Rozlytrek (entrectinib)

This analysis demonstrates continued efficacy of entrectinib in Asian patients with advanced ROS1-fp NSCLC, both overall and in the 1L setting. No new safety signals emerged.

Although NTRK-associated fusions are significant in various cancers and have led to the development of targeted therapies, such as larotrectinib and entrectinib, the specific molecular impact of atypical PRUNE2::NTRK2 fusion remains unclear. The PRUNE2::NTRK2 gene fusions described here express a non-functional TrkB protein, and it is unclear whether the PRUNE2 function is intact or affected.

This includes work that led to the FDA approvals of immune checkpoint inhibitors in multiple rare pediatric tumor types, the NTRK inhibitors larotrectinib, entrectinib, and repotrectinib for children and adults with solid tumors with NTRK fusions, the ALK inhibitor crizotinib in children and adults with ALK-positive inflammatory myofibroblastic tumors, and the radioligand LUATHERA for adolescents and adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Despite these advances, the study of rare pediatric cancers faces multiple challenges including a limited number of patients for efficient and well-powered clinical trials and a dearth of financial incentives. Ongoing, coordinated efforts are needed to continue the advancement of novel treatments and improve survival and minimize late effects.

This case report identifies a novel SNX25-ROS1 fusion mutation in NSCLC, showing strong sensitivity to ROS1-targeted therapy. It highlights the importance of molecular profiling in detecting rare genetic alterations and underscores the therapeutic potential of targeted treatments for NSCLC with unique molecular subtypes.

Crizotinib, entrectinib, and repotrectinib have been approved by the US Food and Drug Administration for treatment of ROS1-positive NSCLC. In this nonrandomized clinical trial, lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced ROS1-positive NSCLC, supporting the potential for using lorlatinib in earlier treatment settings. ClinicalTrials.gov Identifier: NCT03612154.

Crizotinib first demonstrated substantial clinical benefit, but its limitations, including poor central nervous system (CNS) penetration and acquired resistance, highlighted the need for next-generation inhibitors. Several agents have since been developed, including entrectinib, lorlatinib, repotrectinib, taletrectinib, and zidesamtinib, each offering improved intracranial (IC) activity and efficacy against resistance mutations, notably ROS1^G2032R. Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape.

Our study reveals a novel mechanism by which the NOTCH2-NTRK1 fusion confers resistance to osimertinib through its interaction with EGFR in NSCLC.

The United States Food and Drug Administration (FDA) has approved pembrolizumab for MSI-high tumors or tumors with a high TMB. Larotrectinib and entrectinib have been approved for the treatment of NTRK gene fusion-positive tumors. Additionally, the combination of dabrafenib and trametinib has been approved for BRAF V600E mutations, and selpercatinib has been approved for RET fusion-positive cancers as of 2022. Positive responses to agnostic therapy, a significant milestone in cancer treatment, depend on the identification of new agnostic biomarkers. Ongoing research is focused on defining additional molecular changes, such as programmed death-ligand 1 (PD-L1), Kirsten rat sarcoma virus (KRAS), neuregulin 1 (NRG1), fibroblast growth factor receptor (FGFR), anaplastic lymphoma kinase (ALK), AKT serine/threonine kinase (AKT), human epidermal growth factor receptor 2 (HER2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and breast cancer gene (BRCA), as potential agnostic biomarkers in various cancer types.

Importantly, we identified ROS1 p.K1991N as a potential acquired drug resistance mutation to crizotinib, suggesting that entrectinib may serve as a targeted therapy to overcome this resistance mechanism. ROS1 rearrangement could potentially represent a novel driver mutation in MPM, especially in female adults. This case report illustrates the benefits of molecular detection in MPM and underscores the potential for lessons learned from other solid tumors to inform treatment strategies for rare diseases.

The GSEA and DOEA showed that NTRK signalling was enriched for kinase inhibitors responses, representing evidence that NTRK1/2/3 expression may serve as biomarkers for multiple kinase inhibitors, including entrectinib-the tissue-agnostic kinase inhibitor for cancers with NTRK gene fusions. The results demonstrated that fusion-negative NTRK signalling may be active in CRC and may contribute to the molecular pathogenesis and biology of the disease. The results also demonstrated that the NTRK1/2/3 expression may be predictive multiple kinase inhibitors.

Drug sensitivity assays revealed an IC₅₀ of 64.0 nM for entrectinib and 806.8 nM for osimertinib, indicating reduced sensitivity to EGFR inhibition. We provided experimental evidence for that TPM3-NTRK1 fusions can mediate acquired resistance to osimertinib in a new lung adenocarcinoma cell line. LUNK1 represents a useful preclinical model for investigating resistance mechanisms and assessing dual-targeted treatment strategies.

This case highlights a potentially fatal early-phase cardiac complication of entrectinib and supports the use of early electrocardiographic monitoring and therapeutic plasma exchange as management and rescue strategies.