Entrectinib 100mg capsules

PURPOSE: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. PATIENTS AND METHODS: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. RESULTS: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0-38.2]; median PFS was 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1) and median intracranial DoR was 22.1 (95% CI, 7.4-not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. CONCLUSIONS: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

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This report describes a case of a 56-year-old male with non-small cell lung cancer who had been on entrectinib 600 mg daily for five years. He presented with an acute onset of chest pain associated with transient ST elevation and troponin rise in the context of alcohol intoxication. He was investigated with a coronary artery angiogram, a transthoracic echocardiogram, and a cardiac magnetic resonance imaging, which were all unremarkable. The ST elevation resolved after withholding entrectinib for two days. Given that no other cause was identified, it suggests that entrectinib may be the potential cause. Considering the patient's good response to entrectinib in the past, we recommenced entrectinib at a reduced dose of 400 mg daily after withholding it for three weeks. This late onset of ECG changes after such a prolonged treatment duration has not been reported previously, and the underlying mechanism remains unclear. It is also uncertain whether heavy alcohol intake is a contributing factor. Further research is needed to investigate the long-term cardiac toxicity of entrectinib and the potential interactions between entrectinib and alcohol.

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Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 .

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BACKGROUND: Entrectinib, a central nervous system (CNS)-penetrant TRK/ROS1 inhibitor, has demonstrated clinical activity in children with NTRK1/2/3 or ROS1 fusion-positive extracranial solid and CNS tumours. We present integrated data of entrectinib in children with NTRK or ROS1 fusion-positive tumours from the STARTRK-NG, TAPISTRY, and STARTRK-2 trials. METHODS: Efficacy analyses were undertaken on TRK/ROS1 inhibitor-naïve patients aged <18 years with metastatic/locally advanced NTRK1/2/3 or ROS1 fusion-positive extracranial solid or CNS tumours who received ≥1 entrectinib dose and had ≥6 months of follow-up from enrolment. Tumour responses were confirmed by blinded independent central review (BICR) per RECIST v1.1/RANO criteria. PRIMARY ENDPOINT: BICR-assessed confirmed objective response rate (cORR). Key secondary endpoints: duration of response (DoR); time to response (TtR); safety. RESULTS: As of 16 July 2023, out of 91 safety-evaluable patients, 64 (NTRK: n=44; ROS1: n=20) were efficacy evaluable. In the NTRK and ROS1 subgroups, respectively, median age was 4.0 years and 7.5 years; median survival follow-up was 24.2 months and 27.6 months. cORR was 72.7 % (NTRK, 95 % confidence interval [CI]: 57.2-85.0) and 65.0 % (ROS1, 95 % CI: 40.8-84.6). Median DoR was not reached (NTRK, 95 % CI: 25.4-not evaluable [NE]); ROS1, 95 % CI: 16.2-NE); median TtR was 1.9 months in both subgroups. The most frequently reported treatment-related adverse events included weight gain (35.2 %) and anaemia (31.9 %). CONCLUSION: Integrated data from three trials confirm entrectinib induces rapid and durable responses in children with NTRK or ROS1 fusion-positive tumours. The increased duration of safety monitoring does not demonstrate new or cumulative toxicity. Registered clinical trials: STARTRK-NG: NCT02650401; TAPISTRY: NCT04589845; STARTRK-2: NCT02568267.

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Background: The tyrosine receptor kinase inhibitor (TRKi) entrectinib is used to treat neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumors and ROS1-positive patients. Despite its impressive efficacy against cancer, the clinical application is still limited by the central nervous system (CNS)-related toxicities. However, the precise mechanism of such CNS-related toxicities remains elusive. Methods: models. Various assays, including CCK-8, colony formation and EdU incorporation assays were utilized to estimate the cellular viability and proliferation ability. Cell apoptosis was measured by flow cytometry. Next, transcriptome sequencing technology was performed to identify differentially expressed genes (DEGs). Gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) analysis and gene set enrichment analysis (GSEA) were applied to predict the potential functions of DEGs. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting assays were performed to measure the expressions of thrombospondin-1 (THBS1), TGF-β1, PI3K, AKT and phosphorylated AKT (p-AKT) in the entrectinib-treated nerve cells. Additionally, we Preliminary observed and validated whether THBS1 overexpression could rescue nerve cell damage and the abnormalities in PI3K-AKT and TGF-β signaling pathways. Results: Entrectinib significantly inhibited the nerve cells proliferation and colony formation, and induced nerve cells apoptosis. Transcriptome sequencing analysis and qRT-PCR revealed that THBS1 was downregulated within entrectinib treatment. KEGG and GSEA analysis also suggested that entrectinib directly caused the abnormalities in proliferation-related signaling pathway like PI3K-AKT pathway, and apoptosis-related signaling pathway including TGF-β pathway. We further demonstrated that THBS1, TGF-β1, PI3K, AKT and p-AKT were downregulated by entrectinib. Meanwhile, pretreatment with THBS1 overexpression plasmids significantly rescued nerve cells (PC12, HT22 and SK-N-SH) from cell death and the abnormalities in PI3K-AKT and TGF-β signaling pathways. Conclusion: These results identified a critical role of entrectinib in promoting nerve cell damage by downregulating the expression of THBS1 while also inhibiting PI3K-AKT and TGF-β signaling pathways. Our findings will provide potential therapeutic targets for CNS-related toxicities.

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