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

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

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

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

Identification of Anticancer Drugs Associated to Cancer Therapy-Related Cardiac Dysfunction: A VigiBase® Disproportionality Analysis. (PubMed, Eur Heart J Cardiovasc Pharmacother) - P | "This disproportionality study identified 25 anticancer drugs significantly associated with CTRCD reporting, including new signals. It highlights discrepancies compared to drugs recommended for cardiac dysfunction evaluation in the 2022 ESC Guidelines. This underscores the importance of including CTRCD as a safety endpoint in cancer studies."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Oncology • ABL1 • BCR

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

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

Discovery of novel diarylurea derivatives as potent type II TRK inhibitors for combating multiple acquired resistant mutants. (PubMed, Bioorg Chem) - "Tropomyosin receptor kinases (TRKs), a superfamily of transmembrane receptor tyrosine kinases, have recently attracted extensive attention as promising cancer therapeutic targets since the FDA approval of Larotrectinib and Entrectinib. It also showed superior antiproliferative activities against both BaF3-LMNA-TRKAG595R and BaF3-LMNA-TRKAG667C cell lines (IC50 = 23.76 nM and 0.33 nM, respectively), outperforming Repotrectinib (IC50 = 28.14 nM and 25.69 nM, respectively). Collectively, compound 18d can be used as a promising lead candidate for further optimization in the development of therapies targeting drug-resistant TRK mutants."

Journal • Oncology • LMNA

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

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

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

064: Real-World Life-Cycle Evaluation for Precision Medicine: From Conceptualization to Successful Implementation (ISPOR 2025) - "Centred on a case study of entrectinib, a conditionally authorized treatment targeting advanced NTRK-gene fusion-positive cancers, presenters will then: establish comparative effectiveness by concatenating single-arm Phase I/II entrectinib trial data with RWD from British Columbia and the United States (13’ Weymann); determine real-world cost-effectiveness of entrectinib versus standard care, demonstrating how value for money evolves with new evidence in relation to a national index economic evaluation (13’ Krebs); and discuss RWE transportability for informing international regulatory and reimbursement decisions (13’ Adamson). The session will conclude with a facilitated discussion on key challenges for embedding LC-HTA within learning healthcare systems, engaging with the audience through a real-time prioritization polling exercise (10’)."

Clinical • Real-world • Real-world evidence • Oncology • NTRK

Cost-Effectiveness Analyses of Repotrectinib in TKI-Naïve Patients with ROS1+ Advanced Non-Small Cell Lung Cancer (ISPOR 2025) - " The model takes a hypothetical UK NHS perspective and estimates outcomes/costs of repotrectinib versus entrectinib over a 30-year time horizon at a 3.5% annual discount rate. Repotrectinib is a cost-effective option for TKI-naïve patients with ROS1+ advanced NSCLC. These findings were robust across a variety of scenarios and sensitivity analyses."

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

Cost Per PFS-Based Responder for TKI-Naive Patients Receiving Repotrectinib or Entrectinib in ROS1 Fusion Positive Non-Small Cell Lung Cancer (NSCLC) in the United States (US) (ISPOR 2025) - "This study demonstrates the economic and clinical benefits of repotrectinib versus entrectinib in TKI-naive patients with ROS1+ NSCLC. Cost per PFS-based responder provides a pragmatic evaluation of the investment required to extend progression-free outcomes in ROS1+ NSCLC patients."

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

Taletrectinib vs Entrectinib in ROS1-Positive (ROS1+) Non-Small Cell Lung Cancer (NSCLC): A Matching-Adjusted Indirect Comparison (MAIC) (ISPOR 2025) - P1, P2 | "Taletrectinib showed significantly improved outcomes vs entrectinib in TKI-naive patients with ROS1+ NSCLC in the cross-trial MAIC analysis, including higher ORR and substantially reduced rate of progression. Additional analyses with more mature DOR and PFS data, along with a comparative analysis of safety outcomes, will provide a comprehensive benefit-risk assessment."

CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Conversion Surgery After Administration of a TRK Inhibitor for Unresectable Parotid Gland Secretory Carcinoma. (PubMed, Head Neck) - "Conversion surgery and TRK inhibitor use were effective against unresectable parotid gland carcinoma with the NTRK fusion gene. The case provides a reference for conversion surgery use for unresectable parotid gland carcinomas."

Journal • Head and Neck Cancer • Oncology • Otorhinolaryngology • Parotid Gland Cancer • Salivary Gland Cancer • Solid Tumor • ETV6 • NTRK • NTRK3

Primary endpoint of ROSALINE: A phase II neoadjuvant study of endocrine therapy (ET) and entrectinib in invasive lobular breast carcinoma (ILBC) (ESMO-BC 2025) - P2 | "ROSALINE is the first neoadjuvant trial focused on ILBC, evaluating ET and entrectinib in HR+/HER2- disease. This investigator-initiated, single-arm, phase II trial enrolled women with stage IIA–IIIA HR+/HER2– ILBC treated with 4 cycles of letrozole (2.5 mg/day) + entrectinib (600 mg/day), + goserelin for premenopausal women, followed by surgery. The primary endpoint was not met and dose reductions were frequent. However, neoadjuvant entrectinib with ET showed activity. Correlative analyses are ongoing to clarify role of ROS1 inhibition in ILBC and identify predictive biomarkers."

