Rozlytrek (entrectinib) / Roche, Nerviano Medical Sciences - LARVOL DELTA

A phase II, multi-center, open-label, single-arm study to evaluate the efficacy and Safety of lorlatinib in TKI naïve, advanced ROS1-positive non-small cell lung cancer patients with brain metastases (ESMO Asia 2025) - P2 | "While ROS1-tyrosine kinase inhibitors (TKIs) (e.g., crizotinib, entrectinib, repotrectinib) improve outcomes in ROS1-positive NSCLC, intracranial efficacy remains suboptimal, representing a critical unmet need. At present, no efficacy or safety results are available. Data collection for safety and efficacy endpoints is ongoing."

Clinical • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Subgroup analysis of japanese patients in the phase II study of taletrectinib in patients with ROS1+ NSCLC: The global TRUST-II study (ESMO Asia 2025) - P2 | "In 10 TKI-pretreated pts (7 crizotinib, 3 entrectinib), cORR 70% (95% CI: 34.8, 93.3), IC-cORR 100% (95% CI: 29.2, 100; 3/3), and median DOR 19.4 months (95% CI: 2.8, NE). Taletrectinib continues to show high and durable overall responses, robust intracranial activity, in Japanese ROS1+ NSCLC both in TKI-naïve and -pretreated in the TRUST-II study. The safety profile, including low neurologic adverse events, was consistent with entire cohort, supporting its efficacy and tolerability in this population."

Clinical • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Novel NOTCH2-NTRK1 fusion confers osimertinib resistance in EGFR-mutant non-small cell lung cancer by interacting with EGFR. (PubMed, Transl Oncol) - "Our study reveals a novel mechanism by which the NOTCH2-NTRK1 fusion confers resistance to osimertinib through its interaction with EGFR in NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NOTCH2 • NTRK • NTRK1

Competing Beyond the First Mover: How Late to Market Analogues Navigate Pricing and Access in Major Global Markets (ISPOR-EU 2025) - "HTA, pricing outcomes and payer perceptions for ten analogues (such as Alecensa, Zejula, Rozlytrek, Eylea, Fasenra) were analysed across seven global markets (US, Germany, France, Spain, UK, Brazil, Canada). Several distinct pricing strategies (discounting, parity or premium) were observed which were highly dependent on the level of clinical differentiation vs. earlier to market options. Analogue assessment considered clinical and other non clinical factors that impacted their pricing and access success or failure which can potentially be used as a guide for future portfolio development and optimisation. Demonstrating clinical differentiation vs. earlier entrants is the critical factor translating into positive HTA outcomes and securing a price premium."

Clinical • Pricing

Advances in Tissue-Agnostic Targeting in Cancer Therapeutics: Current Approvals, Challenges, and Future Directions. (PubMed, Oncol Res) - "The purpose of this review is to explore the impact, safety, and challenges of tissue-agnostic therapies including pembrolizumab, dostarlimab, larotrectinib, entrectinib, repotrectinib, dabrafenib plus trametinib, selpercatinib, and trastuzumab deruxtecan. We discuss emergence of pan-histological biomarkers, such as neoantigen burden, current updates on trials as well as trial outlining strategies to refining patient selection, while also supporting broader access to biomarker testing. Collectively, these insights underscore the transformative role of tissue-agnostic therapies in precision oncology while emphasizing the ongoing need for research to optimize their application and overcome current barriers."

