Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study

Shi, Yuankai; Li, Baolan; Wu, Lin; Pan, Yueyin; Pan, Zhijie; Liu, Yunpeng; Fan, Yun; Ji, Yinghua; Fang, Jian; Shi, Qi; Shi, Jianhua; Gao, Hongjun; Hu, Yanping; Wang, Xiang; Zhou, He; Ma, Rui; Jiang, Da; Bai, Yuansong; Zhang, Yi; Huang, Lingxia; Zhou, Tong; Liu, Hailong; Wang, Daqing; Wen, Qinglian; Chen, Gongyan; Zang, Aimin; Wang, Xiuwen; Zhang, Xinri; Hu, Jinbo; Yang, Runxiang; Zhang, Guojun; Gu, Kangsheng; Wang, Lin; Wang, Qiming; Wei, Zonghui; Zeng, Li; Lu, Hongzhou; Zhang, Helong; Chen, Hongyu; Song, Tingting

doi:10.1016/j.jtho.2022.05.011

Cited by 16 publications

(9 citation statements)

References 23 publications

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“…In a clinical study that included 2,535 patients treated with EGFR-TKIs, 53.3% developed diarrhea (Ding et al, 2017). The probability of EGFR-TKIs causing diarrhea was: afatinib (78%, n = 223) (Cappuzzo et al, 2015), nazartinib (47%, n = 45) (Tan et al, 2022), limertinib (81.7%, n = 289) (Shi et al, 2022b), osimertinib (58%, n = 278) (Soria et al, 2018), and abivertinib (75%, n = 52) (Ma et al, 2018), naquotinib (47%, n = 110) (Yu et al, 2017), and mobocertinib (83%, n = 136) (Riely et al, 2021).…”

Section: Egfr-tkis-associated Gastrointestinal Adverse Eventsmentioning

confidence: 99%

“…The rash mostly occurs in areas rich in sebaceous glands and in severe cases can involve the lower extremities or even the whole body, affecting the patient's quality of life. The probability of rash in EGFR-TKIs was: icotinib (14.8%, n = 418) (Shi et al, 2017), dacomitinib (14%, n = 227) (Wu et al, 2017), afatinib (83%, n = 223) (Cappuzzo et al, 2015) nazartinib (38%, n = 45) (Tan et al, 2022), and limertinib (29.9%, n = 289) (Shi et al, 2022b), poziotinib (48.9%, n = 90) (Le et al, 2022), osimertinib (32%, n = 279) (Tanaka et al, 2021), lazertinib (30%, n = 127) (Ahn et al, 2019), mobocertinib (33%, n = 136) (Riely et al, 2021).…”

Section: Egfr-tkis-related Skin Adverse Eventsmentioning

confidence: 99%

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Challenges of EGFR-TKIs in NSCLC and the potential role of herbs and active compounds: From mechanism to clinical practice

Song

Cao

et al. 2023

Front. Pharmacol.

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Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of lung cancer, especially in the first-line treatment of advanced NSCLC, and EGFR-TKIs monotherapy has achieved better efficacy and tolerability compared with standard chemotherapy. However, acquired resistance to EGFR-TKIs and associated adverse events pose a significant obstacle to targeted lung cancer therapy. Therefore, there is an urgent need to seek effective interventions to overcome these limitations. Natural medicines have shown potential therapeutic advantages in reversing acquired resistance to EGFR-TKIs and reducing adverse events, bringing new options and directions for EGFR-TKIs combination therapy. In this paper, we systematically demonstrated the resistance mechanism of EGFR-TKIs, the clinical strategy of each generation of EGFR-TKIs in the synergistic treatment of NSCLC, the treatment-related adverse events of EGFR-TKIs, and the potential role of traditional Chinese medicine in overcoming the resistance and adverse reactions of EGFR-TKIs. Herbs and active compounds have the potential to act synergistically through multiple pathways and multiple mechanisms of overall regulation, combined with targeted therapy, and are expected to be an innovative model for NSCLC treatment.

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Section: Egfr-tkis-associated Gastrointestinal Adverse Eventsmentioning

confidence: 99%

Section: Egfr-tkis-related Skin Adverse Eventsmentioning

confidence: 99%

Challenges of EGFR-TKIs in NSCLC and the potential role of herbs and active compounds: From mechanism to clinical practice

Song

Cao

et al. 2023

Front. Pharmacol.

