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

Comprehensive genomic profiling to guide personalized targeted and immunotherapy in gastrointestinal tumors: Subgroup analysis of the ROME trial (ESMO-GI 2025) - P2 | "Funding: Erlotinib, Pertuzumab, Vemurafenib, Trastuzumab Emtansine, Alectinib, Vismodegib, Cobimetinib, Atezolizumab, Trastuzumab, Ipatasertib (GDC-0068), Entrectinib and Pralsetinib were provided by Roche; Everolimus, Lapatinib, Alpelisib were provided by Novartis, Palbociclib and Talazoparib were provided by Pfizer, Ipilimumab and Nivolumab were provided by Bristol Myers Squibb (BMS); Brigatinib was provided by Takeda Pharmaceutical Co.; Ponatinib, Itacitinib (INCB039110), Pemigatinib (INCB054828) were provided by Incyte; Selpercatinib was provided by Eli Lilly; Tepotinib was provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). CGP with MTB-guided TT may identify patients with GI cancer who benefit from targeted therapies not routinely available in clinical practice. The roles of TMB and potential disease-specific thresholds deserve further investigation."

IO biomarker • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA • TMB

Recent advances in tropomysosin receptor kinase (TRK) inhibitors: a 2023-2024 patent landscape review. (PubMed, Expert Opin Ther Pat) - "TRK inhibitors like larotrectinib and entrectinib marked a paradigm shift - prioritizing molecular alterations over the tumor's anatomical location...Combination therapies with TRK inhibitors are emerging as a key strategy to enhance efficacy and overcome resistance. The FDA's recent approval of repotrectinib underscores progress in the TRK inhibitor landscape, while highlighting the continued need for innovation."

Journal • Review • Oncology • NTRK

Etv6-ntrk3 Fusion-positive Papillary Thyroid Carcinoma: A Rare And Aggressive Presentation (ENDO 2025) - "This case underscores the aggressive behavior of ETV6-NTRK3 fusion-positive PTC despite the typically favorable prognosis of PTC in young adults. Recognition and molecular characterization of NTRK fusion-driven tumors are critical for risk stratification, aggressive disease management, and potential use of targeted therapies.[1] Although NTRK fusions are actionable genomic targets with FDA-approved TRK inhibitors (larotrectinib and entrectinib), the optimal integration of these therapies into the clinical management of thyroid cancer remains an area of ongoing investigation. [1,3,4,5]"

Late-breaking abstract • Acute Myelogenous Leukemia • Endocrine Cancer • Hematological Malignancies • Leukemia • Oncology • Pain • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • ETV6 • NTRK • NTRK3

DISSECTING THE MOLECULAR MECHANISMS UNDERLYING THE ERKi-ENTRECTINIB COMBINATION IN LKB1-MUTATED NSCLC (EACR 2025) - "These findings highlight the therapeutic potential of ERKi-based combinations for LKB1-mutated NSCLCs, particularly with Entrectinib. The study provides a strong rationale for further preclinical and clinical evaluations to refine combination strategies, enhance efficacy, and minimize toxicity. This offers a new avenue for treating LKB1-deficient NSCLCs, a subtype with limited targeted therapies."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NTRK • STK11

Assessment of two new ROS1+ NSCLC patient-derived cell lines as in vitro models for TKI resistance studies (EACR 2025) - "The IC50 values of unmutated ROS1+ Ba/F3 cells for crizotinib, entrectinib, lorlatinib, repotrectinib and zidesamtinib were 31.4; 44.6; 14.3; 14.9 and 29.9 nM, respectively...Interestingly, these cells were resistant to lorlatinib, while the patient is – after being treated with lorlatinib+cis-platinum+pemetrexed, now currently successfully treated with lorlatinib mono-therapy... In this study we showed that PC1 cells generated from a crizotinib-resistant patient were resistant to all ROS1 inhibitors tested. The G2032R mutated PC2 cells generated from a crizotinib and lorlatinib resistant patient were sensitive to repotrectinib, but not to zidesamtinib. This PC2 cell line can be used to assess off-target resistance mechanism to zidesamtinib."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor • ARID1A • CD74 • PIK3CA • PIK3CG • ROS1

STARTRK-NG: Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options (clinicaltrials.gov) - P1/2 | N=69 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Oncology • Pediatrics • Solid Tumor • NTRK1 • NTRK2 • NTRK3 • ROS1

In silico & in vitro approaches suggest osteoclastogenesis induction underlying fractures in Entrectinib-treated children. (PubMed, Arch Toxicol) - "Pre-treatment with Vitamin D led to partially restored osteoblast function in vitro, while osteoclast function was suppressed. These experiments suggest an on-target effect of Entrectinib underlying increased fractures particularly in children with developing bones, offering potential mitigation strategies if these observations can be confirmed with data from ongoing clinical trials."

Journal • Preclinical • Musculoskeletal Diseases • Orthopedics • Pediatrics • TGFB1

Pulmonary embolism masquerading as ST elevation myocardial infarction and ventricular tachycardia. (PubMed, BMJ Case Rep) - "Subsequently, he developed sustained ventricular tachycardia, managed with an amiodarone infusion. This case highlights pulmonary embolism (PE) occurring despite therapeutic anticoagulation, suggesting direct oral anticoagulant failure, possibly due to entrectinib reducing rivaroxaban bioavailability. It also demonstrates PE mimicking ST-elevation myocardial infarction and VT in a high-risk patient."

Journal • Cardiovascular • Critical care • Hematological Disorders • Lung Adenocarcinoma • Lung Cancer • Myocardial Infarction • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • Solid Tumor • Venous Thromboembolism • Ventricular Tachycardia

Durable Response in NTRK Fusion-Positive Advanced Salivary Gland Tumor: A Case Report. (PubMed, Case Rep Oncol) - "Recent studies have shown that TRK inhibitors, such as entrectinib, larotrectinib and repotrectinib, are effective in treating solid tumors harboring NTRK gene fusions. To our knowledge, this is the first reported case in Bolivia of a salivary gland tumor with an NTRK fusion identified through molecular profiling, followed by successful treatment with compassionate use of entrectinib. This case not only demonstrates the therapeutic benefits and safety of NTRK inhibitors but also underscores the importance of personalized therapy guided by molecular profiling in oncology."

Journal • Oncology • Salivary Gland Cancer • Solid Tumor • NTRK

Entrectinib-Induced Pericarditis with Cardiac Tamponade in a Patient with Neurotrophic Tropomyosin Receptor Kinase 1 Fusion-Positive Breast Cancer. (PubMed, Case Rep Oncol) - "Patients should be closely monitored for signs of pericarditis and cardiac tamponade at the start of entrectinib therapy. In patients who develop cardiovascular toxicity due to entrectinib, larotrectinib may be considered as an alternative treatment."

Journal • Breast Cancer • Cardiovascular • Congestive Heart Failure • Heart Failure • Oncology • Pulmonary Disease • Solid Tumor • NTRK • NTRK1

Visceral crisis in a patient with non-small cell lung cancer and ROS1::SDC4 fusion: intrinsic resistance to entrectinib via L2026M mutation-a case report. (PubMed, Transl Lung Cancer Res) - "The emergence of the L2026M mutation suggests a need for next-generation TKIs and combination strategies to overcome resistance. Future studies should explore novel inhibitors targeting ROS1 resistance pathways to improve outcomes in this subset of NSCLC patients."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1 • SDC4

SPRING: Study of Precision Treatment for Rare Tumours in China Guided by PDO and NGS (clinicaltrials.gov) - P2 | N=200 | Not yet recruiting | Sponsor: Peking University Shenzhen Hospital

Biomarker • New P2 trial • Oncology

Entrectinib in Combination With ASTX727 for the Treatment of Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=12 | Suspended | Sponsor: OHSU Knight Cancer Institute | Recruiting ➔ Suspended

