We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.

Lorlatinib induced a complex dyslipidemia in our patient with elevations of both LDL-C and HDL-C. The underlying mechanism of lorlatinib-induced hyperlipidemia remains unknown and is unlikely to be secondary to nephrotic syndrome in many patients.

This real-world data confirms the efficacy of Lorlatinib in the second line and beyond with adverse effects matching that of registration studies.

In this case, lorlatinib effectively controlled the tumor and improved the patient's liver function and performance status. This case highlights the importance of adapting treatment strategies to manage adverse effects while ensuring the continued use of ALK inhibitors for optimal patient outcomes.

P=N/A, N=100, Not yet recruiting, Peking University Cancer Hospital & Institute

The results showed that while proliferation rates, cell index values, mitotic index and bromodeoxyuridine labeling index decreased, caspase activity values increased. These results demonstrated that the combined application was more effective than the monotherapy application and could be used at lower concentrations than those drugs applied as monotherapy.

Finally, Shapley additive explanations (SHAP) was also used to explain the influence of modeling features on model prediction results. The SHAP results indicated that our models can well reflect the structural features of ALK inhibitors.

In this particular case, treatment with crizotinib demonstrated some initial efficacy, which suggests that this might be a promising strategy for patients with advanced MPM with an ALK gene mutation. This required further research and evaluation in the future.

P1, N=50, Not yet recruiting, Ascentage Pharma Group Inc.

P2, N=25, Not yet recruiting, Peking University People's Hospital

P4, N=71, Completed, Pfizer | Active, not recruiting --> Completed

P2, N=150, Not yet recruiting, Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences); Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sci

P=N/A, N=90, Not yet recruiting, Pfizer | Initiation date: Jul 2024 --> Nov 2024

P=N/A, N=1, Not yet recruiting, Pfizer

The association between CNS progression and breakpoint variants warrants further investigation. Our findings suggest that close monitoring and prompt intervention are crucial in prolonging the quality of life of this patient subset.

Alectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy.

P2, N=150, Not yet recruiting, Hoffmann-La Roche | Trial completion date: Nov 2034 --> Mar 2033 | Trial primary completion date: Oct 2029 --> Jun 2028

In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib. Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC. The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases.

The current state of knowledge on ALK inhibitors used in clinical practice is summarised in this research paper. Methods of diagnosis of abnormalities in ALK have been shown, and the review of research that contributed to the development of the next generation of ALK inhibitors has been presented.

Then we detected 6 repurposable drug molecules (Entrectinib, Imatinib, Ponatinib, Sorafenib, Retevmo, and Pazopanib) by molecular docking with KGs-mediated receptor proteins, ADME/T analysis, and cross-validation with the independent receptors. Therefore, these findings might be useful resources for wet lab researchers and clinicians to consider an effective treatment strategy against THCA.

P2, N=20, Not yet recruiting, MedSIR | Initiation date: Aug 2024 --> Nov 2024

P2, N=240, Active, not recruiting, BioAtla, Inc. | Recruiting --> Active, not recruiting

P=N/A, N=100, Not yet recruiting, Shanghai Pulmonary Hospital, Shanghai, China

After the initial treatment with ensartinib, the patient experienced intracranial disease progression...Subsequent thoracic RT resulted in a partial response of the primary tumor; however, new brain and bone metastases were detected, prompting a switch to lorlatinib...Despite pembrolizumab treatment, the patient's condition deteriorated, and she passed away...Our findings revealed heterogeneity in ALK mutations and responses to ALK-TKIs, necessitating the close monitoring of genetic subtypes and associated mutations for tailored treatment strategies. Maintaining a heightened awareness of potential intestinal metastasis and vigilance in monitoring intestinal symptoms and abdominal metastases are pivotal for managing advanced lung adenocarcinoma.

A 43-year-old, female diagnosed with T4N3M1c NSCLC harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant 1 (EML4-ALK v.1) and TP53 co-mutation, displayed only mixed response after three months and highly symptomatic progression after 6 months of first-line brigatinib treatment. The latter may represent a mechanism of intrinsic ALK-TKI resistance and its recognition by FISH, in NGS-negative cases, may be considered before initiating first-line treatment. This recognition is clinically important as combined therapy with ALK-TKI and MET-inhibitor should be the preferred first-line treatment.

P=N/A, N=18, Active, not recruiting, Academic Thoracic Oncology Medical Investigators Consortium | Trial completion date: Aug 2024 --> Aug 2025

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...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.

P=N/A, N=1000, Not yet recruiting, Qilu Pharmaceutical Co., Ltd.

The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALKL1196M/G1202R mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALKG1202R/L1196M-induced NSCLC resistance and optimizing of ALK inhibitors.

ALK inhibition was initiated with alectinib, resulting in rapid improvement of cutaneous lesions and eventual complete resolution of abnormal imaging findings, which was sustained at 24 months of follow-up. This case adds to the spectrum of ALK-positive histiocytoses and further demonstrates the positive response with targeted therapy.

The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.

P2, N=110, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Recruiting --> Active, not recruiting

Aim: We conducted network meta-analysis to assess cardiovascular toxicity of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs).Materials & Eleven articles involving 2855 patients and six interventions including crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and chemotherapy were analyzed. No significant difference was observed in overall cardiovascular risk among ALK-TKIs. For vascular toxicity, crizotinib and ceritinib had a higher risk of thrombotic events than brigatinib. Crizotinib and lorlatinib were more likely to cause blood pressure abnormalities. Clinicians should carefully monitoring cardiovascular events when ALK-TKIs used in NSCLCs patients with baseline cardiovascular diseases.

Administration in combination with PPIs, amlodipine, and magnesium oxide significantly increases the risk of ILD. These results provide risk prediction for ILD related to ALK TKIs and support pharmacovigilance to promote safe prescribing in oncology.

The results of the in vitro stability experiment showed that the selected mixed micelle (F6) was stable at both room temperature and 4 °C, with only minor changes in size and PDI. Our results indicate great potential for the developed Soluplus-TPGS mixed micelles as a delivery system for BGT.

No abstract available

Based on the genomic analysis, we treated the patient with brigatinib, an ALK inhibitor. We describe here a patient with LCNEC who responded significantly to brigatinib without serious adverse events.

P4, N=14, Pfizer, Inc

Consequently, it is postulated that the administration of CEP-37440 to patients may not lead to the accrual of dosages within the human organs. According to in silico P450 metabolic and DEREK software, minor structural alterations to the ethanolamine moiety or substitution of the group in drug design have the potential to enhance the metabolic stability and safety profile of novel derivatives in comparison to CEP-37440.

A bronchoscopy with transbronchial lung biopsy of the right S5 nodule confirmed the diagnosis of adenocarcinoma. The biopsy specimen was analyzed using the AmoyDx® Pan Lung Cancer PCR Panel, which detected ROS1 fusions.

Her symptoms continued despite an antibiotic course with re-imaging concerning for acute appendicitis, which was successfully treated with appendectomy and amoxicillin-clavulanic acid. Both patients remained on alectinib over the courses of appendicitis without interruption. While appendicitis has not been previously described as an adverse effect of alectinib, its incidence in two patients at our center within several months following the administration of alectinib raises its suspicion as a possible adverse effect.

P4, N=73, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=200 --> 73