Ponatinib and STAT5 Inhibitor Pimozide Combined Synergistic Treatment Applications Potentially Overcome Drug Resistance via Regulating the Cytokine Expressional Network in Chronic Myeloid Leukemia Cells.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematological disease characterized by the chimeric breakpoint-cluster region/Abelson kinase1 (BCR::ABL1) oncoprotein; playing a pivotal role in CML molecular pathology, diagnosis, treatment, and possible resistance arising from the success and tolerance of tyrosine kinase inhibitor (TKI)-based therapy. The transcription factor STAT5 constitutive signaling, which is influenced by the cytokine signaling network, triggers BCR::ABL1-based CML pathogenesis and is also relevant to acquired TKI resistance. The unsuccessful therapeutic approaches targeting BCR::ABL1, in particular third-line therapy with ponatinib, still need to be further developed with alternative combination strategies to overcome drug resistance. As treatment with the STAT5 inhibitor pimozide in combination with ponatinib resulted in an efficient and synergistic therapeutic approach in TKI-resistant CML cells, this study focused on identifying the underlying amplification of ponatinib response mechanisms by determining different cytokine expression profiles in parental and ponatinib-resistant CML cells, in vitro. The results showed that expression of interleukin (IL) 1B, IL9, and IL12A-B was increased by 2-fold, while IL18 was downregulated by 2-fold in the ponatinib-resistant cells compared to sensitive ones. Importantly, ponatinib treatment upregulated the expression of 21 of the 23 interferon and IL genes in the ponatinib-resistant cells, while treatment with pimozide or a combination dose resulted in a reduction in the expression of 19 different cytokine genes, such as for example, inflammatory cytokines, IL1A-B and IL6 or cytokine genes associated with supporting tumor progression, leukemia stem cell growth or poor survival, such as IL3, IL8, IL9, IL10, IL12, or IL15. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis results showed that the genes were mainly enriched in the regulation of receptor signaling through the Janus kinase/signal transducer and activator of transcription pathway, cytokine-cytokine receptor interaction, and hematopoietic cell lineage. Protein-protein interaction analysis showed that IL2, IL6, IL15, IFNG, and others appeared in the top lists of pathways, indicating their high centrality and importance in the network. Therefore, pimozide could be a promising agent to support TKI therapies in ponatinib resistance. This research would help to clarify the role of cytokines in ponatinib resistance and advance the development of new therapeutics to utilize the STAT5 inhibitor pimozide in combination with TKIs.

Pimobendan controlled release guar gum printlets: Tailoring drug doses for personalised veterinary medicines.

Treating chronic heart diseases in dogs is challenging due to variations in mass within and between species. Pimobendan (PBD), a veterinary drug only, is prescribed in specific cases of chronic heart disease in dogs and is available on the market in only a few different doses. Furthermore, the therapy itself is challenging due to the large size of the chewable tablets and the requirement for twice-daily administration. The development of customised and on-demand PBD medicines by three-dimensional (3D) printing has been proposed to circumvent these disadvantages. In this study, we designed controlled-release flavoured printlets containing PBD. We evaluated the use of two natural polymers, guar or xanthan gums, as the main component of the printing inks. Guar gum showed the better rheological behavior and printability by semisolid extrusion. The printlets were produced in three different shapes and sizes to allow dose customisation. Guar gum printlets showed a PBD controlled release profile, regardless of their shape or size. Therefore, we have demonstrated a novel approach for controlling PBD drug release and tailoring the dose by employing a natural polymer to produce 3D-printed tablets. This study represents a significant step towards the development of 3D-printed guar gum controlled-release formulations for veterinary applications.

Pyridazine and pyridazinone derivatives: Synthesis and in vitro investigation of their anti-inflammatory potential in LPS-induced RAW264.7 macrophages.

