Dillon Patrick M, Petroni Gina R, Horton Bethany J, Moskaluk Christopher A, Fracasso Paula M, Douvas Michael G, Varhegyi Nikole, Zaja-Milatovic Snjezana, Thomas Christopher Y
UVA Cancer Center at the University of Virginia, Charlottesville, Virginia.
Wake Forest University, Winston-Salem, North Carolina.
Clin Cancer Res. 2017 Aug 1;23(15):4138-4145. doi: 10.1158/1078-0432.CCR-16-2942. Epub 2017 Apr 4.
Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC. In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints. Of 34 evaluable patients, 2 (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on treatment ( < 0.001). Toxicity was moderate; 63% of patients developed grade 3-4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on FDG-PET scans was seen in 3 of 15 patients but did not correlate with RECIST response. gene translocation was observed and significantly correlated with overexpression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably with those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine whether FGFR signaling is a valid therapeutic target in ACC. .
基因和临床前研究表明FGFR信号传导与腺样囊性癌（ACC）的发病机制有关。多韦替尼是一种FGFR活性抑制剂，可能对ACC有效。在一项两阶段的II期研究中，35例进展期ACC患者连续7天中有5天口服500mg多韦替尼。主要终点是客观缓解率和肿瘤生长率的变化。无进展生存期、总生存期、代谢反应、生物标志物和生活质量为次要终点。在34例可评估患者中，2例（6%）有部分缓解，22例（65%）疾病稳定>4个月。中位无进展生存期为8.2个月，总生存期为20.6个月。治疗期间总体肿瘤生长率的斜率从1.95降至0.63（P<0.001）。毒性为中度；63%的患者出现3-4级毒性，94%的患者需要调整剂量，21%的患者提前停止治疗。15例患者中有3例基于FDG-PET扫描出现早期代谢反应，但与RECIST反应无关。观察到 基因易位，且与MYB过表达显著相关，但与FGFR1磷酸化或对多韦替尼的临床反应无关。多韦替尼在ACC患者中产生的客观反应较少，但确实抑制了肿瘤生长率，其无进展生存期与其他靶向药物报道的相比具有优势。未来需要在生物标志物选择的患者中对更有效和选择性更强的FGFR抑制剂进行研究，以确定FGFR信号传导是否是ACC中有效的治疗靶点。