Trial suspension • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

Prevalence of histology-agnostic biomarkers in pure squamous cell carcinomas of the genitourinary tract. (ASCO 2025) - "There are 8 FDA-approved histology-agnostic treatments based on biomarker profiling: dostarlimab (dMMR/MSI-H), pembrolizumab (dMMR/MSI-H; TMB-H), larotrectinib (NTRK fusion), entrectinib (NTRK fusion), selpercatinib (RET fusion), trastuzumab deruxtecan (HER2 positive), and dabrafenib plus trametinib (BRAF V600E mutation). This study provides a comprehensive analysis of the genetic landscape of pure SCC of the GU tract that may inform future therapeutic strategies for this rare tumor with limited treatment options. Almost one-third of patients were TMB-High, reflecting a population that may benefit from immune checkpoint inhibitors monotherapy or combination strategies. Other histology-agnostic targets for current therapies were relatively infrequent."

Biomarker • IO biomarker • Tumor mutational burden • Bladder Cancer • Genito-urinary Cancer • Microsatellite Instability • Oncology • Squamous Cell Carcinoma • Urothelial Cancer • BAP1 • BRAF • BRCA1 • BRCA2 • BRIP1 • CDKN2A • CHEK2 • FAT1 • FGFR3 • HER-2 • KDM6A • MSI • NTRK • PALB2 • PIK3CA • PTEN • RAD51 • RET • TERT • TMB • TP53

CUPISCO: A Phase II Randomized Study Comparing the Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy Versus Platinum-Based Chemotherapy in Patients With Cancer of Unknown Primary Site (clinicaltrials.gov) - P2 | N=528 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | Trial completion date: Jun 2024 ➔ Nov 2024

Trial completion • Trial completion date • Oncology

A Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Participants With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P3 | N=71 | Recruiting | Sponsor: Hoffmann-La Roche | N=121 ➔ 71

Biomarker • Enrollment change • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1 • RET • ROS1

Progression-Free Survival and Objective Response Rates As Surrogate Endpoints for Overall Survival Among Patients With ROS1+ Locally Advanced or Metastatic Non-Small Cell Lung Cancer Receiving ROS1 Tyrosine Kinase Inhibitors (ISPOR 2025) - " Twelve cohorts from non-randomized clinical trials involving treatment with crizotinib, entrectinib, lorlatinib, brigatinib or ceritinib were identified; repotrectinib cohorts were excluded. The current analysis demonstrated a strong association between OS and PFS among TKI-treated patients with ROS1+ aNSCLC, lending support to previous real world evidence evaluating surrogacy of PFS. However, OS and ORR demonstrated a weak association with substantial uncertainty. The lack of head-to-head evidence precluded assessment of the correlation between treatment effects."

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

Cost-effectiveness of NTRK testing strategies for detecting NTRK fusions in solid tumors in China. (ASCO 2025) - "With the inclusion of the targeted drug Entrectinib in China's national reimbursement drug list, the demand for NTRK testing has also increased... Initial pan-TRK IHC testing, followed by NGS confirmation for positive results, is the optimal strategy for NTRK fusion detection in patients with locally advanced or metastatic solid tumors in China, providing superior cost-effectiveness compared to NGS testing alone. Cost-effectiveness analysis results.ICER: Incremental cost-effectiveness ratio."

Cost effectiveness • HEOR • Oncology • Solid Tumor • NTRK

Updated efficacy and safety of entrectinib in children with extracranial solid or primary central nervous system (CNS) tumors harboring ROS1 fusions. (ASCO 2025) - P1/2, P2 | "Entrectinib yielded rapid and durable responses in pediatric pts with ROS1 fp extracranial solid or primary CNS tumors. The safety profile of entrectinib was consistent with previous reports. *Per BICR; CI, confidence interval; NE, not evaluable."

Clinical • Anemia • Brain Cancer • CNS Tumor • Hematological Disorders • Musculoskeletal Diseases • Oncology • Orthopedics • Pediatrics • NTRK • NTRK1 • NTRK2 • NTRK3 • ROS1

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 • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • ANXA5 • FLT3

TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer (clinicaltrials.gov) - P2 | N=4200 | Recruiting | Sponsor: American Society of Clinical Oncology | Trial completion date: Jun 2027 ➔ Dec 2028 | Trial primary completion date: Jun 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • Tumor mutational burden • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BRAF

Advancements in neuroblastoma treatment: FDA-approved drugs and role of phytochemicals. (PubMed, Mol Biol Rep) - "FDA-approved drugs like Entrectinib, Dinutuximab, Unitaxin, Doxorubicin, Hydrochloride, Lorlatinib, and Crizotinib are pivotal in treating neuroblastoma. Additional plant extracts have exhibited activity against neuroblastoma. This review highlights the synergistic potential of FDA-approved drugs and plant-derived phytoconstituents in improving neuroblastoma treatment outcomes."