New pyridazine and pyridazinone derivatives 3a-g, 4a-f, 6a, and 6b were designed and synthesized. Cell viability of all compounds was established based on the viability of lipopolysaccharide-induced RAW264.7 macrophage cells determined via the MTT assay. In vitro inhibition assays on human COX-1 and COX-2 enzymes were conducted to probe the newly synthesized compounds' anti-inflammatory activity. The half maximal inhibitory concentration values for the most active compounds, 3d, 3e, and 4e towards COX-2 were 0.425, 0.519, and 0.356 µM, respectively, in comparison with celecoxib. The newly synthesized compounds' ability to inhibit the production of certain proinflammatory cytokines, such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-6, and prostaglandin-E2, was also estimated in lipopolysaccharide-induced macrophages (RAW264.7 cells). Compounds 3d and 3e were identified as the most potent cytokine production inhibitors. The results of molecular modeling studies suggested that these compounds were characterized by a reasonable binding affinity toward the active site of COX-2, when compared to a reference ligand. These results might be taken into consideration in further investigations into new anti-inflammatory agents.

Utilizing Ni(II) complex for metal drug-gel particles in cervical cancer treatment and designing novel drugs through machine learning methods.

In the present study, a novel coordination polymer (CP) based on Ni(II), namely, [Ni(L)(D-CAM)(H2O)]n (1) (H2D-CAM = (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid and L = 3,6-bis(benzimidazol-1-yl)pyridazine), has been produced successfully through applying a mixed ligand synthesis method via reacting Ni(NO3)2·6H2O with 3,6-bis(benzimidazol-1-yl)pyridazine ligand in the presence of a carboxylic acid co-ligand. Hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) are representatives of natural polysaccharides and have good biocompatibility. Based on the chemical synthesis method, HA/CMCS hydrogel was successfully prepared. SEM showed that the lyophilized gel presented a typical macroporous structure with three-dimensional connected pores, which had unique advantages as a drug carrier. Using paclitaxel as a drug model, we further synthesized a novel paclitaxel-loaded metal gel and evaluated its therapeutic effect on cervical cancer. Finally, novel drugs from the reinforcement learning simulation are suggested to have better biological activity against ovarian cancer due to low affinity energy and stronger interaction strength towards the protein receptor.

Comparative adherence of macitentan versus ambrisentan and bosentan in Australian patients with pulmonary arterial hypertension: a retrospective real-world database study.

AIM: Bosentan, ambrisentan, and macitentan are endothelin receptor antagonists (ERAs), currently available in Australia for treatment of pulmonary arterial hypertension (PAH). This study assessed the comparative adherence of these ERAs for PAH in Australian patients. METHODS: This retrospective, observational study used data for adults with PAH from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset (01/2006-10/2020). The primary outcome was treatment adherence (i.e. receiving ≥80% of ERA doses over 12 months). Secondary outcomes were time to treatment change (add-on or switch) and overall survival. RESULTS: The study included 436 patients who took bosentan (n = 200), ambrisentan (n = 69), or macitentan (n = 167). Treatment adherence was significantly greater in patients who received macitentan (65.3%) versus ambrisentan (56.5%) and bosentan (58.0%), with odds ratios (ORs; 95% CI) of 0.51 (0.30-0.88; p = 0.016) for bosentan versus macitentan and 0.48 (0.24-0.96; p = 0.037) for ambrisentan versus macitentan. The median time to treatment change was 47.2 and 43.4 months for bosentan and ambrisentan, respectively (not calculated for macitentan because of insufficient duration of data). LIMITATIONS AND CONCLUSIONS: Real-world data for Australian patients with PAH showed that treatment adherence for ERAs was suboptimal. Adherence was higher for macitentan compared with ambrisentan and bosentan.

Modelling the Effectiveness of Tepotinib in Comparison to Standard-of-Care Treatments in Patients with Advanced Non-small Cell Lung Cancer (NSCLC) Harbouring METex14 Skipping in the UK.

