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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In addition to the ALK-related agents described above, many other types of similar kinases might be targeted with potential clinical benefit, and the list of potential targets is growing. For example, entrectinib has Orphan Drug and Rare Pediatric Disease designations for the treatment of neuroblastoma, and Orphan Drug designation for TrkA-, TrkB-, TrkC-, ROS1-, and ALK-positive NSCLC cancers. NPM-ALK is a different variation/fusion of ALK that drives anaplastic large-cell lymphomas (ALCLs) and is the target of other ALK inhibitors.
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models [99]. The approval of entrectinib is based on the results of three phase 1/2 entrectinib trials with data integrated in a large cohort of adults with ROS1 fusion-positive NSCLC ROS1-positive or NTRKL fusion-positive solid tumors [100]. Across studies, 53 patients with ROS1 mutation positive NSCLC, the ORR was 55% (31.5–76.9%), median duration of response was 12.9 months (5.6 months versus not evaluable), and median PFS was 7.7 months (3.8–19.3 months). Entrectinib induced clinically meaning durable responses, including responses in CNS metastases.
Evaluating entrectinib as a treatment option for non-small cell lung cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Jiyun Lee, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Entrectinib is an oral pan-TRK, ALK, and ROS1 inhibitor that has demonstrated its antitumor activity in murine, human tumor cell lines, and patient-derived xenograft (PDX) tumor models [4,8,11]. In vitro, entrectinib inhibits the TRK family members TRKA, TRKB, and TRKC at low nanomolar concentrations with half maximal inhibitory concentrations (IC50) of 1, 3, and 5 nmol/L, respectively. It also inhibits ALK and ROS1 with IC50 of 12 and 7 nmol/L, respectively [8]. Entrectinib behaves as a pure ATP competitor, as it competitively inhibits ATP, but is not a peptide substrate [4]. When entrectinib was administered in the fasted state, exposure (Cmax and AUC) appeared to increase in a dose-proportional manner across the dose range of 100 to 800 mg/m2. Its exposure increased in a less than dose-proportional manner when it was administered with food. The exposure increased in a linear manner from 100 to 400 mg/m2, and from 600 to 800 mg flat dosing [12]. It is highly bound to plasma proteins (~99.5%), and can readily diffuse across the blood-brain barrier (BBB). In one study, the time to maximal concentration of entrectinib was 2–4 hours in the fasted state and 5–7 hours in the fed state [13]. The steady state was reached within 2 weeks of continuous dosing. Its plasma half-life was 20–22 hours, compatible with a once-daily, continuous dosing regimen [12]. It is mainly metabolized by CYP3A4 (~76%), with minor contributions from CYP2C9 and CYP1C19 [8]. It is mainly excreted through feces (83%), with minimal excretion in the urine (3%).
Site-agnostic biomarker-guided oncology drug development
Published in Expert Review of Molecular Diagnostics, 2020
In August 2019, another site-agnostic drug obtained regulatory approval, which was entrectinib, which is a central nervous system (CNS) active multi-kinase inhibitor that inhibits TRKA, TRKB, and TRKC as well as ROS1 and ALK. With somewhat lower potency entrectinib also inhibits JAK2 and TNK2 [30–32]. Together with the approval for patients with NTRK gene fusion-positive solid tumors, entrectinib was also approved for patients with NSCLC whose tumors are ROS1-positive. As for the other site-agnostic drugs, entrectinib was approved under accelerated approval based on tumor response rate and duration of response data obtained from three multicenter, open-label, non-randomized enrichment basket trials, as shown in Figure 5. The efficacy was assessed in 54 adult patients with unresectable or metastatic solid tumors harboring NTRK genes fusion [31]. The most common tumor types were sarcoma (24%), lung cancer (19%), salivary gland cancer (13%), and breast cancer (11%). The median age of the patients was 57 years and 69% of them had metastatic disease, including 22% with CNS metastases. All patients had received prior treatment for their cancer disease including surgery, radiotherapy, or systemic therapy.
Tropomyosin receptor kinase inhibitors: an updated patent review for 2016–2019
Published in Expert Opinion on Therapeutic Patents, 2020
Justin J. Bailey, Carolin Jaworski, Donovan Tung, Carmen Wängler, Björn Wängler, Ralf Schirrmacher
The novel design of basket clinical trials, wherein a targeted therapy is evaluated on multiple diseases sharing a common molecular alteration, has provided a streamlined path to approval for the two established pan-Trk inhibitors larotrectinib (branded Vitrakvi, formerly LOXO-101; Loxo Oncology, Stamford, CT) and entrectinib (branded Rozlytrek, formerly RXDX-101; Ignyta, San Diego, CA). Larotrectinib was approved in 2017 to treat NTRK-positive cancers after just roughly 4 years of clinical testing, making it the second drug ever approved that targets a tumor’s specific genetic mutation, regardless of the tissue of origin (the first being Merck’s (Kenilworth, NJ) anti-PD-1 antibody pembrolizumab (branded Keytrunda) in 2017). Entrectinib was the third approved tissue-agnostic therapeutic, granted by the Food and Drug Administration (FDA) in 2019 for patients with NTRK-positive tumors, further validating the use of basket trials as a viable regulatory approach to clinical drug development. This proven tissue-agnostic approach to drug development is being embraced by other companies clinically developing Trk inhibitors (vide infra).