Biomarker • Journal • Pan tumor • Review • Oncology

Emerging Targeted Therapies and Ongoing Clinical Trials in Pediatric Brain Tumors (PubMed, No Shinkei Geka) - "Dabrafenib plus trametinib has shown superiority over chemotherapy in pediatric low-grade gliomas and activity against high-grade diseases. Larotrectinib and entrectinib provide tumor-agnostic options for NTRK-fusion-positive tumors with central nervous system penetration. Selumetinib offers clinical benefits in NF1-associated plexiform neurofibromas and shows promise for treating NF1-related low-grade gliomas. Tovorafenib, a type II RAF inhibitor active in BRAF-altered tumors (including BRAFKIAA1549 fusion), achieved robust responses, thereby leading to FDA approval. ONC201 (dordaviprone) has received accelerated approval for the treatment of H3 K27M-mutant diffuse midline gliomas, with Japanese trials and patient-initiated programs expanding access. Abemaciclib, a CDK4/6 inhibitor, is under phase II evaluation for pediatric high-grade glioma and diffuse midline glioma, including sites in Japan. Neurosurgeons play a pivotal role in securing high-quality biopsies, thus..."

Journal • Review • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • High Grade Glioma • Neurofibromatosis • Oncology • Pediatrics • Solid Tumor • BRAF • KIAA1549 • NF1 • NTRK

Next-Generation Targeted Therapy: The Evolving Role of Taletrectinib in Fusion-Positive Malignancies. (PubMed, Zhongguo Ying Yong Sheng Li Xue Za Zhi) - "First-generation tyrosine kinase inhibitors (TKIs) such as crizotinib displayed significant early reactions but faced challenges due to restricted central nervous system (CNS) penetration and mutation resistance, while entrectinib and larotrectinib expanded treatment options but also experienced resistance...Safety data shows an acceptable toxicity profile, mainly featuring gastrointestinal and hepatic adverse effects, with fewer neurocognitive side effects compared to lorlatinib...Current trials and regulatory activities in China, the U.S., and other locations demonstrate taletrectinib's growing clinical significance. Taletrectinib's well-rounded pharmacological attributes of systemic action, intracranial effectiveness, resistance range, and tolerability render it an intriguing enhancement to the framework of precision oncology."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NTRK • ROS1

Evolving Therapeutic Landscape of ROS1-Positive Non-Small Cell Lung Cancer: An Updated Review. (PubMed, Curr Oncol) - "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."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Experts Unpack the Most Notable NCCN Guideline Changes Heading Into 2026 (OncLive) - "'[During 2025], adjuvant therapy regimens from the [phase 3] ATOMIC trial [NCT02912559]—FOLFOX or CAPEOX in combination with atezolizumab—were added in stage III dMMR/MSI-H colon cancer. This change represents the addition of checkpoint inhibitor therapies at earlier points of the patient journey.' Al B. Benson, III, MD...said in a statement to OncLive."

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Rare but not forgotten: Therapeutic advancements for rare childhood cancers. (PubMed, Mol Ther Oncol) - "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."

Journal • Review • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Melanoma • Nasopharyngeal Carcinoma • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Pediatrics • Sarcoma • Solid Tumor • NTRK • SSTR

Lorlatinib in Tyrosine Kinase Inhibitor-Naive Advanced ROS1-Positive Non-Small Cell Lung Cancer: A Phase 2 Nonrandomized Clinical Trial. (PubMed, JAMA Oncol) - P2 | "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."

Clinical • Journal • P2 data • Dyslipidemia • Hypertriglyceridemia • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • ROS1

Impact of Long-Term Structured Exercise on Body Composition in an NTRK Fusion-Positive NSCLC Patient Treated With Entrectinib. (PubMed, Thorac Cancer) - "Despite an initial 13 kg weight gain over 9 months, split between fat and lean mass, subsequent fat loss (~3.5 kg) occurred while lean mass was preserved. This case suggests that prolonged, structured exercise is a safe and feasible strategy to attenuate entrectinib-associated metabolic effects and support physical function during targeted therapy in advanced NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NTRK

Entrectinib in Asian patients with ROS1 fusion-positive non-small cell lung cancer: updated efficacy and safety analysis. (PubMed, Lung Cancer) - "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."

Journal • Constipation • Gastroenterology • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Agnostic Biomarkers in Molecular Pathology. (PubMed, J Clin Pract Res) - "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..."

