Trivedi M;Accordino M;Califano A;Hershman DL;Silva J;Kalinsky K
临床前数据表明，STAT3在HER2+肿瘤中是一个重要的规则，IL6-JAK2-STAT-S100A8/S100A9信号级联的破坏会降低HER2+细胞的活力。Ruxolitinib是FDA批准的JAK1和JAK2抑制剂。我们进行了一项I/II期试验，研究曲妥珠单抗和鲁索利替尼联合治疗曲妥珠单抗耐药转移性HER2+乳腺癌患者的安全性和有效性。转移性HER2+乳腺癌患者至少接受2种HER2定向治疗。I期部分确定了ruxolitinib联合曲妥珠单抗的耐受剂量。II期的主要目标是评估与历史对照组相比，鲁索利替尼加曲妥珠单抗联合治疗的无进展生存期（PFS）。28名患者入组，既往治疗中位数为4.5次。Ruxolitinib 25mg每日2次是推荐的II期剂量，无dlt。在26名可评估的II期患者中，中位PFS为8.3周（95% CI: 7.1, 13.9）。14例可测疾病患者中，1例部分缓解，4例病情稳定。大多数不良事件为血液学。虽然具有良好的耐受性和强大的临床前理论基础，但与曲妥珠单抗耐药转移性HER2+乳腺癌患者的历史对照相比，ruxolitinib和曲妥珠单抗联合使用并未导致PFS改善。
Preclinical data demonstrate STAT3 as an important regular in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2-directed therapy were eligible. The phase I portion determined the tolerable dose of ruxolitinib in combination with trastuzumab. The primary objective of the phase II was to assess the progression free survival (PFS) of the combination of ruxolitinib plus trastuzumab compared to historical control. Twenty-eight patients were enrolled, with a median number of prior therapies of 4.5. Ruxolitinib 25mg twice daily was the recommended phase II dose with no DLTs. Of 26 evaluable patients in phase II, the median PFS was 8.3 weeks (95% CI: 7.1, 13.9). Among the 14 patients with measurable disease, 1 patient had a partial response and 4 patients had stable disease. Most of the adverse events were hematologic. While well-tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in PFS compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer.
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影响因子：
3.4
作者：
Hurwitz H;Van Cutsem E;Bendell J;Hidalgo M;Li CP;Salvo MG;Macarulla T;Sahai V;Sama A;Greeno E;Yu KH;Verslype C;Dawkins F;Walker C;Clark J;O'Reilly EM
通讯作者：
O'Reilly EM
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
影响因子：
3.8
作者：
O'Shaughnessy, Joyce;DeMichele, Angela;Rugo, Hope S.
通讯作者：
Rugo, Hope S.
DOI：
10.1056/nejmoa1409002
发表时间：
2015-01-29
期刊：
The New England journal of medicine
影响因子：
--
作者：
Vannucchi AM;Kiladjian JJ;Griesshammer M;Masszi T;Durrant S;Passamonti F;Harrison CN;Pane F;Zachee P;Mesa R;He S;Jones MM;Garrett W;Li J;Pirron U;Habr D;Verstovsek S
通讯作者：
Verstovsek S