Laetsch Theodore W, Voss Stephan, Ludwig Kathleen, Hall David, Barkauskas Donald A, DuBois Steven G, Ronan Joan, Rudzinski Erin R, Memken Amanda, Robinson Krystal, Sorger Joel, Reid Joel M, Bhatla Teena, Crompton Brian D, Church Alanna J, Fox Elizabeth, Weigel Brenda J
Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
Department of Radiology, Dana-Farber Cancer Institute, Boston, MA.
J Clin Oncol. 2025 Apr;43(10):1188-1197. doi: 10.1200/JCO-24-01854. Epub 2024 Dec 9.
The TRK inhibitor larotrectinib is US Food and Drug Administration approved for fusion-positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed fusion-positive solid tumors with response-adapted duration of therapy and local control.
Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS).
Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities.
Larotrectinib is highly active in patients with newly diagnosed fusion-positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other fusion-positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.
TRK抑制剂拉罗替尼已获美国食品药品监督管理局批准，用于治疗缺乏满意替代疗法或治疗后病情进展的融合阳性实体瘤，但尚未作为具有明确治疗疗程的一线疗法进行系统研究。ADVL1823研究评估了拉罗替尼在新诊断的融合阳性实体瘤患者中的疗效，治疗疗程根据反应进行调整，并关注局部控制情况。
患者接受拉罗替尼治疗，每日两次，每28天为一个周期，治疗疗程预先设定，根据治疗反应和手术可切除性，疗程为6至26个周期。主要终点是婴儿纤维肉瘤（IFS）患者在六个周期内的客观缓解率（ORR）；其他组织学诊断的患者在单独队列中进行分析。次要目标包括无事件生存期（EFS）和总生存期（OS）。
共纳入33例患者：18例为IFS患者，15例为其他实体瘤患者。IFS患儿六个周期内的ORR为94%（17/18；95%校正CI，72.7至98.6），其他实体瘤患儿的ORR为60%（9/15；95%CI，32.3至83.7）。6%（2/33；95%CI，0.7至22.2）的患者在治疗期间出现疾病进展。这些组中IFS患者的两年EFS和OS分别为82.2%（95%CI，54.3至93.9）和93.8%（95%CI，63.2至99.1），其他实体瘤患者分别为80%（95%CI，50.0至93.1）和93.3%（95%CI，61.3至99.0）。接受肿瘤手术切除的患者EFS延长，16例此类患者中只有1例出现疾病进展。33例患者中有4例出现剂量限制性毒性。
拉罗替尼在新诊断的融合阳性实体瘤患者中具有高活性。拉罗替尼应作为IFS患者和其他融合阳性实体瘤患者的一线治疗选择。手术切除实现局部控制在IFS患者治疗中仍然很重要。
