Search Results (45)

We report a rare case of pulmonary tumor thrombotic microangiopathy (PTTM) in a patient with metastatic neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive transverse colon cancer who exhibited a marked radiologic and biochemical response to entrectinib. Despite significant tumor shrinkage, progressive dyspnea and hypoxemia developed approximately four weeks after therapy initiation. Chest CT revealed diffuse interstitial infiltrates, initially interpreted as drug-induced pneumonitis or infection. Entrectinib was discontinued, but respiratory failure progressed, and the patient died shortly thereafter. Autopsy revealed widespread pulmonary microangiopathy with fibrocellular intimal proliferation and tumor emboli in small pulmonary arteries, consistent with PTTM. Notably, no hematogenous metastases were identified; instead, tumor spread appeared to occur via an atypical lymphatic route through the thoracic duct. The tumor exhibited microsatellite stability and a modest mutation burden, suggesting that lymphatic dissemination and microvascular pathology may progress independently of these genomic features. This case underscores a critical dissociation between oncologic response and vascular complications, indicating that tropomyosin receptor kinase (TRK) inhibitor monotherapy may be insufficient to prevent PTTM. Comprehensive management may require concurrent strategies targeting the pulmonary microvasculature, including antiangiogenic therapy and modulation of cytokine and growth factor signaling. Full article

Liver cancer is one of the most common malignancies and the second leading cause of cancer-related deaths worldwide, particularly in developing countries, where it poses a significant financial burden. Early detection and timely treatment remain challenging due to the complex mechanisms underlying the initiation and progression of liver cancer. This study aims to uncover key genomic features, analyze their functional roles, and propose potential therapeutic drugs identified through molecular docking, utilizing single-cell RNA sequencing (scRNA-seq) data from liver cancer studies. We applied two advanced hybrid methods known for their robust identification of differentially expressed genes (DEGs) regardless of sample size, along with four top-performing individual methods. These approaches were used to analyze four scRNA-seq datasets, leading to the identification of essential DEGs. Through a protein−protein-interaction (PPI) network, we identified 25 hub-of-hub genes (hHubGs) and 20 additional hHubGs from two naturally occurring gene clusters, ultimately validating a total of 36 hHubGs. Functional, pathway, and survival analyses revealed that these hHubGs are strongly linked to liver cancer. Based on molecular docking and binding-affinity scores with 36 receptor proteins, we proposed 10 potential therapeutic drugs, which we selected from a pool of 300 cancer meta-drugs. The choice of these drugs was further validated using 14 top-ranked published receptor proteins from a set of 42. The proposed candidates include Adozelesin, Tivozanib, NVP-BHG712, Nilotinib, Entrectinib, Irinotecan, Ponatinib, and YM201636. This study provides critical insights into the genomic landscape of liver cancer and identifies promising therapeutic candidates, serving as a valuable resource for advancing liver cancer research and treatment strategies. Full article

Background: Head-to-head evidence comparing repotrectinib against other approved ROS1 tyrosine kinase inhibitors (TKIs) is not currently available. The objective of this study was to indirectly compare progression-free survival (PFS), the objective response rate (ORR), and the duration of response (DoR) for repotrectinib vs. crizotinib and vs. entrectinib in patients with TKI-naïve ROS1+ locally advanced or metastatic non-small-cell lung cancer (aNSCLC). Methods: Using evidence from a systematic literature review, unanchored matching-adjusted indirect comparisons (MAICs) were used to estimate population-adjusted hazard ratios (HRs) for PFS and DoR and odds ratios (ORs) for ORR for repotrectinib vs. crizotinib and vs. entrectinib among patients with TKI-naïve aNSCLC. The MAICs were adjusted for imbalances in baseline patient characteristics that were pre-specified as being prognostic or predictive of treatment effects. Weighted Cox (for PFS and DoR) and logistic (for ORR) regression models were fit. Supplementary analyses (SAs) explored the impact of missing data and modeling assumptions on effect estimates. Results: The evidence base was formed by TRIDENT-1 EXP-1 (repotrectinib; N = 71), a pooled set of five trials involving crizotinib (N = 273), and the pooled ALKA-372–001/STARTRK-1 and -2 trials (entrectinib; N = 168). After population adjustment, repotrectinib was associated with statistically significant improvements in PFS relative to crizotinib (HR = 0.44; 95% confidence interval [CI]: 0.29, 0.67) and entrectinib (HR = 0.57; 95% CI: 0.36, 0.91). Differences in ORR and DoR were not statistically significant but numerically favored repotrectinib. SAs were consistent with the main analyses across all comparisons. Conclusions: The analysis demonstrated the strong benefits of repotrectinib in PFS, which was robust across different SAs and supported by numerically favorable results for DoR (where available) and ORR. These results, alongside the published TRIDENT-1 clinical data, further support repotrectinib as a potential new standard of care for TKI-naïve patients with ROS1+ aNSCLC. Full article