FDA event • Journal • Review • Neuroblastoma • Oncology • Pediatrics • Solid Tumor

Role of External Control Arm (ECA) Derived from Real World Data (RWD) in US FDA Regulatory Approval from 2020-2024 (ISPOR 2025) - "OBJECTIVES: To analyze role of ECA in US FDA approvals ( 2020 - 2024) & summarize the key disease areas leveraging ECA. systematic literature review and analysis of all novel drug approvals including NDA (New Drug Application) and BLA (Biological License Application)submitted from 2020-2024 were analyzed. The percentage of approvals involving external control arms increased steadily, particularly in rare diseases, oncology, and conditions with small or hard-to-recruit patient populations from 2020-2024 2020: Early Exploration (5-7% of Approvals) : 1.Ibrance (palbociclib): Used retrospective RWD to support male breast cancer indication...Blincyto (blinatumomab): Supplemental approvals for rare cancers based on external data. 2021: Accelerated Adoption Amid COVID-19 (10-15% of Approvals) 1.Veklury (remdesivir): Approval supported by real-world hospital data as external comparisons...Keytruda (pembrolizumab): Label expansion for certain cancers using external control..."

Clinical • Real-world • Real-world evidence • Alzheimer's Disease • Breast Cancer • CNS Disorders • Genetic Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Infectious Disease • Male Breast Cancer • Movement Disorders • Muscular Atrophy • Novel Coronavirus Disease • Oncology • Rare Diseases • Solid Tumor • HER-2

Summary of Evolving Role and Impact of Real World Evidence (RWE) in US FDA Regulatory Approvals (2020-2024) (ISPOR 2025) - "Notable cases like Rozlytrek (entrectinib) for rare cancers leveraged synthetic control arms, Zolgensma (onasemnogene abeparvovec-xioi) used RWE for expanded indications...Examples include Enhertu (fam-trastuzumab deruxtecan-nxki) for HER2-low breast cancer and Evrysdi (risdiplam) for spinal muscular atrophy, supported by longitudinal real-world data. 1) 2020, RWE was primarily used in label expansions and post-marketing safety evaluations, particularly in oncology and rare diseases. Notable approvals included Ibrance (palbociclib) for male breast cancer, based on real-world data from EHRs.2) 2021, during COVID-19 pandemic, RWE played a key role in Emergency Use Authorizations (EUAs) and full approvals of treatments like Veklury (remdesivir). The % of approvals involving RWE increased to 15-20%, with RWE supporting label expansions for drugs like Keytruda (pembrolizumab).3)2022, RWE contributed to 25-30% of approvals, including initial NDAs and BLAs."

Clinical • HEOR • Real-world • Real-world evidence • Alzheimer's Disease • Breast Cancer • CNS Disorders • Genetic Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Infectious Disease • Male Breast Cancer • Movement Disorders • Muscular Atrophy • Novel Coronavirus Disease • Oncology • Rare Diseases • Solid Tumor • HER-2

Synovium-on-a-Chip Reveals Fibroblast-Macrophage Crosstalk Underpinning Joint Homeostasis and Evaluation of Gout Therapies. (PubMed, Adv Healthc Mater) - "Pharmacological interventions with MCC950 and entrectinib effectively inhibit the inflammasome activation, demonstrating the platform's utility for preclinical drug evaluation. This synovium-on-a-chip provides a reliable in vitro model for studying synovial inflammation and serves as a valuable tool for the therapeutic discovery of inflammatory joint diseases."

Journal • Gout • Inflammation • Inflammatory Arthritis • Rheumatology • CD14 • NLRP3 • TJP1