entrectinib and Neoplasms

Larotrectinib and entrectinib are tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors that are indicated for the treatment of advanced or metastatic solid tumor cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Regulatory approval of both agents was based on data from single-arm phase 1/2 studies, including tumor-agnostic basket trials. In the absence of randomized controlled trials, there remains a paucity of data to demonstrate the comparative effectiveness of larotrectinib and entrectinib vs established standard-of-care treatments in cancers with NTRK gene fusions. Furthermore, no studies have directly compared the 2 agents. This article reviews what is known about the comparative effectiveness of larotrectinib and entrectinib vs standard therapies in TRK fusion cancer and examines the comparative effectiveness of the 2 TRK inhibitors. Historical and intrapatient comparisons suggest that TRK inhibitors improve disease response compared with preexisting treatments across most tumor histologies; indirect and limited comparisons of phase 1/2 data and preliminary simulation modeling suggest a potential advantage for larotrectinib over entrectinib in terms of clinical response and survival. Although limited, these data provide some insight into the position of these treatments in established treatment paradigms for TRK fusion cancer, a setting where real-world evidence will be slow to accrue due to the rare nature of these tumors but may be the only way in the future to answer the outstanding questions regarding these 2 agents. Meanwhile, we need to try to obtain the maximum benefit that can be achieved for our patients using the currently available knowledge.

Topics: Benzamides; Gene Fusion; Humans; Indazoles; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Gene rearrangements involving the neurotrophic receptor kinase genes NTRK1, NTRK2, and NTRK3 (referred to as TRK, encoding TRKA, TRKB, and TRKC, respectively) result in highly oncogenic fusions. TRK fusions are rare, with a prevalence of < 1% in solid tumors. Detection of TRK fusions can be based on fluorescence in-situ hybridization (FISH), immunohistochemistry (IHC), and next-generation sequencing (NGS), where RNA sequencing is the most sensitive method. Inhibition of TRK fusions with highly selective small-molecule TRK inhibitors (TRKi) such as entrectinib and larotrectinib, results in profound responses in most cancer patients, regardless of cancer histology. Even response in CNS metastases is relatively common. Although responses are often durable, many patients develop resistance to TRKi due to mutations in one of the TRK genes, or due to genetic alterations conferring activation of alternative oncogenic signaling pathways. Second-generation TRKi have been developed, which can overcome some of the TRK resistance mutations. TRKi are well tolerated, with most common adverse events being related to on-target/off-tumor inhibition of TRKs.

Topics: Antineoplastic Agents; Benzamides; Humans; Indazoles; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA

Targeted therapy has shown to be a very effective treatment in tumors with specific genomic drivers. Trk has proven to be one such target. Efforts to target the Trk fusion with specific inhibitors have shown remarkable responses in a tumor agnostic fashion, with responses seen even in patients with intracranial metastasis. Entrectinib is a first-generation Trk inhibitor with impressive activity in early phase trials performed in patients with. Lay abstract Advances in medical science has allowed us to analyze genes within cancer cells and target abnormal genes more precisely. One such target is called

Topics: Animals; Benzamides; Cell Line, Tumor; Clinical Trials as Topic; Disease Models, Animal; Drug Approval; Drug Evaluation, Preclinical; Humans; Indazoles; Membrane Glycoproteins; Molecular Targeted Therapy; Neoplasms; Oncogene Proteins, Fusion; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA; Receptor, trkB; Receptor, trkC

Topics: Animals; Benzamides; Drug Design; Drug Development; Humans; Indazoles; Membrane Glycoproteins; Neoplasms; Patents as Topic; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA; Receptor, trkB; Receptor, trkC