There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma. The FDA has also recently granted accelerated approval for autologous T-cell therapy with afami-cel in patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. There are other promising treatments that are still investigational, such as MDM2 and CDK4/6 inhibitors in well-/dedifferentiated liposarcoma, immune checkpoint inhibitors in the head and neck angiosarcoma and a subset of patients with undifferentiated pleomorphic sarcoma, and PARP inhibitors in leiomyosarcoma. The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale. Full article

Recent advancements in oncology have led to the development of histology-agnostic therapies, which target genetic alterations irrespective of the tumor’s tissue of origin. This review aimed to provide a comprehensive update on the current state of histology-agnostic drug development, focusing on key therapies, including pembrolizumab, larotrectinib, entrectinib, dostarlimab, dabrafenib plus trametinib, selpercatinib, trastuzumab deruxtecan, and reprotrectinib. We performed a detailed analysis of each therapy’s mechanism of action, clinical trial outcomes, and associated biomarkers. The review further explores challenges in drug resistance, such as adaptive signaling pathways and neoantigen variability, as well as diagnostic limitations in identifying optimal patient populations. While these therapies have demonstrated efficacy in various malignancies, significant hurdles remain, including intratumoral heterogeneity and resistance mechanisms that diminish treatment effectiveness. We propose considerations for refining trial designs and emerging biomarkers, such as tumor neoantigen burden, to enhance patient selection. These findings illustrate the transformative potential of histology-agnostic therapies in precision oncology but highlight the need for continued research to optimize their use and overcome existing barriers. Full article

We present a case of a lung adenocarcinoma patient harboring a novel kinesin family member 5B (KIF5B)-NTRK1 gene fusion that responds well to entrectinib. Moreover, KIF5B-NTRK1 gene chimera has been shown to be an oncogene, activating both the MAPK and PI3K/AKT signaling pathways. The biopsy sample was analyzed using various methods such as hematoxylin–eosin staining (HE), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) based on a 1267-gene panel. Additionally, human lung adenocarcinoma cell lines A549 and H1755 were used to obtain a stable expression of chimera gene products. The cell proliferation was confirmed using CCK8 and adhesion-dependent colony formation assay. Cell invasion was confirmed using the transwell invasion assay. The protein levels of the MAPK and PI3K/AKT signaling pathways were assessed using Western blotting. The patient, a 66-year-old Chinese male, was diagnosed with adenocarcinoma (stage IVB) located in the upper lobe of the left lung. NGS analysis identified a novel KIF5B-NTRK1 fusion gene, which was further confirmed by FISH and IHC analyses. As a first-line therapy, entrectinib was administered to the patient at a dose of 600 mg once daily, resulting in a partial response. The patient’s progression-free survival (PFS) has now been more than 12 months, and no serious toxicities have been observed so far. Furthermore, stable KIF5B-NTRK1-expressing cells were generated and the experimental results demonstrate enhanced proliferation abilities, along with increased levels of proteins involved in the MAPK and PI3K/AKT signaling pathways. Our study reports a novel KIF5B-NTRK1 genetic rearrangement that supports favorable responses to entrectinib. Moreover, in vitro experiments showed that the fusion gene could exert oncogenic properties by activating the MAPK and PI3K/AKT signaling pathways. To summarize, our findings broaden the spectrum of NTRK gene fusions in the context of lung adenocarcinoma. Full article

NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normal NTRK can be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective. Full article

ROS1 rearrangements are considered rare in non-small-cell lung cancer (NSCLC). This retrospective real-world study aimed to evaluate first-line treatment with crizotinib, a tyrosine kinase inhibitor (TKI) standard of care vs. new generation ROS1 anti-cancer agents. Forty-nine ROS1-expressing NSCLC patients, diagnosed with advanced metastatic disease, were included. Molecular profiling using either FISH/CISH or NGS was performed on tissue samples. Twenty-eight patients were treated with crizotinib, while fourteen patients were administered newer drugs (entrectinib, repotrectinib) and seven patients received platinum-doublet chemotherapy in a first-line setting. Overall response rate and disease control rate for the crizotinib and entrectinb/repotrectinib cohort were 68% and 82% vs. 86% and 93%, respectively. Median progression free survival was 1.6 years (95% CI 1.15–2.215) for the crizotinib treatment vs. 2.35 years for the entrectinib/repotrectinib cohort (95% CI 1.19–3.52). Central nervous system progression was noted in 20% and 25% of the crizotinib and entrectinib/repotrectinib cohorts, respectively. This multi-center study presents real-world treatment patterns of ROS1 NSCLC population, indicating that crizotinib exhibited comparable results to entrectinib/repotrectinib in a first-line setting, although both response rate and survival was numerically longer with treatment with newer agents. Full article

