Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: Two integrated analyses published in The Lancet Oncology support the use of the tropomyosin receptor kinase A, B and C inhibitor entrectinib for the treatment of advanced and metastatic cancers with NTRK or ROS1 gene fusions.
The first analysis by George Demetri, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors collated data from the ongoing phase I–II ALKA-372-001, STARTRK-1 and STARTRK-2 trials of an entrectinib dose of at least 600 mg/day among 355 patients with locally advanced or metastatic solid tumours who received at least one dose.
Of the 54 participants with NTRK fusion-positive disease that were assessable for efficacy, over a third (37%) were treatment-naïve, while 20% had received one, 26% two and 17% at least three prior lines of treatment for 10 different types of tumours. These included sarcoma (24%), non-small cell lung cancer (NSCLC, 19%), salivary carcinoma (13%), and breast cancer (11%), and a fifth (22%) of patients had central nervous system (CNS) metastases at baseline.
At data cutoff, after a median of 12.9 months of follow-up, 7% of the NTRK fusion-positive patients had experienced a complete objective response and 50% a partial response, with responses lasting a median of 10 months.
Analysis of both the full study population and the 68 patients in the NTRK fusion-positive safety group who had received at least one dose of entrectinib showed that the most common grade 3–4 treatment-related adverse events (TRAEs) were weight gain (10% and 5%, respectively) and anaemia (5% and 12%).
“These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours”, say George Demetri et al, who believe their findings “highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.”
Robert Doebele, from the University of Colorado in Aurora, USA, and co-authors of the second integrated analysis, report “systemic and intracranial activity” for the use of entrectinib in the 53 ROS1 fusion-positive NSCLC participants of the same three trials.
Efficacy analysis at cutoff after a median of 15.5 months revealed objective responses in 77% of the patients, including a complete response in 6%, and these responses lasted a median of 24.6 months.
Objective responses occurred in 74% of the 23 patients with baseline CNS metastases and 80% of those without CNS disease at baseline, with a median duration of 12.6 and 24.6 months, respectively.
“The intracranial activity of entrectinib is of particular importance because of the frequency of CNS involvement in ROS1 fusion-positive NSCLC and the suboptimal ability of crizotinib to penetrate the CNS”, the investigators emphasize.
The safety evaluation cohort of 134 patients revealed grade 1 or 2 TRAEs in 59% and grade 3 or 4 TRAEs in 34%, with the latter mostly commonly being weight gain (8%) and neutropenia (4%). Serious TRAEs were reported in 11% of this group, with 3% affecting the CNS and 2% the cardiovascular system.
“The safety profile of entrectinib is favourable, making it amenable to long-term dosing in this population in which durable disease control was observed”, comment Alexander Drilon et al.
“These results underscore the need to routinely test for ROS1 fusions in the clinic to broaden therapeutic options for patients as is already recommended by several independent groups”, they say.
Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol; Advance online publication 11 December 2019. https://doi.org/10.1016/S1470-2045(19)30691-6
Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol; Advance online publication 11 December 2019. https://doi.org/10.1016/S1470-2045(19)30690-4
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