Clinical • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDH1 • HER-2

Entrectinib-Induced Brugada Syndrome Leading to Ventricular Tachycardia in A Patient with ROS1 Fusion-Positive Lung Adenocarcinoma. (PubMed, Eur J Case Rep Intern Med) - "The relationship between entrectinib and drug-induced Brugada syndrome remains unclear, and reports of entrectinib-induced Brugada syndrome are rare.We performed risk stratification using electrophysiological examinations in a case of entrectinib-induced Brugada syndrome in a patient with ROS1 fusion-positive lung adenocarcinoma.Our results suggest that continuous electrocardiogram monitoring or frequent electrocardiogram recording at least once a day several days following entrectinib initiation may help detect entrectinib-induced Brugada syndrome irrespective of being in or out of hospital."

Journal • Cardiovascular • Genetic Disorders • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Ventricular Tachycardia • ROS1

Molecular Testing and Targeted Therapies in Hepatobiliary Cancers: A Review. (PubMed, JAMA Surg) - "Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for NTRK fusions; selpercatinib for RET fusions; dabrafenib and trametinib combination for BRAF V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden ≥10 mutations/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue-agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease."

IO biomarker • Journal • Tumor mutational burden • Biliary Cancer • Biliary Tract Cancer • Hepatocellular Cancer • Hepatology • Microsatellite Instability • Oncology • Solid Tumor • BRAF • HER-2 • MSI • NTRK • RET • TMB

Neoadjuvant Letrozole/Entrectinib Shows Limited Activity in Invasive Lobular Breast Cancer (OncLive) - P2 | N=65 | ROSALINE (NCT04551495) | "Data presented at the 2025 ESMO Breast Congress showed that the rates of RCB II and III after treatment with entrectinib plus letrozole with or without goserelin in the efficacy-evaluable patient population were 61% and 39%, respectively. In the intention-to-treat (ITT) population (n = 52), which included patients who received fewer than 80% of the planned doses of entrectinib, 1 patient achieved an RBC of 0 or I. The rates of RCB II and III were 50% and 48%, respectively."

P2 data • Breast Cancer

Nuvation Bio to Present Matching-adjusted Indirect Comparison Data for Taletrectinib vs. Entrectinib at ISPOR 2025 (Businesswire) - "Nuvation Bio...announced that new data from a matching-adjusted indirect comparison study evaluating taletrectinib versus entrectinib in ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC) will be presented in a poster session at ISPOR 2025, the Professional Society for Health Economics and Outcomes Research’s annual conference, taking place May 13-16, 2025 in Montreal, QC, Canada."

Clinical data • Non Small Cell Lung Cancer

Marine-inspired spirooxindole PIM-1 kinase inhibitors endowed with concomitant TRKA/CDK2 inhibition for multifaceted NSCLC apoptotic induction. (PubMed, ChemMedChem) - "Recently, targeting TrkA gained attention following FDA approval of entrectinib and larotrectinib for NSCLC. Compounds 6e and 7f emerged as the most balanced inhibitors of PIM-1 (IC50 = 3.9 nM, 4.6 nM), CDK2, and TrkA. Molecular docking and dynamics simulations highlighted key interactions stabilizing these compounds, which disrupted the A549 cell cycle and induced apoptosis by over 30%."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PIM1

The Research Progress of Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusions and Tropomyosin Receptor Kinase (TRK) Inhibitors: A Narrative Review. (PubMed, Iran J Public Health) - "The first-generation TRK inhibitors, larotrectinib and entrectinib, have been approved for the treatment of pediatric and adult patients with metastatic or locally advanced solid tumors harboring NTRK fusion proteins, demonstrating remarkable anticancer efficacy in clinical settings. Currently, efforts are underway to develop next-generation TRK inhibitors based on sequence, structural, and kinetic methodologies, as well as to explore the intracellular signaling pathways of TRK and the mechanisms underlying resistance. The main focus of this review was to discuss the fusion of NTRK genes and the application of TRK inhibitor treatment."

Journal • Review • Oncology • Pediatrics • Solid Tumor • NTRK • NTRK1 • NTRK2 • NTRK3

Loss of CARM1 alters the developmental programming of Glioma stem-like cells and creates a druggable NGFR/NTRK dependency. (PubMed, bioRxiv) - "Moreover, CARM1 depleted cells reprogram their signaling to develop an increased survival dependency on NGFR/NTRK signaling and are hypersensitive to the FDA approved brain penetrant NTRK inhibitor-Entrectinib...Altogether, we demonstrate that CARM1 regulates the cell lineage of GSCs at the transcriptomic and proteomic level, and naturally represses NGFR/NTRK signaling-likely through CARM1 dependent methylation of NFIA. Further, CARM1 depletion leads GSCs to develop a survival dependency on NGFR/NTRK signaling and creates a therapeutic vulnerability to NTRK inhibition."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • GFAP • NGFR • NTRK • PDGFRA