BACKGROUND: Patients with non-small cell lung cancer harbouring mesenchymal-epithelial transition exon 14 (METex14) skipping typically demonstrate poorer prognosis than overall non-small cell lung cancer. Until recently, no targeted treatments were available for patients with non-small cell lung cancer harbouring METex14 skipping in the UK, with limited treatments available. OBJECTIVE: This study estimates the long-term survival and quality-adjusted life-year benefit of MET inhibitor tepotinib versus current standard of care from a UK perspective. METHODS: A partitioned-survival model assessed the survival and quality-adjusted life-year benefits of tepotinib versus immunotherapy ± chemotherapy and chemotherapy for untreated and previously treated patients, respectively, using evidence from the single-arm VISION trial (NCT02864992). Two approaches were used to inform an indirect treatment comparison: (1) published clinical trials in overall non-small cell lung cancer and (2) real-world evidence in the METex14 skipping population. Results are presented as median and total quality-adjusted life-year gain and survival for progression-free survival and overall survival. Survival curves were validated against the external literature and uncertainty assessed using a probabilistic sensitivity analysis. RESULTS: Using the indirect treatment comparison against the published literature, tepotinib is estimated to have a median progression-free survival gain versus pembrolizumab ± chemotherapy (11.0 and 9.2 months) in untreated patients, and docetaxel ± nintedanib (5.1 and 6.4 months) in previously treated patients. Across the populations, tepotinib is estimated to have a median survival gain of 15.4 and 9.2 months versus pembrolizumab ± chemotherapy in untreated patients and 12.8 and 5.1 months versus docetaxel ± nintedanib in previously treated patients. The total quality-adjusted life-year gain ranges between 0.56 and 1.17 across the untreated and previously treated populations. Results from the real-world evidence of indirect treatment comparisons are consistent with these findings. CONCLUSIONS: Despite the limitations of the evidence base, the numerous analyses conducted have consistently indicated positive outcomes for tepotinib versus the current standard of care.

Norflurazon causes cell death and inhibits implantation-related genes in porcine trophectoderm and uterine luminal epithelial cells.

Norflurazon, an inhibitor of carotenoid synthesis, is a pre-emergent herbicide that prevents growth of weeds. The norflurazon is known to hamper embryo development in non-mammals. However, specific toxic effects of norflurazon on mammalian maternal and fetal cells have not been elucidated. Thus, the hypothesis of this study is that norflurazon may influence the toxic effects between maternal and fetal cells during early pregnancy in pigs. We aimed to examine the toxic effects of norflurazon in porcine trophectoderm (Tr) and uterine luminal epithelium (LE) cells. Norflurazon, administered at 0, 20, 50 or 100 µM for 48 h was used to determine its effects on cell proliferation and cell-cycle arrest. For both uterine LE and Tr cell lines, norflurazone caused mitochondrial dysfunction by inhibiting mitochondrial respiration and ATP production, and down-regulated expression of mRNAs of mitochondrial complex genes. Norflurazon increased cell death by increasing intracellular calcium and regulating PI3K and MAPK cell signaling pathways, as well as endoplasmic reticulum (ER) stress, ER-mitochondrial contact, and autophagy-related target proteins. Norflurazone also inhibited expression of genes required for implantation of blastocysts, including SMAD2, SMAD4, and SPP1. These findings indicate that norflurazon may induce implantation failure in pigs and other mammals through adverse effects on both Tr and uterine LE cells.

Prescription patterns of ambrisentan in some cities of Colombia.

INTRODUCTION: Ambrisentan is a selective type A endothelin receptor antagonist that has shown significant effectiveness and safety in the management of patients with pulmonary hypertension. Its use pattern with real-world evidence in Colombia is unknown. OBJECTIVE: The objective of this study is to determine the prescription patterns of ambrisentan in some cities of Colombia. METHODS: A longitudinal descriptive study on the prescription patterns of ambrisentan in patients with pulmonary hypertension (all the groups) was conducted between January 2021 and December 2022 based on a population database of members of the Colombian Health System. Adherence at 1 year was determined using the Medication Possession Ratio (days the drug was dispensed/days from first dispensing to the end of the follow-up period × 100). Descriptive analysis was carried out. RESULTS: Sixty-seven patients taking ambrisentan were identified in 10 cities of the country. The individuals had a median age of 51.5 years (interquartile range-IQR: 39.8-64.0 years), and 82.1% were women. The drug possession rate was 82.2% (IQR: 65.0-96.8%), and persistence at 1 year was present in 49.3% (n = 33) of the cases. The average dose was 8.8 ± 5.0 mg/day, and 76.1% (n = 51) received it in combination therapy, mainly with phosphodiesterase type 5 inhibitors (61.2%, n = 41). CONCLUSIONS: Adherence to ambrisentan was good, but its persistence at 1 year was low. The dosages of the drug used were in accordance with the recommendations of the clinical practice guidelines, and it was used in combination therapy, especially with phosphodiesterase 5 inhibitors.