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure–activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors. Full article

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAF^V600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types. Full article

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option. Full article

Patients with differentiated thyroid cancer usually present with early-stage disease and undergo surgery followed by adjuvant radioactive iodine ablation, resulting in excellent clinical outcomes and prognosis. However, a minority of patients relapse with metastatic disease, and eventually develop radioactive iodine refractory disease (RAIR). In the past there were limited and ineffective options for systemic therapy for RAIR, but over the last ten to fifteen years the emergence of tyrosine kinase inhibitors (TKIs) has provided important new avenues of treatment for these patients, that are the focus of this review. Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway. Full article

In the search for new potential drug candidates acting as anticancer agents, we were interested in a small molecule derived from 4-hydroxy-2-quinolone, which is newly synthesized from the condensation of a β-enaminone and diethylmalonate under microwave irradiation. This compound was subjected to an in silico study in order to investigate its potentiality to act against lung cancer through inhibiting a tyrosine kinase: Anaplastic Lymphoma Kinase (ALK). A docking simulation was performed in the active pocket of the human ALK complexed with a commercialized anticancer agent—Entrectinib (Pdb: 5FTO)—using Schrodinger suite. The studied derivative showed good stability inside the active site with an estimated docking score equal to −8.054 kcal·mol⁻¹. In addition, significant interactions, similar to those formed by the co-crystallized ligand, were present in the studied compound, counting hydrogen bonds with Met1199 and Glu1197 as well as hydrophobic contacts with residues in the cavity of the ALK. Keeping in mind that the pharmacokinetic properties and the toxicity of a drug candidate are very important factors in conceiving a safe admissible therapeutic substance, we carried out an ADMET prediction for the studied molecules using SwissADME, MolSoft, and ProTox-II, which gave promising results. Full article

The first-generation tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, represent exciting new developments in cancer treatment that offer relevant, rapid, and long-lasting clinical benefits. Larotrectinib and entrectinib are recommended as first-line treatments for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with positive TRK gene fusions. In this study, using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database between 2019 and 2022, a retrospective analysis was conducted to evaluate the safety profiles of these drugs. During our study period, 807 individual case safety reports (ICSRs) related to larotrectinib or entrectinib were retrieved from the FAERS database, of which 48.7% referred to females and 24.7% referred to adult patients (18–64 years) with a median age of 61.0 years. A total of 1728 adverse drug reactions (ADRs) were identified. The most frequently reported ADRs were dizziness and pain, which belong to the System Organ Classes (SOCs) “nervous system disorders” and “general disorders and administration site conditions”. Regarding all ADRs, the median time to onset was 37.0 days for larotrectinib and 12.0 days for entrectinib. No evident safety concerns emerged in the long-term safety profiles (>365 days). Only 18 ICSRs were related to pediatric populations (≤16 years), of which 94.0% of the ICSRs were related to larotrectinib. The median age was 10.5 years, while most patients were female (44.4%). Our results show favorable risk-benefit profiles for larotrectinib and entrectinib. Considering the increased use of neurotrophic tyrosine receptor kinase (NTRK) inhibitors, continuous safety monitoring of larotrectinib and entrectinib is required for the detection of possible new adverse drug reactions. Full article

Entrectinib is an oral selective inhibitor of the neurotrophic T receptor kinase (NTRK). It is used in the treatment of solid tumors in NTRK gene fusion lung cancer. The study aimed to develop and validate an analytical method for quantifying entrectinib plasma by UPLC-MS/MS using quizartinib as an internal standard. The method involves liquid–liquid extraction of entrectinib from plasma using tert butyl methyl ether. The mass-to-charge transitions were 561.23 → 435.1 for entrectinib and 561.19 → 114.1 for quizartinib. The method was successfully validated according to ICH and FDA guidelines. The method has a low quantification limit of 0.5 ng/mL, and the calibration curves constructed over a wide range of 0.5–1000 ng/mL showed good linearity (≥0.997). This method exhibits a tenfold increase in sensitivity compared with the previous method. The method is also accurate, precise, and reproducible, as evidenced by the inter-day and intra-day accuracy and precision values of 82.24–93.33% and 3.64–14.78%, respectively. Principles of green analytical chemistry were considered during all analytical steps to ensure safety. The greenness of the methods was evaluated using two assessment tools. These tools are the Analytical Eco-Scale and the analytical greenness metric approach (AGREE). The results were satisfactory and compatible with the criteria of these tools for green assessment. This method is green, accurate, precise, and reproducible. The method can be used to quantitate entrectinib in plasma and its pharmacokinetics in preclinical, and therapeutic drug monitoring. Full article