Thavaneswaran Subotheni, Sim Hao-Wen, Grady John, Espinoza David, Huang Min Li, Lin Frank, McGrath Margaret, Desai Jayesh, Charakidis Michail, Brown Michael, Kansara Maya, Simes John, Thomas David
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW 2050, Australia.
The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW 2010, Australia.
Oncologist. 2025 Aug 4;30(8). doi: 10.1093/oncolo/oyae339.
TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear.
This trial enrolled patients with advanced cancers harboring NTRK fusions or extreme mRNA overexpression, defined as NTRK1/2/3 expression by RNA profiling >5 SDs for a given cancer type. The primary endpoint was objective response rate (ORR), with secondary endpoints including time-to-progression (TTP) ratio [TTP on study to TTP on previous systemic therapy (TTP1)], progression-free survival (PFS), and overall survival (OS). Initially planned for 2 non-comparator groups: primary central nervous system (CNS) and non-CNS tumours with NTRK fusions, the protocol was amended to permit NTRK overexpression.
Seventeen patients were treated with larotrectinib: one glioblastoma with a SPECC1L::NTRK2 fusion (group 1), and a peripheral nerve sheath tumor with a TPM3::NTRK1 fusion and 15 patients with overexpression (group 2). The ORR was 6%. An additional 3 of 12 (25%) TTP1-evaluable patients achieved a TTP ratio ≥1.3 and 2 of 5 without an evaluable TTP1 had a PFS >6 months. Median PFS and OS were 3.5 (95% CI, 1.4-6.0) and 15.9 months (95% CI, 6.4-NR), respectively.
Unlike its efficacy in NTRK-fusion positive cancers, larotrectinib did not demonstrate a signal of efficacy among tumors with NTRK overexpression.
TRK抑制剂已在多种伴有NTRK融合的癌症中显示出疗效。其在NTRK过表达癌症中的活性尚不清楚。
本试验纳入了患有NTRK融合或极端mRNA过表达的晚期癌症患者，极端mRNA过表达定义为通过RNA分析，NTRK1/2/3的表达高于给定癌症类型的5个标准差。主要终点是客观缓解率（ORR），次要终点包括疾病进展时间（TTP）比率[TTP（研究中的TTP）与先前全身治疗的TTP（TTP1）之比]、无进展生存期（PFS）和总生存期（OS）。该方案最初计划分为2个非对照组：原发性中枢神经系统（CNS）和伴有NTRK融合的非CNS肿瘤，后修订为允许NTRK过表达。
17例患者接受了拉罗替尼治疗：1例伴有SPECC1L::NTRK2融合的胶质母细胞瘤（第1组），1例伴有TPM3::NTRK1融合的外周神经鞘瘤，以及15例过表达患者（第2组）。ORR为6%。在12例可评估TTP1的患者中，另有3例（25%）达到TTP比率≥1.3，5例无可评估TTP1的患者中有2例PFS>6个月。中位PFS和OS分别为3.5个月（95%CI，1.4 - 6.0）和15.9个月（95%CI，6.4 - NR）。
与在NTRK融合阳性癌症中的疗效不同，拉罗替尼在NTRK过表达的肿瘤中未显示出疗效信号。