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases.

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.

Ponatinib-Related Vasospastic Angina.

Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.

Bosentan and ambrisentan in the treatment of idiopathic pulmonary fibrosis: a meta-analysis.

OBJECTIVE: The aim is to showcase the effectiveness and safety of bosentan or ambrisentan in individuals diagnosed with idiopathic pulmonary fibrosis (IPF) and offer fresh evidence for the management of this condition. MATERIALS AND METHODS: For this research, we conducted a meta-analysis of randomized controlled trials by searching various databases, including the Cochrane Library, Excerpta Medica Database, PubMed, and Web of Science. The retrieval was conducted until November 2021. We analyzed the variances in 6-minute walk distance (6MWD), death, diffusion capacity for carbon monoxide (DLCO), forced vital capacity (FVC), hospitalization, IPF worsening, mean pulmonary arterial pressure, serious adverse events (SAEs), Short Form-36 improved, and St. George's Respiratory Questionnaire between the treatment and control groups. RESULTS: A sum of six studies involving 1,928 participants were found to meet the inclusion criteria. The quality of evidence was high. The control group had significantly higher values for 6MWD, DLCO, and FVC compared to the ambrisentan treatment group. The rates of hospitalization and IPF worsening were considerably greater in comparison with the control group. The bosentan group exhibited significantly reduced rates of hospitalization and IPF worsening in comparison with the control group. Both drugs did not cause any raising in death or SAEs when in comparison with the control group. CONCLUSIONS: The findings of this research validate the effectiveness and safety of bosentan for treating IPF patients. This medication can enhance the quality of life for individuals with IPF without causing any significant increase in SAEs. However, it does not have a notable influence on the long-term prognosis. The findings of this research do not endorse the utilization of ambrisentan in individuals diagnosed with IPF.

Comparison of Tepotinib, Paclitaxel, or Ramucirumab Efficacy According to the Copy Number or Phosphorylation Status of the MET Gene: Doublet Treatment versus Single Agent Treatment.

Although conventional combination chemotherapies for advanced gastric cancer (GC) increase survival, such therapies are associated with major adverse effects; more effective and less toxic treatments are required. Combinations of different anti-cancer drugs, for example, paclitaxel plus ramucirumab, have recently been used as second-line treatments for advanced GC. This study evaluated how copy number variations of the MET gene, MET mutations, and MET gene and protein expression levels in human GC cells modulate the susceptibility of such cells to single-agent (tepotinib, ramucirumab, or paclitaxel) and doublet (tepotinib-plus-paclitaxel or ramucirumab-plus-paclitaxel treatment regimens. Compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibited the growth of GC cells with MET exon 14 skipping mutations and those lacking MET amplification but containing phosphorylated MET; such inhibition was dose-dependent and associated with cell death. Tepotinib-plus-paclitaxel and ramucirumab-plus-paclitaxel similarly inhibited the growth of GC cells lacking MET amplification or MET phosphorylation, again in a dose-dependent manner, but without induction of cell death. However, tepotinib alone or tepotinib-plus-ramucirumab was more effective against c-MET-positive GC cells (>30 copy number variations) than was ramucirumab or paclitaxel alone or ramucirumab-plus-paclitaxel. These in vitro findings suggest that compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibits the growth of c-MET-positive GC cells, cells lacking MET amplification but containing phosphorylated MET, and cells containing MET mutations. Clinical studies are required to confirm the therapeutic effects of these regimens.

Activity of Tepotinib in Hepatocellular Carcinoma With High-Level MET Amplification: Preclinical and Clinical Evidence.

