Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors.

Aberrant RET kinase signaling is activated in numerous cancers including lung, thyroid, breast, pancreatic, and prostate. Recent approvals of selective RET inhibitors, pralsetinib and selpercatinib, has shifted the focus of RET kinase drug discovery programs towards the development of selective inhibitors. However, selective inhibitors invariably lose efficacy as the selective nature of the inhibitor places Darwinian-like pressure on the tumor to bypass treatment through the selection of novel oncogenic drivers. Further, selective inhibitors are restricted for use in tumors with specific genetic backgrounds that do not encompass diverse patient classes. Here we report the identification of a pyrimido indole RET inhibitor found to also have activity against TRK. This selective dual RET/TRK inhibitor can be utilized in tumors with both RET and TRK genetic backgrounds and can also provide blockade of NTRK-fusions that are selected for from RET inhibitor treatments. Efforts towards developing dual RET/TRK inhibitors can be beneficial in terms of encompassing more diverse patient classes while also achieving blockade against emerging resistance mechanisms.

Acquired NF2 mutation confers resistance to TRK inhibition in an ex vivo LMNA::NTRK1-rearranged soft-tissue sarcoma cell model.

Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired NF2 loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK-targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium-throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an LMNA::NTRK1-rearranged soft-tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Sequential treatments with TRK inhibitors in a patient with NTRK fusion-positive sarcoma: A case report.

RATIONALE: Precision medicine and tumor-agnostic treatment strategies have recently been promoted for clinical use. One of the most successful treatments in patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors is targeting the tropomyosin receptor kinase (TRK) with an inhibitor. The TRK inhibitors, larotrectinib, and entrectinib, have been approved in many countries. Nevertheless, the most effective administration regimen for these TRK inhibitors is uncertain. To date, no reports have shown the efficacy of sequential treatment with larotrectinib and entrectinib in patients with NTRK fusion-positive tumors. In this report, we present a patient with NTRK fusion-positive sarcoma arising from the anterior mediastinum, with tumor progression after 4 months of entrectinib use. The patient took larotrectinib subsequently and maintained disease control for more than 21 months. PATIENT CONCERNS: A 48-year-old female visited a physician because she experienced difficulty in breathing and chest and back pain with no obvious cause 2 months ago. Computed tomography (CT)-guided biopsy was performed at a district general hospital, and histopathological examination revealed a small round cell tumor. She was referred to our hospital, and a second CT-guided biopsy was performed to confirm the pathological diagnosis. Considering the results of the histopathological examination, Ewing sarcoma was suspected, but a specific fusion gene was not detected due to poor quality specimens. DIAGNOSES: After 3 regimens of cytotoxic chemotherapy, biopsy was repeated, and specimens were analyzed using next-generation sequencing. The PHF20-NTRK1 fusion gene was detected, and the tumor was finally diagnosed as an NTRK fusion-positive sarcoma. INTERVENTIONS: She was administered the TRK inhibitor entrectinib, but the tumor started to grow after 4 months of medication, and she stopped taking entrectinib. After 1 cycle of cytotoxic chemotherapy, another TRK inhibitor, larotrectinib, was administered. OUTCOMES: Her stable disease was maintained for more than 21 months. Here, we have shown that sequential administration of both drugs can be effective. LESSONS: In the treatment of NTRK fusion-positive tumors, there are cases in which 2 approved first-generation TRK inhibitors can be used sequentially.

Discovery of a benzimidazole-based dual FLT3/TrKA inhibitor targeting acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) enzyme overexpression and mutations are the most common molecular abnormalities associated with acute myeloid leukemia (AML). In addition, recent studies investigated the role of tropomyosin receptor kinase A (TrKA) enzyme fusions in promoting AML growth and survival. Based on these premises, targeting both kinases using dual inhibitors would constitute a promising therapeutic approach to target resistant AML. Guided by ligand-based design and structure simplification of the FLT3 inhibitor, quizartinib, we developed a benzimidazole-based small molecule, 4ACP, that exhibited nanomolar activity against wild-type FLT3, FLT3-Internal tandem duplications (FLT3-ITD), and FLT3-D835Y (FLT3-TKD) mutation (IC50 = 43.8, 97.2, and 92.5 nM respectively). Additionally, 4ACP demonstrated potent activity against colon cancer KM12 cell line (IC50 = 358 nM) and subsequent mechanistic deconvolution identified TrKA enzyme as a second plausible target (IC50 = 23.6 nM) for our compound. 4ACP manifested preferential antiproliferative activity against FLT3-ITD positive AML cell lines (MV4-11 IC50 = 38.8 ± 10.7 nM and MOLM-13 IC50 = 54.9 ± 4.1 nM), while lacking activity against FLT3-ITD negative AML cell lines. Western blot analysis confirmed 4ACP ability to downregulate ERK1/2 and mTOR signaling downstream of FLT3-ITD in AML cells. Furthermore, 4ACP prompted apoptotic and necrotic cell death and G0/G1 cell cycle arrest as indicated by cell cycle analysis. 4ACP did not show cytotoxic effects on normal BNL and H9c2 cells and demonstrated decreased activity against c-Kit enzyme, hence, indicating lower probability of synthetic lethal toxicity and a relatively safer profile. In light of these data, 4ACP represents a novel FLT3/TrKA dual kinase inhibitor for targeted therapy of AML.

Structural Optimization and Structure-Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants.

Tropomyosin receptor kinases (TrkA, TrkB, and TrkC) are attractive therapeutic targets for multiple cancers. Two first-generation small-molecule Trks inhibitors, larotrectinib and entrectinib, have just been approved to use clinically. However, the drug-resistance mutations of Trks have already emerged, which calls for new-generation Trks inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of 6,6-dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one derivatives as a new class of pan-Trk inhibitors. The prioritized compound 11g exhibited low nanomolar IC50 values against TrkA, TrkB, and TrkC and various drug-resistant mutants. It also showed good kinase selectivity. 11g displayed excellent in vitro antitumor activity and strongly suppressed Trk-mediated signaling pathways in intact cells. In in vivo studies, compound 11g exhibited good antitumor activity in BaF3-TEL-TrkA and BaF3-TEL-TrkCG623R allograft mouse models without exhibiting apparent toxicity. Collectively, 11g could be a promising lead compound for drug discovery targeting Trks and deserves further investigation.

Preparation and characterization of a high-affinity monoclonal antibody against nerve growth factor.

Nerve growth factor (NGF) is produced and released in injured tissues or chronic pain tissues caused by other diseases. Studies have shown that monoclonal antibodies targeting NGF have a good efficacy in the treatment of osteoarthritis (OA), low back pain and chronic pain, which may be a promising therapy. In this study, DNA sequences of NGF-his and NGF-hFc were synthesized using eukaryotic expression system and subcloned into pTT5 expression vector. After that, NGF proteins were expressed by transient expression in HEK293E cells. We immunized mice with NGF-hFc protein and fused mouse spleen cells to prepare hybridomas. NGF-His protein was used to screen out the hybridoma supernatant that could directly bind to NGF. Antibodies were purified from hybridioma supernatant. Futhermore, via surface plasmon resonance (SPR) screening, six anti-NGF mAbs were screened to block the binding of NGF and TrkA receptor in the treatment of chronic pain. Among them, 58F10G10H showed high affinity (KD = 1.03 × 10-9 M) and even better than that of positive control antibody Tanezumab (KD = 1.53 × 10-9 M). Moreover, the specific reactivity of 58F10G10H was demonstrated by TF-1 cell proliferation activity experiments, competitive binding Enzyme-linked immunosorbent assay (ELISA) and the arthritis animal models in mice, respectively. In conclusion, in this study, a method for the preparation of high-yield NGF-HFC and NGF-His proteins was designed, and a high-affinity monoclonal antibody against NGF with potential for basic research and clinical application was prepared.

Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies.

Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of numerous tumor types and chronic pain. However, most of the reported TrkA inhibitors are ATP competitive pan-Trks inhibitors that lack subtype selectivity. A selective TrkA inhibitor may provide valuable therapeutic benefits. Here, we described the discovery of novel TrkA allosteric inhibitors by structure-based virtual screening. A promising hit (D5261, TrkA cell IC50 = 3.32 µM) was selected for further studies. The binding free energy between TrkA and D5261 was calculated. In addition, the preliminary structure-activity relationship (SAR) studies with D5261 were investigated. The results suggest that D5261 can be used as a starting point for development of TrkA allosteric inhibitors.

Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation.

Tropomyosin receptor kinase (TRK) inhibition is an effective therapeutic approach for treatment of a variety of cancers. Despite the use of first-generation TRK inhibitor (TRKI) larotrectinib (1) resulting in significant therapeutic response in patients, acquired resistance develops invariably. The emergence of secondary mutations occurring at the solvent-front, xDFG, and gatekeeper regions of TRK represents a common mechanism for acquired resistance. However, xDFG mutations remain insensitive to second-generation macrocyclic TRKIs selitrectinib (3) and repotrectinib (4) designed to overcome the resistance mediated by solvent-front and gatekeeper mutations. Here, we report the structure-based drug design and discovery of a next-generation TRKI. The structure-activity relationship studies culminated in the identification of a promising drug candidate 8 that showed excellent in vitro potency on a panel of TRK mutants, especially TRKAG667C in the xDFG motif, and improved in vivo efficacy than 1 and 3 in TRK wild-type and mutant fusion-driven tumor xenograft models, respectively.

Design, synthesis and biological evaluation of macrocyclic derivatives as TRK inhibitors.

Tropomyosin receptor kinases (TRKA, TRKB, TRKC) are transmembrane receptor tyrosine kinases, which are respectively encoded by NTRK1, NTRK2, and NTRK3 genes. Herein, we reported the design, synthesis and Structure-Activity Relationship (SAR) investigation of a series of macrocyclic derivatives as new TRK inhibitors. Among these compounds, compound 9e exhibited strong kinase inhibitory activity (TRKG595R IC50 = 13.1 nM) and significant antiproliferative activity in the Ba/F3-LMNA-NTRK1 cell line (IC50 = 0.080 µM) and compound 9e has shown a better inhibitory effect (IC50 = 0.646 µM) than control drug LOXO-101 in Ba/F3-LMNA-NTRK1-G595R cell line. These results indicate that compound 9e is a potential TRK inhibitor for further investigation.

Discovery of the Next-Generation Pan-TRK Kinase Inhibitors for the Treatment of Cancer.

The neurotrophic receptor tyrosine kinase (NTRK) genes including NTRK1, NTRK2, and NTRK3 encode the tropomyosin receptor kinase (Trk) proteins TrkA, TrkB, and TrkC, respectively. So far, two TRK inhibitors, larotrectinib sulfate (LOXO-101 sulfate) and entrectinib (NMS-E628, RXDX-101), have been approved for clinical use in 2018 and 2019, respectively. To overcome acquired resistance, next-generation Trk inhibitors such as selitrectinib (LOXO-195) and repotrectinib (TPX-0005) have been developed and exhibit effectiveness to induce remission in patients with larotrectinib treatment failure. Herein, we report the identification and optimization of a series of macrocyclic compounds as potent pan-Trk (WT and MT) inhibitors that exhibited excellent physiochemical properties and good oral pharmacokinetics. Compound 10 was identified via optimization from the aspects of chemistry and pharmacokinetic properties, which showed good activity against wild and mutant TrkA/TrkC in in vitro and in vivo studies.

NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake.

BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization.

Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC50 = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC50 = 3.74-151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor.

Design, synthesis, biological evaluation and pharmacophore model analysis of novel tetrahydropyrrolo[3,4-c]pyrazol derivatives as potential TRKs inhibitors.

The tropomyosin receptor kinases TRKs are responsible for different tumor types which caused by NTRK gene fusion, and have been identified as a successful target for anticancer therapeutics. Herein, we report a potent and selectivity TRKs inhibitor 19m through rational drug design strategy from a micromolar potency hit 17a. Compound 19m significantly inhibits the proliferation of TRK-dependent cell lines (Km-12), while it has no inhibitory effect on TRK-independent cell lines (A549 and THLE-2). Furthermore, kinases selectivity profiling showed that in addition to TRKs, compound 19m only displayed relatively strong inhibitory activity on ALK. These data may indicate that compound 19m has a good drug safety. Partial ADME properties were evaluated in vitro and in vivo. Compound 19m exhibited a good AUC values and volume of distribution and low clearance in the pharmacokinetics experiment of rats. Finally, a pharmacophore model guided by experimental results is proposed. We hope this theoretical model can help researchers find type I TRK inhibitors more efficiently.

Tropomyosin receptor kinases in sarcomas - of joy and despair.

PURPOSE OF REVIEW: The relatively recent discovery of neurotrophic tropomyosin receptor kinase (NTRK) gene arrangements as pan-tumor predictive biomarkers has led to impressive novel treatments for patients with TRK fusions. Although the number of patients who qualify for treatment is vanishingly small for cancer patients in general, a few histological subsets of sarcomas exhibit NTRK fusions more commonly leading to large expectations within the sarcoma community. RECENT FINDINGS: Larotrectenib and entrectenib have recently been approved based on durable responses in TRK positive cancers with nonresectable or metastatic disease, including many sarcomas. Identification of resistance mutations to TRKi has led to the development of novel salvage therapies which may soon further expand the armamentarium of treatments. The greatest barrier and frustration to date is the actual identification of patients who harbor the fusion. The dimension of rarity in sarcomas remains difficult to comprehend for both patients and caregivers. Diagnosis of NTRK fusions is complex, particularly in the context of sarcomas and can involve immunohistochemistry as a screening tool but frequently requires fluorescence-in-situ hybridization or next-generation sequencing (NGS) to confirm the diagnosis. SUMMARY: The growing evidence on subtype-specific incidence of NTRK fusions will help to improve strategic prioritization or exclusion of subtypes to reduce the burden of negative testing. Next-generation inhibitors provide potential salvage treatment options for patients failing first-line therapy.

The antibiotic doxycycline mimics the NGF signaling in PC12 cells: A relevant mechanism for neuroprotection.

Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.

Evolving role of entrectinib in treatment of NTRK-positive tumors.

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 NTRK fusion positive solid tumors and ROS1 positive non-small-cell lung cancers with subsequent approval for those indications. Entrectinib was also found to be effective in treatment of brain metastasis and generally well tolerated.

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 NTRK, which carries genetic information and has been targeted using a medication called entrectinib. This medication is also very effective in patients with cancers that has spread to the brain. This medication can be used in any type of cancer if the cancer cells possess the abnormal DNA. Some of the side effects of entrectinib include weight gain, lightheadedness, throwing up, taste changes, swelling of legs, lack of energy and so on. Based on the benefit of entrectinib seen in clinical trials the medication was approved by the US FDA for treatment of any type of cancer with the NTRK problem. We hope that this new approach to cancer treatment will result in patients having greater benefit and live longer.

A Quantitative Bioassay to Determine the Inhibitory Potency of NGF-TrkA Antagonists.

In this article, we demonstrate and validate a new bioassay named the NTAB [NGF-TrkA (nerve growth factor-tropomyosin receptor kinase A) antagonist bioassay] for the determination of the inhibitory potency of NGF-TrkA antagonists, based on the inhibition of NGF-dependent proliferation of the human TF1 erythroleukemic cell line.It is well known that NGF holds great therapeutic potential due to its neurotrophic and neuroprotective properties. NGF is also involved in some pathways, however, principally driven by TrkA that, if not correctly regulated, can lead to unwanted pathological outcomes linked to pain, angiogenesis, and cancer.Indeed, there is an increasing interest, from a therapeutic perspective, in designing new effective molecules (antibodies, antibody fragments, or small molecules) able to inhibit the undesired NGF-TrkA pathway. For these reasons, there is an interest to develop functional cell-based assays for determination of the inhibition potency of compounds inhibiting the NGF-TrkA axis. The NTAB presents significant advantages over other published NGF-TrkA functional bioassays, for these reasons: (1) It is quantitative, (2) it measures a pure TrkA response, (3) it is simpler, (4) it is based on a natural biological response, and (5) it is easily scalable from a lab scale to an automated industrial assay.The NTAB assay was validated with a panel of well-characterized NGF-TrkA inhibitors, yielding characteristic dose-response curves, from which the relative strength of the inhibitors was quantitatively determined and used for comparisons. This new bioassay will be very useful to assist in the validation and prioritization of the best inhibitors among a large number of candidates.

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

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.

Neurotoxicity studies with a tropomyosin-related kinase A inhibitor, ASP7962, on the sympathetic and sensory nervous systems in rats.

ASP7962 is a small molecule inhibitor for the nerve growth factor (NGF) receptor, tropomyosin-related kinase A (TrkA). NGF contributes to the survival of sensory and sympathetic neurons through TrkA receptor activation. Gross, microscopic, and quantitative effects to the nervous system were evaluated following oral ASP7962 administration to Sprague Dawley rats for 4 weeks and 13 weeks and after a recovery period. Histopathological findings included reversible neuronal atrophy but no neuronal death in the sympathetic ganglia (cervicothoracic ganglion, cranial mesenteric ganglion or superior [cranial] cervical ganglion). Stereological analysis showed reversible decreased ganglion volume and/or decreased neuron size in the superior (cranial) cervical ganglion in both the 4-week and the 13-week repeated dose studies. There were no test article related changes in the brain, dorsal root ganglia with spinal nerve roots or trigeminal ganglia and no functional deficits. ASP7962 did not cause any detectable dysfunction of the sympathetic and sensory nervous system in either study.