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

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.'"

Media quote

An individual patient-level meta-analysis of non–small-cell lung cancer leptomeningeal metastases treated with epidermal growth factor receptor inhibitors. (ASCO 2023) - "EGFR-TTs evaluated were erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, zorifertinib, and furmonertinib. In the largest cohort of NSCLC LM treated with EGFR TT compiled to date, osimertinib is associated with marginally improved outcomes compared to other EGFR TTs. ECOG performance status is an independent predictor of prognosis in these patients. These results highlight the need for prospective studies for this difficult to treat patient population."

Retrospective data • 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

Developing CuS for Predicting Aggressiveness and Prognosis in Lung Adenocarcinoma. (PubMed, Genes (Basel)) - "Furthermore, we predicted six potential drugs targeting high-CuS patients, including AZD3759, which is a targeted drug for LUAD. In conclusion, cuproptosis is involved in LUAD aggressiveness, and CuS can accurately predict the prognosis of patients. These findings provide a basis for precise treatment of patients with high CuS in LUAD."

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

"While these are great results for zorifertinib, the comparator is not SOC anymore. Wish they tested it vs. osimertinib." (@CeramicCrow)

"Confirmation from $AZN: zorifertinib is licensed to Alpha Bio and we don’t have any involvement in development." (@JacobPlieth)

AZD3759 Elicits Responses in Untreated EGFR-Mutant NSCLC With CNS Metastases (OncLive) - P2 | N=400 | TRUMP (NCT03574402) | "The EGFR TKI AZD3759 elicited clinical responses and had an acceptable toxicity profile when administered at a dose of 200 mg twice daily in patients with untreated EGFR-mutant non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases, according to data from the phase 2 TRUMP (CTONG1702; NCT03574402) presented at the 2023 European Lung Cancer Conference. At a median follow-up of 21.9 months, AZD3759 induced an overall response rate (ORR) of 70% (95% CI, 50.6%-85.3%) in all patients (n = 30), meeting the primary end point of the trial. All responders had confirmed partial responses to treatment. In patients who received 200 mg and 300 mg of AZD3759, the ORRs were 80% (95% CI, 51.9%-95.7%) and 60% (95% CI, 32.3%-83.7%), respectively."

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

Efficacy and safety of AZD3759 in previously untreated EGFR-mutant non-small-cell lung cancer with central nervous system metastases in a multi-center, phase 2 umbrella trial (CTONG1702) (ELCC 2023) - P2 | "We suggested 200 mg BID was a better dose with superior response and lower toxicity. EGFR T790M was the most common resistant mutation, and these patients still have the opportunity to receive osimertinib after progression of AZD3759."

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

Alpha Biopharma Submits New Drug Application for Zorifertinib, a Next-Generation EGFR-TKI to Treat EGFR-mutated NSCLC Patients with CNS Metastases (PRNewswire) - "Alpha Biopharma...announces that the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) has accepted its New Drug Application (NDA) for Zorifertinib, a next-generation EGFR-TKI specially designed to treat advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastases....Results from the EVEREST study demonstrated that Zorifertinib effectively reduced the risk of disease progression and patient deaths in the target patient population and showed significant efficacy in treating metastatic lesions in the CNS."

Non-US regulatory • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR

Evaluate Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of AZD3759 (clinicaltrials.gov) - P1/2 | N=15 | Completed | Sponsor: LYZZ Alpha Holding Ltd | Unknown status ➔ Completed

Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

First Line Treatment in EGFR Mutation Positive Advanced NSCLC Patients With Central Nervous System (CNS) Metastases (clinicaltrials.gov) - P2/3 | N=492 | Completed | Sponsor: Alpha Biopharma (Jiangsu) Co., Ltd. | Active, not recruiting ➔ Completed | Trial completion date: Nov 2022 ➔ Jul 2022 | Trial primary completion date: Oct 2022 ➔ Jul 2022

Trial completion • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anti-cancer therapy. (ASCO 2017) - P1; "AZD3759 was well-tolerated, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor activity in patients with LM who progressed after multiple lines of treatment. Updated clinical data will be shared at the meeting."

Clinical • P1 data • Biosimilar • Non Small Cell Lung Cancer