Neurotrophic tyrosine receptor kinase (NTRK) inhibitors represent the latest advancement as a treatment option in targeted therapies for malignant disease. NTRK gene fusions involving NTRK1, 2 or 3 are implicated as genetics drivers for a number of tumour types which arise within adult and paedatric patients. NTRK inhibitors (Larotrectinib and Entrectinib) are effective agents which have demonstrated clinical benefit in the treatment of NTRK fusion positive solid tumours. Larotrectinib represents the first targeted agent to receive approval from international authorisation and commissioning bodies for the treatment of a specific genetic expression indiscriminate of the site from which the tumour has arisen. As such NTRK inhibitors could pave the way for international healthcare bodies to adopt a similar approach for future targeted therapies thereby altering the manner in which healthcare providers and patients are able to access and utilise innovative, targeted treatment options in future. The potential implications of this new approach are likely to impact upon several aspects of the traditional authorisation and commissioning pathways with potential changes to the design of clinical trials, the review and approval process by regulatory bodies and immunohistopathology services.

Topics: Adult; Benzamides; Delivery of Health Care; Humans; Indazoles; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases

NTRKs and their expression product tropomyosin receptor kinases (Trks) are widely distributed in mammals. While neural growth factor (NGF)-induced normal Trk activation plays a key role in nerve growth, NTRK alternations occurring in tumor cells were highly correlated to tumor progression and invasion. Recent clinical data from several pan-Trk inhibitors have demonstrated potential and broad applications in various cancers. This intrigues us to summarize the development of inhibitors targeting Trks with different mechanisms of action and their applications in cancer therapy. We believe that this perspective would be of great help in investigating novel anticancer drugs with better therapeutic index.

Topics: Antineoplastic Agents; Drug Design; Humans; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA

TRK fusions are oncogenic drivers of various adult and paediatric cancers. The first-generation TRK inhibitors, larotrectinib and entrectinib, were granted landmark, tumour-agnostic regulatory approvals for the treatment of these cancers in 2018 and 2019, respectively. Brisk and durable responses are achieved with these drugs in patients, including those with locally advanced or metastatic disease. In addition, intracranial activity has been observed with both agents in TRK fusion-positive solid tumours with brain metastases and primary brain tumours. While resistance to first-generation TRK inhibition can eventually occur, next-generation agents such as selitrectinib (BAY 2731954, LOXO-195) and repotrectinib were designed to address on-target resistance, which is mediated by emergent kinase domain mutations, such as those that result in substitutions at solvent front or gatekeeper residues. These next-generation drugs are currently available in the clinic and proof-of-concept responses have been reported. This underscores the utility of sequential TRK inhibitor use in select patients, a paradigm that parallels the use of targeted therapies in other oncogenic driver-positive cancers, such as ALK fusion-positive lung cancers. While TRK inhibitors have a favourable overall safety profile, select on-target adverse events, including weight gain, dizziness/ataxia and paraesthesias, are occasionally observed and should be monitored in the clinic. These side-effects are likely consequences of the inhibition of the TRK pathway that is involved in the development and maintenance of the nervous system.

Topics: Animals; Antineoplastic Agents; Benzamides; Child; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Screening Assays, Antitumor; Humans; Indazoles; Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases

Topics: Benzamides; Biomarkers, Tumor; Gene Fusion; Genetic Testing; Humans; Indazoles; Neoplasms; Patient Selection; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Nerve Growth Factor; Time Factors; Treatment Outcome

The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date. Although the NTRK gene fusions are infrequent in most cancer types, certain rare tumor types are predominately driven by these events. Conversely, in more common histologies, such as lung and colorectal cancers, prevalence of the NTRK fusions is well below 5%. Selective inhibition of TRK signaling may therefore be beneficial among patients whose tumors vary in histologies, but share underlying oncogenic NTRK gene alterations. Currently, several TRK-targeting compounds are in clinical development. The ongoing Phase 2 trials with entrectinib and LOXO-101, two of the leading TRK inhibitors, are designed as 'basket trials', inclusive of patients whose tumors harbor NTRK gene fusions, independent of histology. Additional Phase 1 studies of other TRK inhibitors, including MGCD516, PLX7486, DS-6051b, and TSR-011, are underway. Interim data examining NTRK-rearranged tumors treated with entrectinib or LOXO-101 demonstrate encouraging activity, with patients achieving rapid and durable responses. Consequently, both drugs have achieved orphan designation from regulatory agencies, and efforts are underway to further expedite their development.

Topics: Animals; Antineoplastic Agents; Benzamides; Drug Design; Humans; Indazoles; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA; Receptor, trkB; Receptor, trkC

Receptor tyrosine kinases (RTKs) and their signaling pathways, control normal cellular processes; however, their deregulation play important roles in malignant transformation. In advanced non-small cell lung cancer (NSCLC), the recognition of oncogenic activation of specific RTKs, has led to the development of molecularly targeted agents that only benefit roughly 20% of patients. Entrectinib is a pan-TRK, ROS1 and ALK inhibitor that has shown potent anti-neoplastic activity and tolerability in various neoplastic conditions, particularly NSCLC.. This review outlines the pharmacokinetics, pharmacodynamics, mechanism of action, safety, tolerability, pre-clinical studies and clinical trials of entrectinib, a promising novel agent for the treatment of advanced solid tumors with molecular alterations of Trk-A, B and C, ROS1 or ALK.. Among the several experimental drugs under clinical development, entrectinib is emerging as an innovative and promising targeted agent. The encouraging antitumor activity reported in the Phase 1 studies, together with the acceptable toxicity profile, suggest that entrectinib, thanks to its peculiar mechanism of action, could play an important role in the treatment-strategies of multiple TRK-A, B, C, ROS1, and ALK- dependent solid tumors, including NSCLC and colorectal cancer. That being said, further evidence for its clinical use is still needed.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Benzamides; Humans; Indazoles; Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Receptor, trkA; Receptor, trkB; Receptor, trkC

A total of 276 cancer patients receiving oral entrectinib were included in the analysis. A model-based population approach was used to characterize the PK profiles of both entities using NONMEM. The absorption of entrectinib was best described using a sequential zero- and first-order absorption model and the disposition with one-compartment model for each entity with linear elimination. Moderate-to-high between-patient variability was estimated in model parameters (from 30.8% for the apparent clearance of entrectinib to 122% for the first-order absorption rate constant). Theory-based allometric scaling using body weight on clearances and volumes and a 28% lower relative bioavailability of the F1 formulation in pediatric patients were retained in the model. The VPC confirmed the good predictive performance of the PopPK model.. A robust population PK model was built and qualified for entrectinib and M5, describing linear PK for both entities. This model was used to support the ROZLYTREK

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzamides; Female; Follow-Up Studies; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prognosis; Protein Kinase Inhibitors; Tissue Distribution; Young Adult

Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics.. The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100-400 mg/m. Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics.. Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food.

Topics: Adult; Aged; Antineoplastic Agents; Benzamides; Capsules; Cross-Over Studies; Fasting; Feces; Female; Food-Drug Interactions; Healthy Volunteers; Humans; Indazoles; Male; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Therapeutic Equivalency; Young Adult

This study tackles several challenges of evaluating histology-independent treatments using entrectinib as an example. Histology-independent treatments are provided based on genetic marker(s) of tumors, regardless of the tumor type. We evaluated the lifetime cost-effectiveness of testing all patients for NTRK fusions and treating the positive cases with entrectinib compared with no testing and standard of care (SoC) for all patients.. The health economic model consisted of a decision tree reflecting the NTRK testing phase followed by a microsimulation model reflecting treatment with either entrectinib or SoC. Efficacy of entrectinib was based on data from basket trials, whereas historical data from NTRK-negative patients were corrected for the prognostic value of NTRK fusions to model SoC.. "Testing" (testing for NTRK fusions, with subsequent entrectinib treatment in NTRK-positive patients and SoC in NTRK-negative patients) had higher per-patient quality-adjusted life-years (QALYs) and costs than "No testing" (SoC for all patients), with a difference of 0.0043 and €732, respectively. This corresponded to an incremental cost-effectiveness ratio (ICER) of €169 957/QALY and, using a cost-effectiveness threshold of €80 000/QALY, an incremental net monetary benefit of -€388. When excluding the costs of genetic testing for NTRK fusions, the ICER was reduced to €36 290/QALY and the incremental net monetary benefit increased to €188.. When treatment requires the identification of a genetic marker, the associated costs and effects need to be accounted for. Because of the low prevalence of NTRK fusions, the number needed-to-test to identify patients eligible for entrectinib is large. Excluding the testing phase reduces the ICER substantially.

Topics: Cost-Benefit Analysis; Cost-Effectiveness Analysis; Genetic Markers; Humans; Neoplasms; Quality-Adjusted Life Years

Histology-independent pharmaceuticals are a new phenomenon in cancer care. Most chemotherapies are prescribed based on the tumor's (primary) location, while histology-independent therapies are prescribed based on genetic markers in the tumor DNA. In this study, the added value of the histology-independent treatment entrectinib, which is aimed at cancer patients with so-called

Topics: Adult; Benzamides; Cost-Benefit Analysis; Europe; Humans; Indazoles; Neoplasms

Tropomyosin receptor kinase (TRK) is an ideal target for treating cancers caused by the NTRK gene fusion. In this study, more than 60 2,4-diaminopyrimidine derivatives were prepared to understand the structure-activity relationship and confirm the rationality of the pharmacophore model reported previously. Among them, compound 19k was found to be a potent pan-TRK inhibitor that inhibits the proliferation of Km-12 cell lines. Additionally, compound 19k induced the apoptosis of Km-12 cells in a concentration-dependent manner. Western blot analysis revealed that compound 19k inhibited the phosphorylation of TRK to block downstream pathways. Compound 19k also possessed outstanding plasma stability and liver microsomal stability in vitro, with half-lives greater than 289.1 min and 145 min, respectively. Pharmacokinetic studies indicated that the oral bioavailability of compound 19k is 17.4%. These results demonstrate that compound 19k could serve as a novel lead compound for overcoming NTRK-fusion cancers.

Topics: Antineoplastic Agents; Drug Design; Humans; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor, trkA; Structure-Activity Relationship

Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored.. We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions.. NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value.. Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

Topics: Benzamides; Biomarkers, Tumor; Circulating Tumor DNA; High-Throughput Nucleotide Sequencing; Humans; Indazoles; Neoplasm Staging; Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA

Topics: Benzamides; Humans; Indazoles; Neoplasms

Topics: Benzamides; Humans; Indazoles; Neoplasms

The FDA-approved entrectinib on August 15, 2019, for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (

Topics: Benzamides; Drug Approval; Humans; Indazoles; Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Receptor, trkA; Receptor, trkB; Receptor, trkC; United States; United States Food and Drug Administration

The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System.

Topics: Adult; Age Factors; Benzamides; Child; Consensus; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Indazoles; Membrane Glycoproteins; Molecular Targeted Therapy; Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA; Receptor, trkB; Receptor, trkC; Reverse Transcriptase Polymerase Chain Reaction; Societies, Medical; Spain

Lemur tyrosine kinase 3 (LMTK3) is oncogenic in various cancers. In breast cancer, LMTK3 phosphorylates and modulates the activity of estrogen receptor-α (ERα) and is essential for the growth of ER-positive cells. LMTK3 is highly expressed in ER-negative breast cancer cells, where it promotes invasion via integrin β1. LMTK3 abundance and/or high nuclear expression have been linked to shorter disease free and overall survival time in a variety of cancers, supporting LMTK3 as a potential target for anticancer drug development. We sought to identify small molecule inhibitors of LMTK3 with the ultimate goal to pharmacologically validate this kinase as a novel target in cancer. We used a homogeneous time resolve fluorescence (HTRF) assay to screen a collection of mixture-based combinatorial chemical libraries containing over 18 million compounds. We identified several cyclic guanidine-linked sulfonamides with sub-micromolar activity and evaluated their binding mode using a 3D homology model of the LMTK3 K

Topics: Antineoplastic Agents; Combinatorial Chemistry Techniques; Drug Discovery; Gene Expression Regulation, Neoplastic; Humans; Membrane Proteins; Molecular Structure; Neoplasms; Protein Serine-Threonine Kinases; Small Molecule Libraries; Sulfonamides

Advances within molecular diagnostics have enabled us to identify a number of oncogenic drivers across different cancers. Many cancers can now be divided into subgroups based on molecular characteristics, and an increasing number of targeted anticancer drugs have been developed together with a predictive biomarker assay using the drug-diagnostic codevelopment model. With the recent approval of entrectinib, larotrectinib, and pembrolizumab for site-agnostic indications, biomarker-guided drug development has entered into a new phase.. The review focuses on the general principles of drug-diagnostic codevelopment, especially basket trials and site-agnostic drug development. Special attention is paid to entrectinib, larotrectinib, and pembrolizumab.. The recent approval of entrectinib, larotrectinib, and pembrolizumab must be regarded as a paradigm shift in biomarker-guided oncology drug development. For a site-agnostic indication, it is important to have in mind the central role of the companion diagnostic (CDx), as the assay defines the 'disease' and the patient population to be treated. A number of site-agnostic drugs are currently in development and here, it is important that CDx assay development is given high priority, so an analytical and clinical validated assay is available at the time of drug approval.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Clinical Decision-Making; Clinical Trials as Topic; Drug Approval; Drug Development; Humans; Indazoles; Molecular Targeted Therapy; Neoplasms; Organ Specificity; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic

Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.. An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).. Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.. Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.. Ignyta/F Hoffmann-La Roche.

Topics: Aged; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Gene Fusion; Humans; Indazoles; Male; Membrane Glycoproteins; Middle Aged; Neoplasm Metastasis; Neoplasms; Protein Kinase Inhibitors; Receptor, trkA; Receptor, trkB; Receptor, trkC; Receptors, Nerve Growth Factor; Time Factors; Treatment Outcome

NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.

Topics: Animals; Apoptosis; Bcl-2-Like Protein 11; Benzamides; Cell Line, Tumor; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; ErbB Receptors; Female; HEK293 Cells; Humans; Indazoles; Lung Neoplasms; Male; Mice, Inbred NOD; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Neoplasms; Pancreatic Neoplasms; Protein Kinase Inhibitors; Receptor, trkA

Topics: Benzamides; Humans; Indazoles; Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins

Topics: Adult; Benzamides; Child; Drug Approval; France; Humans; Indazoles; Membrane Glycoproteins; Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA; Receptor, trkB; Receptor, trkC

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.

Topics: Animals; Antineoplastic Agents; Catalytic Domain; Cell Line, Tumor; Drug Discovery; Humans; Mice, Inbred BALB C; Neoplasms; Precision Medicine; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Receptor, trkA; Receptor, trkB; Receptor, trkC

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition

Topics: Adolescent; Adult; Animals; Benzamides; Cell Proliferation; Cell-Free Nucleic Acids; Child; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Heterografts; Humans; Imidazoles; Indazoles; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Neoplasms; Oncogene Proteins, Fusion; Oximes; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Receptor, trkA; Young Adult

Topics: Benzamides; Drug Approval; Humans; Indazoles; Neoplasms; Protein Kinase Inhibitors; United States; United States Food and Drug Administration

Topics: Benzamides; Humans; Indazoles; Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases

Topics: Animals; Antineoplastic Agents; Benzamides; Humans; Indazoles; Mice; Neoplasms; Oncogene Proteins, Fusion; Oncogenes; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA