Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

Abstract

Background Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. In all patients, the 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45–100), 56% (95% CI: 38–74), and 85% (95% CI: 71–99), respectively. Median time to response was 1.9 months (range 1.0–3.8 months). Duration of treatment ranged from 1.2–31.3+ months. Treatment-related adverse events were reported for 20 patients, with Grade 3–4 in 3 patients. No new safety signals were identified. Conclusions In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.

The Challenge and Opportunity of NTRK Inhibitors in Non-Small Cell Lung Cancer

“…Although intracranial ORR was not carefully assessed in this trial, CNS progression was uncommon on larotrectinib. Furthermore, there are also multiple published case reports of CNS objective responses that have been observed on larotrectinib [ 27 , 28 , 29 ]. While the CNS activity is more robustly detailed for entrectinib, the available data suggest that both larotrectinib and entrectinib are active against CNS disease.…”

“…Similar to other TKIs, the durability of the first generation NTRK inhibitors is often limited by mutations that affect NTRK inhibitors’ binding interactions, including both primary and acquired resistance [ 29 , 30 ]. Thus, 2nd generation NTRK inhibitors were developed to overcome these resistance mutations.…”

“…As expected, there would be drug resistance to both 1st and 2nd generation NTRK inhibitors. NTRK drug resistance can be classified into on-target resistance, which means drug resistance mediated by mutation of the TRK kinase domain, and off-target resistance, which activates bypass or downstream pathways [ 29 , 30 , 31 ].…”

Molecular Aberrations Stratify Grade 2 Astrocytomas Into Several Rare Entities: Prognostic and Therapeutic Implications

“…Moreover, targeted therapy might also become a new potential treatment strategy. Indeed, encouraging results from basket trials showed clinically meaningful efficacy in gliomas harboring BRAF V600E mutation or NTRK 1/2/3 fusions, although missing enough data about grade 2 astrocytoma (73,74). Currently, as previously mentioned, since these data derive from retrospective cohorts of patients treated according to clinicians' choice, American Society of Clinical Oncology (ASCO)-SNO guidelines were found to be really helpful and affordable for the therapeutic management of diffuse astrocytic and oligodendroglial tumors in adults (50).…”

Entrectinib demonstrates prolonged efficacy in an adult case of radiation-refractory NTRK fusion glioblastoma

“…However, of 6 patients for which lesion size could be quantifiably assessed, 4 achieved a decrease in tumor size that did not qualify as a RANO partial response, and the 24-week disease control rate was 57% in adult patients. 12 …”