Biomarker • IO biomarker • Journal • Review • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Microsatellite Instability • Oncology • Sarcoma • Solid Tumor • ALK • BRAF • BRCA • FGFR • HER-2 • KRAS • MSI • NRG1 • NTRK • PD-L1 • PIK3CA • RET • TMB

Identification of a novel PRUNE2::NTRK2 gene fusion in soft tissue sarcoma patients-friend or foe? Case series. (PubMed, Ther Adv Med Oncol) - "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."

Journal • Colorectal Cancer • Genito-urinary Cancer • Neuroblastoma • Oncology • Prostate Cancer • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • NTRK • NTRK2

Novel SNX25-ROS1 fusion mutation confers therapeutic sensitivity to entrectinib: a case report and literature review. (PubMed, J Chemother) - "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."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pain • Solid Tumor • ROS1

Pediatric Pleomorphic Xanthoastrocytoma: Insights in Biology and Targeted Therapy (WFNOS 2025) - "Targeted therapy was used in 15 cases (9 PXA grade 3 and 6 PXA grade 2) with combination of dabrafenib and trametinib in 12 and entrectinib in 3. RTK fusions should be investigated in all BRAF-negative cases. Targeted therapy demonstrated promising results."

Clinical • Astrocytoma • Brain Cancer • Oncology • Pediatrics • Pleomorphic Xanthoastrocytoma • Solid Tumor • ALK • BRAF • CDKN2A • ETV6 • NACC2 • NTRK1 • NTRK2 • NTRK3 • ROS1 • TPM3

High-throughput transcriptomic screening reveals entrectinib as a repositioning opportunity in 19q12 autism spectrum disorder. (PubMed, Sci Rep) - "Biomarkers from blood recapitulated Entrectinib's pharmacodynamic effect and normalized the disease signature. We show how generation of transferrable transcriptomics-derived disease signatures allows for measuring drug effects on a signature in related wild-type cell lines, making the screen universally applicable and reducing the need for expensive screens in disease models."

Journal • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Psychiatry • Rare Diseases • ZKSCAN1

A deep representation learning algorithm on drug-target interaction to screen novel drug candidates for Alzheimer's disease. (PubMed, Artif Intell Med) - "Our results identified that several drugs could be promising for AD treatment, including human C1-esterase inhibitor, quetiapine, dasatinib, miconazole, aniracetam, chlorpromazine, hypericin, entrectinib, torcetrapib, bosutinib, sunitinib, aniracetam, rosiglitazone, tarenflurbil, milrinone, and MITO-4509. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a systematic and versatile method, our approach can also be applied to identify efficacious therapies for other complex diseases."

Journal • Alzheimer's Disease • CNS Disorders

Pediatric Pleomorphic Xanthoastrocytoma: Insights in Biology and Targeted Therapy (SNO 2025) - "Targeted therapy was used in 15 cases (9 PXA grade 3 and 6 PXA grade 2) with combination of dabrafenib and trametinib in 12 and entrectinib in 3. RTK fusions should be investigated in all BRAF-negative cases. Targeted therapy demonstrated promising results."

Clinical • Astrocytoma • Brain Cancer • Oncology • Pediatrics • Pleomorphic Xanthoastrocytoma • Solid Tumor • ALK • BRAF • CDKN2A • ETV6 • NACC2 • NTRK1 • NTRK2 • NTRK3 • ROS1 • TPM3

HTA Readiness for Tumor-Agnostic Therapies: Lessons From Analogues Across Major Markets (ISPOR-EU 2025) - "HTA outcomes and payer perceptions were analysed for pembrolizumab, entrectinib, larotrectinib and selpercatinib across 6 key global markets (Australia, Canada, England, France, Germany and Scotland) to determine commonalities and differences in payer reviews and constructive suggestions provided to the manufacturers by the payers. The evidence package for these tumor-agnostic drugs comprised of pooled results from multiple single arm trials. Tumor-agnostic therapies have faced payer scrutiny owing to evidence issues however, there were some signals that payers are willing to engage with manufacturers to provide patient access even without a robust evidence package. It is imperative for the manufacturers and the global market access teams to adopt a tumor-agnostic approach in evidence generation, such as pooled analysis of tumor types."

Pan tumor • Oncology

In Vitro Drug Profiling to Guide Treatment for Relapse/Refractory AML (ASH 2024) - "Significant correlation was observed among drugs of the same classes, for example between inhibitors of PARP (e.g. niraparib-talazoparib, r=0.78, p=1.3e-22), proteasome (e.g. bortezomib-ixazomib, r=0.90, p=4.2e-36), JAK (ruxolitinib-tofacitinib, r=0.91, p=8.3e-35), MEK (cobimetinib-trametinib, p=0.93, p=8.8e-47) and CDK (abemaciclib-palbociclib, p=0.56, p=2.7e-10), confirming that the readout is biologically meaningful. Intriguingly, there were unexpected correlations between specific pairs of drugs of different classes, for instance homoharringtonine (protein translation inhibitor)-abemaciclib (CDK inhibitor) (r=0.65, p=4.3e-17) and between specific gene mutations and drug sensitivity was observed, e.g. sensitivity of CEBPAbZIP mutated samples to PARP inhibitors (p=0.00156), and of AML with inv(16) to MEK inhibitors (p=0.0016)...Drug response to daunorubicin showed good prediction of chemo-resistance in patients who had non-remission after "7+3" (ROC curve AUC..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • FLT3

In-silico discovery of druggable molecular signatures that drive dengue fever to severe dengue fever highlighting common pathogenesis through single-cell RNA-Seq analysis. (PubMed, Sci Rep) - "Finally, chKGs-guided three candidate drug agents (Entrectinib, Imatinib, and QL47) were recommended against dengue virus infection (DENVI) through molecular docking, drug-likeness screening, ADME/T analysis, DFT analysis. Therefore, the findings of this study may provide valuable insights for diagnosis and therapies against DENVI."

Journal • Cardiovascular • Dengue Fever • Infectious Disease • CD4 • HSPA5 • IL6 • IRF7 • SOCS3 • SYK • TNFSF13B

Phase 1 Trial Testing the Novel Combination Therapy of Entrectinib and ASTX727 in TP53 Mutated Relapsed/Refractory Acute Myeloid Leukemia Patients (ASH 2024) - "Introduction : The TP53 apoptotic network and mitochondrial functionality have been established as drivers of response to the BCL2 inhibitor, venetoclax, in acute myeloid leukemia (AML). The study is ongoing and an MTD has not yet been identified. More data and correlative findings will be presented at the meeting."

Clinical • Combination therapy • IO biomarker • P1 data • Tumor mutational burden • Acute Myelogenous Leukemia • Febrile Neutropenia • Hypotension • Neutropenia • Thrombocytopenia • NTRK • TMB • TP53

Targeting IGF1R/Insr Pathway with Approved ALK-Inhibitors Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma (ASH 2023) - "Background: The treatment of multiple myeloma (MM) has advanced rapidly with the discovery of proteasome inhibitors (PIs) bortezomib (BTZ) and carfilzomib (CFZ)...The combination of ceritinib, brigatinib, and entrectinib showed synergistic cytotoxicity with PI BTZ and CFZ and overcame PI-resistance in four different sets of PI-adapted cells... Ceritinib, an FDA-approved drug, overcomes PI resistance in MM by targeting InsR/IGF1R signaling, which is essential for PI resistance in MM. Therefore, ceritinib represents a promising, potential option for the treatment of PI-resistant MM."

Hematological Malignancies • Multiple Myeloma • Oncology • DDIT4 • IGF1 • IGF1R • IR • TSC1