YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non–Small Cell Lung Cancer

Yun, Jun-Won; Hong, Min Hee; Kim, Seok Young; Park, Chae Won; Kim, Soyoung; Yun, Mi Ran; Kang, Han Sol; Lee, Sung Sook; Koh, Jai‐Kyoung; Song, Ho Juhn; Kim, Dong Kyun; Lee, Young Sung; Oh, Seung Joon; Choi, Soongyu; Cho, Byoung Chul

doi:10.1158/1078-0432.ccr-18-2906

Cited by 84 publications

(85 citation statements)

References 38 publications

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“…Moreover, nowadays, there are advanced novel immunotherapies and targeted therapies that was reported to show increased blood–brain barrier penetration and realize high response rates and more durable control of BM, and advances in radiotherapies and minimally invasive surgical techniques, which are thought to improve the survival outcome of patients with BM 7,17 . For example, EGFR/ALK TKIs had significant intracranial activity and could achieve longer intracranial progression free survival, higher overall response rate than chemotherapy or radiotherapy, which have been proved in many retrospective and prospective studies 18–22 . And some studies have confirmed that stereotactic radiotherapy (SRS) was a well‐tolerated safe option for patients with four or more BM 23–25 .…”

Section: Discussionmentioning

confidence: 94%

Prognostic impacts of extracranial metastasis on non‐small cell lung cancer with brain metastasis: A retrospective study based on surveillance, epidemiology, and end results database

Wang

Zhang

et al. 2020

Cancer Medicine

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This study was designed to investigate the prognostic value of the number and sites of extracranial metastasis (ECM) in NSCLC patients with BM. NSCLC patients with BM from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 were enrolled in analysis. Patients from 2010 to 2013 were included in the training set and those from 2014 to 2015 in the validation set. ECM sites among different subtypes of NSCLC were compared by Chi‐square tests. Kaplan–Meier methods and Cox regression models were performed to analyze survival data. Competing‐risks analysis was used to predict cumulative incidence rates for CSS and non‐CSS cause. We included 5974 patients in the training cohort and 3561 patients in the validation cohort. Most (nearly 80%) NSCLC patients with BM showed 0–1 involved extracranial organ, with the most and least common ECM organ being bone and distant lymph nodes (DLNs) among all subtypes of NSCLC, respectively. The number of involved extracranial organs was an independent prognostic factor for patients with BM from NSCLC ( p < 0.001). Patients with 0–1 ECM had better survival than those with larger number of involved extracranial organs ( p < 0.001). Cumulative incidence rates for CSS were increased with the number of ECM raising ( p < 0.001). All involved extracranial organs were associated with worse survival ( p < 0.05). In patients with single‐organ ECM, we observed a better prognosis in lung and bone metastasis, while liver metastasis showed worst survival. But the difference in survival in these patient groups was relatively small. Patients with liver metastasis had higher cumulative incidence rates for CSS than that in patients with lung and bone metastasis ( p < 0.05). More extracranial metastases were associated with poor prognosis in NSCLC patients with BM and ECM sites showed limited effect on survival. Tailored treatments would be reasonable for BM patients from NSCLC with different metastasis patterns.

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Section: Discussionmentioning

confidence: 94%

Prognostic impacts of extracranial metastasis on non‐small cell lung cancer with brain metastasis: A retrospective study based on surveillance, epidemiology, and end results database

Wang

Zhang

et al. 2020

Cancer Medicine

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“…Novel targeted therapies have demonstrated preclinical CNS results that may support a role in the treatment or prevention of IMD, with improved selectivity for EGFR alterations and reduced CNS efflux compared with osimertinib. 60,61 In addition, innovation in therapeutic delivery modalities may guide treatment sequencing or support the use of existing systemic treatments, which have historically been limited by their lack of BBB permeability. Methods of increasing BBB penetrance of systemic drugs include modification through rational drug design, conjugation to ligands targeted to receptor-mediated transport, and disruption of the BBB through the use of osmotic media, biochemical agents, focused ultrasonography, or radiotherapy.…”

Section: Jama Network Open | Oncologymentioning

confidence: 99%

Assessment of Effectiveness and Safety of Osimertinib for Patients With Intracranial Metastatic Disease

2020

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IMPORTANCE Intracranial metastatic disease (IMD) is a serious and life-altering complication for many patients with cancer. Targeted therapy may address the limitations of current treatments as an additional agent to achieve intracranial disease control in some patients with IMD. Given the paucity of evidence regarding effectiveness, current guidelines have not made recommendations on the use of targeted therapy. Osimertinib mesylate is a mutant epidermal growth factor receptor (EGFR) inhibitor that can penetrate the blood-brain barrier and inhibit tumor cell survival and proliferation in patients with non-small cell lung cancer (NSCLC) with specific EGFR alterations. OBJECTIVE To assess the effectiveness and safety of osimertinib in the management of IMD. DATA SOURCES Studies were selected from MEDLINE and Embase databases from their inception to September 20, 2019, using the following search query: (osimertinib OR mereletinib OR tagrisso OR tamarix OR azd9291) AND (brain metastases OR intracranial metastatic disease OR cns). STUDY SELECTION Studies reporting intracranial outcomes for patients with metastatic EGFRvariant NSCLC and IMD treated with osimertinib were included in this systematic review and metaanalysis. Among 271 records identified in the systematic review, 15 studies fulfilled eligibility criteria for inclusion in the meta-analysis. DATA EXTRACTION AND SYNTHESIS Data were extracted from published studies and supplements. These data were pooled using a random-effects model. Risk of bias was assessed using the Cochrane risk of bias tool and the modified Newcastle-Ottawa Scale. MAIN OUTCOMES AND MEASURES Information extracted included study characteristics, intracranial effectiveness measures, and safety measures. Meta-analyses of proportions were conducted to pool estimates for central nervous system (CNS) objective response rate and CNS disease control rate. RESULTS Fifteen studies reporting on 324 patients were included in the meta-analysis. The CNS objective response rate was 64% (95% CI, 53%-76%; n = 195), and CNS disease control rate was 90% (95% CI, 85%-93%; n = 246). Included studies reported complete intracranial response rates of 7% to 23%, median best decrease in intracranial lesion size of −40% to −64%, and Common Terminology Criteria for Adverse Events (version 3.0) grade 3 or higher adverse event rates of 19% to 39%. Subgroup analyses did not reveal additional sources of heterogeneity. CONCLUSIONS AND RELEVANCE Findings reported herein support a potential role for osimertinib in the treatment of patients with metastatic EGFR-variant NSCLC and IMD treated with osimertinib.

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“…Lazertinib is an oral, potent, irreversible third-generation EGFR TKI that is highly selective for activating EGFR and T790M resistance mutations. In pre-clinical studies, lazertinib induced profound tumour regression in a brain metastasis model with favourable brain/plasma and tumour/ brain area under the concentration-time curve values (39).…”

Section: Lazertinib (Yh25448/gns-1480)mentioning

confidence: 98%

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

Wright¹,

Goss²

2019

Transl. Lung Cancer Res.

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Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable genomic drivers of non-small cell lung cancer (NSCLC), occurring in approximately 50% and 10-15% of adenocarcinomas of the lung in Asian and Western populations, respectively. The most common EGFR-activating mutations, the exon 19 deletion and the L858R point mutation occurring in the receptor tyrosine kinase domain, are susceptible to inhibition. The first EGFR tyrosine kinase inhibitors (TKIs) to be evaluated were the reversible first-generation EGFR TKIs, gefitinib and erlotinib, followed by the irreversible second-generation EGFR TKIs, afatinib and dacomitinib. The study of acquired resistance mechanisms to first-and second-generation EGFR TKIs in patients with activating EGFR-mutated NSCLC identified the gatekeeper T790M point mutation, present in over 50% of cases, as the most common mechanism of acquired resistance. The need to overcome this resistance mechanism led to the development of third-generation EGFR TKIs, of which osimertinib is the only one to date with regulatory approval. In this review, we present the clinical context leading to the development of third-generation EGFR TKIs, the mode of action of these inhibitors and the clinical data supporting their use. We review third-generation TKI agents that are approved, in development, and those that failed in clinical trials. Finally, we will touch upon ongoing studies and future directions, such as combination treatment strategies, currently being explored to improve the efficacy of treatment with third-generation EGFR TKIs.

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YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non–Small Cell Lung Cancer

Cited by 84 publications

References 38 publications

Prognostic impacts of extracranial metastasis on non‐small cell lung cancer with brain metastasis: A retrospective study based on surveillance, epidemiology, and end results database

Prognostic impacts of extracranial metastasis on non‐small cell lung cancer with brain metastasis: A retrospective study based on surveillance, epidemiology, and end results database

Assessment of Effectiveness and Safety of Osimertinib for Patients With Intracranial Metastatic Disease

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

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