Toffalorio Francesca, Spitaleri Gianluca, Catania Chiara, Dal Zotto Laura, Noberasco Cristina, Delmonte Angelo, Santarpia Mariacarmela, Vecchio Fabio, Brunelli Veronica, Rampinelli Cristiano, Barberis Massimo, Fumagalli Caterina, Zucchetti Massimo, Zangarini Monique, Diena Tullia, Danesi Romano, de Braud Filippo, De Pas Tommaso
European Institute of Oncology, Milan, Italy;
Oncologist. 2014 Apr;19(4):344-5. doi: 10.1634/theoncologist.2013-0335. Epub 2014 Mar 27.
Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated.
Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2.
The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas.
The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.
PI3K和Ras通路的分子改变在人类癌症中经常发生。在本试验中，研究了两种抑制这些通路的药物——依维莫司和索拉非尼的药代动力学、毒性及活性。
13例实体瘤进展患者按照3+3方案接受依维莫司和索拉非尼治疗。根据肿瘤分子靶点（包括磷酸化AKT、-p70S6K和-ERK1/2）的免疫组化表达选择患者。
确定的每日推荐剂量为依维莫司2.5mg和索拉非尼600mg。剂量限制性毒性包括3级乏力和手足皮肤反应。未观察到4级不良事件。最常见的3级毒性为低磷血症（30.8%）、丙氨酸转氨酶水平升高、乏力和厌食（14%）。未发现依维莫司和索拉非尼之间存在药代动力学相互作用。在12例可评估患者中，观察到2例部分缓解，另外5例患者肿瘤缩小超过10%。在1例胸腺瘤患者和1例肺腺癌患者中观察到客观缓解。在1例腹部平滑肌肉瘤和1例腺样囊性癌患者中观察到未达到部分缓解标准的肿瘤缩小。
依维莫司和索拉非尼联合用药安全。在不同肿瘤类型中观察到的肿瘤活性可能是这些药物联合作用以及所治疗人群分子选择的结果。有必要进一步开展研究，以更好地研究同时阻断PI3K和Ras通路的药物，并优化患者选择。