PURPOSE: MET amplification (METamp) has been reported in 1%-5% of patients with hepatocellular carcinoma (HCC) and may be sensitive to MET inhibition. Tepotinib, a selective MET inhibitor, has shown promising activity in HCC with MET overexpression. We investigated the preclinical and clinical activity of tepotinib in HCC with METamp (MET gene copy number [GCN] ≥5), including high-level METamp (MET GCN ≥10). METHODS: Preclinical antitumor activity of tepotinib 100 mg/kg (orally, days 1-5, every 7 days, 3-5 weeks; 3-12 replicates) was evaluated according to METamp status, as determined using the nCounter platform (NanoString), in 37 HCC patient-derived xenografts (PDXs) in immunodeficient mice. Clinical outcomes were evaluated in patients with METamp by fluorescence in situ hybridization who received tepotinib 500 mg (450 mg active moiety) in two phase Ib/II trials in HCC with MET overexpression. RESULTS: Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level METamp. Median tumor volume reductions were 100% and 99.8% in models with MET GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had METamp. Disease control was achieved by 11/15 patients with METamp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level METamp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level METamp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years. CONCLUSION: High-level METamp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.

Morphological and genetic differences in legs of a polygamous beetle between sexes, Glenea cantor (Coleopter: Cerambycidae: Lamiinae).

The legs of insects play an important role in their daily behaviour, especially reproduction. Entomologists have performed much research on the role of the leg in different behaviours of beetles, an important group in the insect family, but relatively little has been done to study the ultrastructure and transcriptome of their legs. Hence, we systematically studied the ultrastructure and gene expression of the leg of G. cantor, a polygynous beetle, and compared its male and female diversity. In this study, we found the fore-leg, mid-leg and hind-leg of the female were significantly longer than those of the male. From the perspective of intuitive structural differences, we also compared the ultrastructures of the adhesion structure (tarsal) of males and females. The tarsal functional structure of the adult leg mainly includes sensilla and an adhesion structure. The sensilla on the tarsal joint mainly include sensilla chaetica (SCh II, SCh III) and sensilla trichodea (ST II). The adhesion structure includes disc-shaped bristles (di), lanceolate bristles (la), serrated bristles (se), spatula-shaped bristles (spl) and mushroom-shaped bristles (mus). Although there was no significant difference in sensillum distribution or type between males and females, there were significant differences in the distribution and species of adhesion structures between the fore-leg, mid-leg, and hind-leg of the same sex and between males and females. Therefore, different adhesion structures play different roles in various behaviours of beetles. On the other hand, the transcriptome results of male and female legs were screened for a subset of olfaction- and mechanics-related genes. We discovered that the male leg showed upregulation of 1 odorant binding protein (OBP), 2 Olfactory receptors (ORs) and 2 Chemosensory proteins (CSPs). Meanwhile, the female leg showed upregulation of 3 OBPs, 1 OR, 1 Gustatory receptor (GR) and 3 Mechanosensitive proteins (MSPs). An in-depth examination of the ultrastructure and molecular composition of the legs can elucidate its function in the reproductive behavior of G. cantor. Moremore, this investigation will serve as a cornerstone for subsequent research into the underlying behavioral mechanisms.

Ponatinib: A comprehensive drug profile.

Ponatinib is a prescription medication used to treat a rare form of blood cancer called Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that is resistant to other treatments. It belongs to a class of drugs called tyrosine kinase inhibitors, which work by blocking abnormal proteins that promote the growth of cancer cells. In this chapter, the synthesis methods and physicochemical properties of ponatinib were reviewed, besides the characterization of the ponatinib structure using different techniques such as elemental analysis, IR, UV, (1H and 13C) NMR, MS, and XRD. Furthermore, the compendial method for analysis of ponatinib was not found, while the literature review of a non-compendial method for analysis of ponatinib, such as spectroscopic, chromatographic, and immunoassay methods, was covered. Moreover, pharmacology and biochemistry were surveyed in the pharmacokinetic and pharmacodynamic studies.

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

Long-term experience with tepotinib in Japanese patients with MET exon 14 skipping NSCLC from the Phase II VISION study.

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION.