naquotinib (ASP8273) / Astellas - LARVOL DELTA

First-line treatment for advanced or metastatic EGFR mutation-positive non-squamous non-small cell lung cancer: a network meta-analysis. (PubMed, Front Oncol) - "The study encompassed the following 19 treatments: Chemotherapy; Afatinib; Afatinib + Cetuximab; Apatinib + Gefitinib; Befotertinib; Cetuximab + Chemotherapy; Erlotinib; Erlotinib + Bevacizumab; Erlotinib + Chemotherapy; Gefitinib; Gefitinib + Chemotherapy; Gefitinib + Olaparib; Icotinib; Icotinib + Chemotherapy; Lazertinib; Naquotinib; Osimertinib; Osimertinib + Bevacizumab; Osimertinib + Chemotherapy. However, due to the limitations in the number and quality of included studies, these conclusions await further validation through more high-quality research. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024562981, identifier CRD42024562981."

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

Third generation vs first generation EGFR-TKIs in the first line treatment for EGFR-mutated locally advanced or metastatic non-small cell lung cancer: a meta-analysis based on randomized controlled trials. (PubMed, J Cancer) - " We analyzed 15 studies from 6 RCTs on six third-generation TKIs: Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Naquotinib, and Befotertinib. Except for Naquotinib, TGETs demonstrate superiority over FGETs in treating EGFR-mutated locally advanced or metastatic NSCLC, showing improved survival and responses. However, the increased incidence of AEs necessitates careful consideration."

Journal • Retrospective data • Cardiovascular • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Embolism • Respiratory Diseases • Solid Tumor

An integrated transomics approach reveals significant differences between EGFR inhibitors with the potential to identify novel targets to overcome EGFR resistance (AACR 2023) - "Approved drugs included erlotinib, afatinib (first- and second-generation EGFRi, respectively), and osimertinib (third-generation drug that can overcome the T790M gatekeeper mutation that confers resistance to earlier drugs). The remaining drugs (maverlertinib, naquotinib, olmutinib, rociletinib) are unapproved third-generation inhibitors...Transomic analysis of EGFRi has the potential to identify important differences between successful drugs, drugs that failed in clinical development, and to identify non-EGFR targets that may overcome resistance to current drugs. This hypothesis is currently being investigated across various resistant and undruggable cancers to unlock novel therapeutic targets."

Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Clinical Activity of ASP8273 in Asian Non-Small Cell Lung Cancer Patients with EGFR Activating and T790M Mutations (WCLC 2017) - P1/2; "ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations."

Biomarker • Clinical • Non Small Cell Lung Cancer

Tolerability and antitumor activity of ASP8273 in TKI-naive Japanese subjects with EGFR mutation–positive non-small cell lung cancer. (ASCO 2017) - P2; "Once-daily ASP8273 300 mg was tolerable in TKI-naïve Japanese subjects with EGFRmut+ NSCLC and demonstrated antitumor activity."

Biomarker • Clinical • Biosimilar • Gene Therapies • Non Small Cell Lung Cancer • Pain • Systemic Sclerosis

Beyond osimertinib: The development of 3-generation EGFR Tyrosine Kinase Inhibitors. (PubMed, J Thorac Oncol) - P3 | "In this review, we profiled many of the third-generation EGFR TKIs in late stage clinical development (e.g. almonertinib, lazertinib, alflutinib, rezivertinib, ASK120069, SH-1028, D-0316 and abivertinib) of their interim results of phase 1-3 trials and their chemical structures when publicly available. Additionally, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, maverlertinib) including phase 3 results of rociletinib and naquotinib. We further profiled the next-generation combination clinical trial design of third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704) and ACROSS2 (NCT04500717)."

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

Analysis to determine the effect of mutations on binding to small chemical molecules. (PubMed, J Bioinform Comput Biol) - "In this paper, the authors present and describe, in detail, an original software-implemented numerical methodology used to determine the effect of mutations on binding to small chemical molecules, on the example of gefitinib, AMPPNP, CO-1686, ASP8273, erlotinib binding with EGFR protein, and imatinib binding with PPARgamma. Furthermore, the developed numerical approach makes it possible to determine the stability of a molecular complex, which consists of a protein and a small chemical molecule. The description of the software package that implements the presented algorithm is given in the website: https://binomlabs.com/."

Journal • EGFR • PPARG

In vitro and in silico growth inhibitory, anti-ovarian & anti-lung carcinoma effects of 1,5 diarylpenta-1,4-dien-3-one as synthetically modified curcumin analogue. (PubMed, J Biomol Struct Dyn) - "The obtained results were compared with the reference compound 7 and drugs 8-10 (7: GO-035; 8: Quinazolin; 9: Naquotinib and 10: Ribofuranuronamide)...In vitro anti-proliferative activity was tested via MTT method against human ovarian carcinoma (PA-1) and human lung adenocarcinoma (A549) cells and further screened for apoptotic parameters such as nuclear fragmentation and ROS generation. Compound 4 exhibits good dose-dependent anti-proliferative activity (IC 73 and 79.7 µM) against human ovarian carcinoma and human lung adenocarcinoma, respectively.Communicated by Ramaswamy H. Sarma."

Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • EGFR • HSP90AA1 • KDR

Naquotinib exerts antitumor activity in activated B-cell-like diffuse large B-cell lymphoma. (PubMed, Leuk Res) - "The ABC subtype is associated with worse prognosis than the GCB subtype using currently available therapies such as combination treatment with rituximab plus standard cytotoxic chemotherapy...As sequence alignment analysis indicates that irreversible EGFR-TKIs also inhibit Bruton's tyrosine kinase (BTK), here, we characterized the inhibitory effects of naquotinib against BTK in comparison to ibrutinib, acalabrutinib, tirabrutinib and spebrutinib...Pharmacokinetics studies in the TMD8 xenograft model showed higher concentration and slower elimination of naquotinib in tumors than other BTK inhibitors. These data suggest that naquotinib may have therapeutic potential in ABC DLBCL patients."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Phase 3, Randomized, Open-label Study of ASP8273 Versus Erlotinib or Gefitinib in Patients With Advanced Stage IIIB/IV Non-Small Cell Lung Cancer. (PubMed, Ann Oncol) - P3 | "First-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib."

Clinical • Journal • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Mutant-selective irreversible EGFR inhibitor, naquotinib, inhibits tumor growth in NSCLC models with EGFR activating mutations, T790M mutation and AXL overexpression. (PubMed, Mol Cancer Ther) - "In addition, unlike erlotinib and osimertinib, naquotinib inhibited the phosphorylation of AXL and showed antitumor activity against PC-9 cells overexpressing AXL in vitro and in vivo. Our findings suggest that naquotinib has therapeutic potential in NSCLC patients with EGFR activating mutations, T790M resistance mutation and AXL overexpression."

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

Antitumor activity of ASP8273 300 mg in subjects with EGFR mutation-positive non-small cell lung cancer: Interim results from an ongoing phase 1 study (ASCO 2016) - P1, N=60; NCT02113813; Sponsor: Astellas; "For the 45 subjects treated with ASP8273 300 mg with evaluable data, disease control rate (DCR) was 62% (n = 28/45); 16 subjects achieved a partial response (PR) and 12 subjects achieved durable stable disease (SD)."

P1 data • Non Small Cell Lung Cancer • Oncology

A phase III, randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer. (PubMed, Ann Oncol) - P3; "First-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib. CLINICALTRIAL."

Clinical • Journal • P3 data

An Open Study of ASP8273 in Patients With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations (clinicaltrials.gov) - P1/2; N=124; Recruiting; Sponsor: Astellas Pharma Inc

Clinical • New P1/2 trial

A Dose Escalation Study of ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations (clinicaltrials.gov) - P1; N=65; Recruiting; Sponsor: Astellas Pharma Global Development, Inc.

Clinical • New P1 trial

A Study of ASP8273 in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-Naïve Patients With Non-Small Cell Lung Cancer Harboring EGFR Mutations (clinicaltrials.gov) - P2; N=30; Recruiting; Sponsor: Astellas Pharma Inc

Clinical • New P2 trial

An Open Study of ASP8273 in Patients With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations (clinicaltrials.gov) - P1/2; N=124; Terminated; Sponsor: Astellas Pharma Inc; Active, not recruiting ➔ Terminated; Following recommendation by SOLAR Study IDMC, Astellas closed enrollment in ASP8273 studies.

Clinical • Trial termination

A Study of ASP8273 in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-Naïve Patients With Non-Small Cell Lung Cancer Harboring EGFR Mutations (clinicaltrials.gov) - P2; N=31; Terminated; Sponsor: Astellas Pharma Inc; Active, not recruiting ➔ Terminated; Trial primary completion date: Dec 2017 ➔ Jun 2017; Following recommendation by SOLAR Study IDMC, Astellas closed enrollment in ASP8273 studies.

Clinical • Trial primary completion date • Trial termination

A Dose Escalation Study of ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations (clinicaltrials.gov) - P1; N=133; Completed; Sponsor: Astellas Pharma Global Development, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Jun 2019 ➔ Feb 2019

Clinical • Trial completion • Trial completion date

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer. (PubMed, Cancer Res) - "The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance...Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010...Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance."

Journal • Review

Pharmacological and structural characterizations of naquotinib, a novel third generation EGFR tyrosine kinase inhibitor, in EGFR mutated non-small-cell lung cancer. (PubMed, Mol Cancer Ther) - "...In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant EGFR mutations, including L858R, exon 19 deletion, L858R+T790M, exon 19 deletion+T790M with or without a C797S mutation, and several exon 20 insertion mutations...The efficacy of naquotinib in cells with L858R, exon 19 deletion and exon 19 deletion+T790M was comparable with that of osimertinib...In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using in vitro and structural analyses, and suggested the mechanism of activation and resistance to EGFR-TKIs of EGFR exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations, and help clarify the biology of EGFR exon 20 insertion mutations."

Journal

A Dose Escalation Study of ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations (clinicaltrials.gov) - P1; N=133; Active, not recruiting; Sponsor: Astellas Pharma Global Development, Inc.; Trial completion date: Dec 2018 ➔ Jun 2019; Trial primary completion date: Dec 2018 ➔ Jul 2017

Clinical • Trial completion date • Trial primary completion date