Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

Abstract

Entrectinib (Rozlytrek ® ) is an orally active, CNS-penetrant, small-molecule, selective inhibitor of the tropomyosin receptor tyrosine kinases TRKA/B/C [encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1/2/3 , respectively], the proto-oncogene tyrosine-protein kinase ROS1 ( ROS1 ) and the anaplastic lymphoma kinase gene ( ALK ). It is approved for the treatment of adults and paediatric patients aged ≥ 12 years with NTRK fusion-positive ( NTRK+ ) solid tumours and adults with ROS1 fusion-positive ( ROS1+ ) non-small-cell lung cancer (NSCLC). In trials in adults, entrectinib induced clinically meaningful and durable systemic responses in tyrosine kinase inhibitor (TKI)-naïve patients with locally-advanced or metastatic NTRK + solid tumours or ROS1 + NSCLC, irrespective of the presence or absence of CNS metastases at baseline. Moreover, entrectinib demonstrated substantial intracranial efficacy in patients with baseline CNS metastases. Entrectinb efficacy in paediatric patients was established on the basis of extrapolation of clinical trial data from adults with NTRK+ solid tumours and children and adolescents aged < 21 years with recurrent or refractory NTRK+ CNS/solid tumours. Entrectinib was generally well tolerated, with a manageable safety profile. Thus, entrectinib expands the range of treatment options for advanced NTRK + solid tumours and ROS1 + NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases.

Trends in treatment patterns and survival outcomes in advanced non-small cell lung cancer: a Canadian population-based real-world analysis

“…In the early-to-mid 2000s, the first approvals of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with a better understanding of the role of "driver" mutations in the pathogenesis and progression of NSCLC marked the start of the targeted therapy era [4,5]. Subsequently, TKIs targeting other driver mutations, such as anaplastic lymphoma kinase (ALK), ROS1, BRAF V600E, or NTRK1/2/3 alterations have been approved for patients with NSCLC tumors harboring these mutations [6][7][8][9][10]. More recently, immuno-oncology (I-O) therapies, primarily immune checkpoint inhibitors targeting the programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway, have demonstrated improved survival outcomes versus standard chemotherapy in randomized clinical trials and have emerged as recommended first-and second-line treatments in Europe and North America for patients with advanced NSCLC without actionable driver mutations [3,[11][12][13][14][15].…”

Case report: complete remission with crizotinib in ROS1 fusion-positive sinonasal mucosal melanoma

“…Since the NTRK basket trial demonstrates the efficacy of entrectinib as a monotherapy in metastatic NTRK rearranged solid tumors ( 26 ). Basket trails can be attempted for ROS1 rearranged or ROS1 fusion tumors, in which ROS1 inhibitors such as crizotinib are used whenever ROS1 rearranged or ROS1 fusion is detected, regardless of tumor types, for a broader tumor agnostic approval.…”

Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies

“…Entrectinib ( 45 ) is a tropomyosin receptor tyrosine kinase (TRK) TRKA, TRKB, TRKC, proto-oncogene tyrosine protein kinase ROS1 (ref. 98) and anaplastic lymphoma kinase (ALK) inhibitor for the treatment of ROS1-positive metastatic non-small cell lung cancer with NTRK gene fusion-positive solid tumors (Fig. 27a).…”