Zorifer (zorifertinib) / Alpha Biopharma, AstraZeneca - LARVOL DELTA

Subtype-specific APOBEC enrichment links genomic instability to predict immunotherapy response in breast cancer subtypes. (PubMed, Int J Biol Macromol) - "Based on in vivo experiments in mice, our research highlights that the administration of specific agents-AZD3759 for HER2+, Vorinostat for TNBC, and SGC0946 for Luminal-when combined with anti-PD-1 therapy, not only boosts therapeutic effectiveness but also transforms the immunological environment within tumors. This synergistic approach led to notable reductions in tumor volume and an increase in cytotoxic T cell density in in vivo and in vitro experiments, further validating the role of AMrs scores in tailoring treatment modalities across BRCA subtypes. Overall, our study elucidates the critical role of APOBEC family genes in BRCA heterogeneity, highlighting their potential as biomarkers for personalized therapeutic approaches and pointing towards future research directions in integrating APOBEC-related mechanisms with immunotherapy."

IO biomarker • Journal • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • HER-2 • TMB

Identification of Poor Prognosis-Associated Fibroblast Subpopulation Signature Genes Utilizing the Scissor Algorithm to Classify Colorectal Cancer Subtypes and Evaluate the Immune Landscape. (PubMed, Gut Liver) - "Drug sensitivity predictions suggested that patients with this cell subtype may respond better to specific anticancer agents (e.g., AZD3759, Erlotinib, Gefitinib). Moreover, their predictive value in CRC therapy was revealed. The study provided new perspectives for CRC prognosis evaluation and personalized immune-targeted combination therapies."

Journal • Colorectal Cancer • Oncology • Solid Tumor • SPP1

MATCHING-ADJUSTED INDIRECT COMPARISON AND COST-UTILITY OF ZORIFERTINIB VERSUS OSIMERTINIB IN TREATING NEWLY DIAGNOSED EGFR-MUTANT NSCLC WITH CNS METASTASES IN CHINA (ISPOR 2026) - P2/3, P3 | "From the perspective of the Chinese healthcare system, zorifertinib is a cost-effective treatment for newly diagnosed EGFRm+ NSCLC patients with CNS metastases compared with osimertinib, which provided patients with an effective and cost-saving treatment option."

HEOR • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EGFR

Epidermal growth factor receptor tyrosine kinase inhibitor for the treatment of non-small cell lung cancer in the past 30 years (1997-2026). (PubMed, Chin Med J (Engl)) - "Since 1997, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have evolved from first-generation agents, such as gefitinib, erlotinib, and icotinib, to second-generation agents like afatinib and dacomitinib, now to third-generation agents, including osimertinib, aumolertinib, furmonertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, mifanertinib for EGFR L858R, sunvozertinib for EGFR exon 20 insertion (20ins), and zorifertinib for EGFR-sensitive mutation with brain metastases. Over the past 30 years, substantial advancements have been made in the comprehensive management of EGFR-mutant NSCLC. This systemic review provides the history of the development of EGFR-TKI therapy for NSCLC from 1997 to 2026, highlighting clinical milestones, emerging therapies, and future directions in this rapidly evolving field."

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

A Prospective Cohort Study of Zorifertinib as a First-line Treatment in Patients With Epidermal Growth Factor Receptor-mutant Advanced Non-small Cell Lung Cancer With Central Nervous System (CNS) Metastases (clinicaltrials.gov) - P=N/A | N=800 | Recruiting | Sponsor: Alpha Biopharma (Jiangsu) Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Tumor • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Zorifertinib With Osimertinib for NSCLC With Meningeal Progression (clinicaltrials.gov) - P1 | N=42 | Not yet recruiting | Sponsor: Alpha Biopharma (Jiangsu) Co., Ltd.

New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis. (ASCO 2023) - P2/3 | "First-line AZD3759 demonstrated superior systemic and IC antitumor efficacy compared with first generation EGFR TKIs in pts with EGFRm+ NSCLC and CNS metastasis. Adverse events were as expected and manageable. IC antitumor activity."

Clinical • P3 data • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

A real-world, prospective clinical study of zorifertinib combined with furmonertinib in leptomeningeal metastases patients with EGFR mutation-positive NSCLC and third-generation EGFR-TKIs resistance (ChiCTR) - P2 | N=29 | Not yet recruiting | Sponsor: Nanjing Brain Hospital; Nanjing Brain Hospital

New P2 trial • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Immunogenic cell death-related genes as prognostic biomarkers and therapeutic insights in uterine corpus endometrial carcinoma: an integrative bioinformatics analysis. (PubMed, Front Oncol) - "Finally, we found that hyper-immunogenicity may be sensitive to immunotherapy and certain drugs (AZD5991, Ibrutinib, Osimertinib, AGI-5198, Savolitinib, Sapitinib, AZ960, AZD3759 and Ruxolitinib), while PCI-34051 and Vorinostat showed sensitivity in patients with hypo-immunogenicity. Our results demonstrate that ICD plays an important role in UCEC progression, suggesting that ICD-related markers could serve as potential targets for prognosis and treatment."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Endometrial Cancer • Oncology • Solid Tumor • Uterine Cancer • CD52 • STAT1 • TMB

A Prospective Cohort Study of Zorifertinib as a First-line Treatment in Patients With Epidermal Growth Factor Receptor-mutant Advanced Non-small Cell Lung Cancer With Central Nervous System (CNS) Metastases (clinicaltrials.gov) - P=N/A | N=800 | Not yet recruiting | Sponsor: Alpha Biopharma (Jiangsu) Co., Ltd.

New trial • CNS Tumor • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Structure-Property Relationships Reported for the New Drugs Approved in 2024. (PubMed, Mini Rev Med Chem) - "The analysis focused on aprocitentan, flurpiridaz F-18, inavolisib, vorasidenib, ensitrelvir, golidocitinib, and zorifertinib, highlighting the key structural modifications that enhanced their drug-like properties. When developing central nervous system-penetrant drugs such as zorifertinib, careful control of rotatable bonds, hydrogen bond donors, and molecular lipophilicity was critical for optimizing blood-brain barrier penetration while remaining suitable for oral administration. These findings on structureproperty relationships offer valuable guidance for future drug development, particularly in addressing challenges related to solubility, bioavailability, and tissue-specific drug distribution."

Journal

Comparing the Effectiveness and Safety of First-line Interventions in Patients With Advanced Epidermal Growth Factor Receptor-mutant Non-small Cell Lung Cancer, With Particular Focus on Brain Metastatic Status: A Systematic Review and Network Meta-analysis. (PubMed, Clin Oncol (R Coll Radiol)) - "In EMAN patients, osimertinib + CT and amivantamab + lazertinib were associated with optimal PFS and OS, respectively. Among BM patients, osimertinib + CT offered the best PFS benefits. These findings may assist in clinical decision-making and personalized care for EMAN and BM patients. The study is registered on PROSPERO (CRD42024506995)."

Journal • Retrospective data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

The climb toward intracranial efficacy: Zorifertinib in EGFR-mutant NSCLC with CNS metastases in the EVEREST trial. (PubMed, Med) - "The phase III EVEREST trial evaluating zorifertinib in the treatment of metastatic EGFR-mutant NSCLC was groundbreaking in its specific inclusion of patients with brain metastases.1 Zorifertinib prolonged systemic and intracranial progression-free survival compared with first-generation EGFR inhibitors, yet questions remain about its efficacy and toxicity compared with osimertinib."

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

Alpha Biopharma received NMPA approval for Zorifertinib Tablets (Zorifer), the world's first EGFR-TKI for lung cancer with brain metastases (PRNewswire) - "On November 20, 2024, the National Medical Products Administration (NMPA) announced on its official website that the NMPA approved the listing of Zorifertinib Hydrochloride Tablets (trade name: Zorifer), a Class 1 innovative drug, developed by Alpha Biopharma. This product is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) accompanied with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation and central nervous system (CNS) metastases....The EVEREST trial, an international multi-center randomized controlled phase III trial of Zorifertinib, demonstrated its superior ability to control intracranial lesions."

China approval • Non Small Cell Lung Cancer

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial. (PubMed, Med) - P2/3 | "Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC."

Journal • P3 data • CNS Tumor • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Machine learning-based integration develops a multiple programmed cell death signature for predicting the clinical outcome and drug sensitivity in colorectal cancer. (PubMed, Anticancer Drugs) - "In addition, the high-MPCDI group was more sensitive to AZD1332, Foretinib, and IGF1R_3801, and insensitive to AZD3759, AZD5438, AZD6482, Erlotinib, GSK591, IAP_5620, and Picolinici-acid, which suggests that the MPCDI can guide drug selection for CRC patients. As a new clinical classifier, the MPCDI can more accurately distinguish CRC patients who benefit from immunotherapy and develop personalized treatment strategies for CRC patients."

Clinical data • Journal • Machine learning • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss. (PubMed, Sci Adv) - "Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials."

Journal • Preclinical • Otorhinolaryngology • CDK2 • EGFR

The combination therapy using tyrosine kinase receptors inhibitors and repurposed drugs to target patient-derived glioblastoma stem cells. (PubMed, Biomed Pharmacother) - "The most cytotoxic compounds for U3042 cells were Disulfiram combined with Copper gluconate (DSF/Cu), Dacomitinib, and Foretinib with IC50 values of 52.37 nM, 4.38 µM, and 4.54 µM after 24 h incubation, respectively. Our findings indicate that the most promising drug combinations are Dacomitinib and Foretinib, Dacomitinib and DSF/Cu, and Foretinib and AZD3759. Since most tested combinations have not been previously examined against glioblastoma stem-like cells, these results can shed new light on designing the therapeutic approach to target the GSC population."

Combination therapy • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Long-term survival of a patient with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and untreated multiple brain metastases treated with zorifertinib: A case report. (PubMed, Thorac Cancer) - "This is the first report of a patient with EGFR-mutant (exon 21 L858R) NSCLC and symptomatic untreated multiple BM who achieved a long overall survival (OS) of more than 65 months after sequential treatment with zorifertinib and a third-generation EGFR-TKI. This new treatment paradigm offers a new treatment option and deserves further clinical exploration to prolong OS of patients with EGFR-mutant NSCLC and untreated multiple BM."

Biomarker • Clinical • Journal • Observational data • P3 data • Retrospective data • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

A Novel Network Pharmacology Strategy Based on the Universal Effectiveness-Common Mechanism of Medical Herbs Uncovers Therapeutic Targets in Traumatic Brain Injury. (PubMed, Drug Des Devel Ther) - "Administration of luteolin or the selective EGFR inhibitor AZD3759 to TBI mice promoted the recovery of body weight and neurological function, reduced astrocyte activation and EGFR expression, decreased chondroitin sulfate proteoglycans deposition, and upregulated GAP43 levels in the cortex...The common effectiveness-based, common target screening strategy suggests that inhibition of EGFR can be an effective therapy for TBI. This strategy can be applied to discover core targets and therapeutic compounds in other diseases."

Journal • CNS Disorders • Vascular Neurology

A Six-gene Prognostic Model Based on Neutrophil Extracellular Traps (NETs)-related Gene Signature for Lung Adenocarcinoma. (PubMed, Comb Chem High Throughput Screen) - "Altogether, this study has identified a novel NET-score signature based on six novel NET-related genes to predict the prognosis of LUAD and ABCC2 and has also explored a new method for personalized chemo-/immuno-therapy of LUAD."

Gene Signature • IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCC2 • UPK1B

Molecular prognostic of nine parthanatos death-related genes in glioma, particularly in COL8A1 identification. (PubMed, J Neurochem) - "Low-score glioma patients were sensitive to AZD3759_1915, AZD5582_1617, AZD8186_1918, Dasatinib_1079, and Temozolomide_1375, while high-score patients were less sensitive to these drugs. Silencing COL8A1 inhibited the malignant characterization. Temozolomide and AZD3759 inhibited COL8A1 expression and cell viability and promoted apoptosis and parthanatos gene expression, which is a target to improve glioma."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CD58 • COL8A1 • FABP5 • SFRP2 • TNFAIP6 • TNFRSF11B • TNFRSF1B

Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial. (PubMed, EClinicalMedicine) - P2 | "The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Chinese Thoracic Oncology Group (CTONG)."

Journal • P2 data • CNS Tumor • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Identification of the novel markers of PPAR signalling affecting immune microenvironment and immunotherapy response of lung adenocarcinoma patients. (PubMed, J Cell Mol Med) - "Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP_5620, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ACSL3 • FABP1

Searching for New Solutions in Treating EGFR-Mutant NSCLC (AJMC) - "What's next? Reiss discussed each trial, noting that a meta-analysis found that 'efficacy of single-agent, PD-1, PD-L1, immune checkpoint blockade in EGFR-mutant lung cancer is suboptimal'...The review found, 'for EGFR wild type, there was an impressive survival benefit, but for EGFR-mutant lung cancer, it faired no better than docetaxel.'"

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