The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas
The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas
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DOI：
10.1002/cncr.31701
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发表时间：
2018-11-01
期刊：
影响因子：
6.2
通讯作者：
Pappo, Alberto S.
中科院分区：
文献类型：
--
作者：
DuBois, Steven G.;Laetsch, Theodore W.;Pappo, Alberto S.
高选择性口服原肌球蛋白受体激酶（TRK）抑制剂larotrectinib在成人和儿童TRK融合癌中表现出显著的活性。在本研究中，作者描述了术前接受larotrectinib治疗并随后接受手术切除的局部晚期TRK融合肉瘤儿童的临床病程。方法共有24名儿童接受了larotrectinib的儿科I期试验（ClinicalTrials.gov标识符NCT 02637687）。目前的分析包括5名患有TRK融合肉瘤并接受手术切除的儿童。前瞻性收集肿瘤缓解（实体瘤疗效评价标准[RECIST]第1.1版）和手术结局。结果5例患者（中位年龄2岁，范围0.4 ~ 12岁），局部晚期婴儿纤维肉瘤（3例）或软组织肉瘤（2例）。4名患者患有标准治疗难治性疾病。根据RECIST 1.1版，所有5例患者对larotrectinib均达到部分缓解，并在中位6个周期（范围，4-9个周期）治疗后接受手术切除。3例患者的手术切除为R 0（阴性切缘，在油墨切缘处无肿瘤），1例患者为R1（切缘处显微镜下残留肿瘤），1例患者为R2（切缘处肉眼可见残留肿瘤）。3名患者达到完全（2名患者）或接近完全（>98%治疗效果; 1名患者）病理学反应。这些患者仍在随访中，术后至少7至15个月内不再接受larotrectinib。2例患者在手术切除时有存活肿瘤，切缘阳性，并继续接受辅助larotrectinib治疗。无患者发生术后并发症或伤口愈合问题。结论：局部晚期TRK融合肉瘤患儿在接受选择性TRK抑制剂larotrectinib治疗后，可继续手术切除，从而避免了目前方法可能导致的严重发病率。这些结果支持评价larotrectinib作为新诊断TRK融合肉瘤儿童的术前治疗。
Background The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. Methods A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. Results A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. Conclusions Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.