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“…We previously identified ASK120067 (limertinib) as a novel 3rd-generation EGFR TKI with comparable preclinical and clinical anti-tumor effects to osimertinib against EGFR T790M positive NSCLC, and its chemical structure was shown in Figure 1A (Zhang et al, 2020;Shi et al, 2022). Now a New Drug Application (NDA) of ASK120067 has been submitted in China.…”

Section: Introductionmentioning

confidence: 99%

ASK120067 (limertinib) exerts pre-clinical anti-tumor activity by inhibiting EGFR exon20 insertion

Zhang

Fěng

Tong

et al. 2022

Front. Drug. Discov.

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are classic strategies for the individualized treatment for patients with non-small cell lung cancer (NSCLC). However, EGFR exon20 insertion (EGFR 20ins) mutations, accounting for 6%–12% of all EGFR mutant cases in NSCLC, are generally resistant to the reversible EGFR TKIs (such as gefitinib and erlotinib), which makes them challenging drug-targets in lung cancer. In our previous study, we identified ASK120067 (limertinib) as a novel 3rd-generation EGFR TKI targeting EGFR T790M mutation with promising clinical activities. Here, we accessed the potency of ASK120067 on EGFR 20ins activation and evaluated its in vitro and in vivo anti-tumor activity against EGFR 20ins driven tumor models. We found that ASK120067 showed potent inhibitory activity on TKI-resistant EGFR 20ins kinase. In TKI-resistant EGFR 20ins-dependent BaF3 cells, it dose-dependently suppressed EGFR phosphorylation, impeded cell proliferation, and induced cell apoptosis with much superior efficacy to gefitinib and erlotinib. Moreover, oral administration of ASK120067 decreased the level of phospho-EGFR 20ins and caused significant tumor regression in EGFR 20ins BaF3 xenograft model. These results presented the pre-clinical anti-tumor efficacy of ASK120067 in EGFR 20ins models and highlighted the potential value of ASK120067 for the treatment of NSCLC patients harboring EGFR 20ins mutations.

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“…11 Limertinib (ASK120067) is a newly developed thirdgeneration EGFR TKI that targets sensitizing EGFR mutations and EGFR T790M mutations. 12 Limertinib is metabolized mainly by cytochrome P450 (CYP) 3A4, followed by CYP2C8, CYP2D6, CYP3A5, CYP2C9, and CYP2C19. N-demethylated M10-2 (CCB4580030) is the main metabolite of limertinib, as well as the active metabolite.…”

mentioning

confidence: 99%

“…In human primary hepatocytes, limertinib does not show an induction effect on CYP2B6 or CYP3A4 (unpublished data). Preclinical studies have demonstrated the antitumor activity of limertinib and its active metabolite CCB4580030, 12 and this compound is now under clinical development.…”

mentioning

confidence: 99%

Effect of Food on the Pharmacokinetics of Limertinib (ASK120067) and its Main Metabolite in Healthy Chinese Volunteers

Yang

Ruan

Guo

et al. 2023

Clinical Pharm in Drug Dev

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Limertinib (ASK120067) is a newly developed third‐generation epidermal growth factor receptor tyrosine kinase inhibitor. This phase I, open‐label, 2‐period crossover study was conducted to evaluate the effect of food on the pharmacokinetics (PK) of limertinib and its active metabolite CCB4580030 in Chinese healthy volunteers (HVs). HVs were randomly assigned (1:1) to receive a single dose of limertinib (160 mg) under the fasted state in period 1 and fed condition in period 2, or vice versa. Twenty‐four HVs were enrolled, and 20 HVs completed both study periods. PK were assessed before dosing and ≤72 hours after dosing. PK parameters were analyzed by a noncompartmental method. Limertinib was absorbed faster in the fasted state compared with the fed state. The geometric mean ratios (fed/fast) of maximum concentration, area under the plasma concentration–time curve from time 0 to the last quantifiable concentration, and area under the plasma concentration–time curve from time 0 to infinity for ASK120067 were 145.5%, 145.4%, and 141.9%, respectively. Geometric mean ratios of the PK parameters of CCB4580030 were >125.00% and 90% confidence intervals were outside the preset bioequivalent range. Safety profiles were similar in both prandial states, and limertinib was well tolerated. Food reduced the rate and increased the extent of limertinib absorption following oral administration. Whether limertinib can be administered regardless of prandial state in patients warrants further investigation of efficacy and safety.

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Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study

Cited by 16 publications

References 23 publications

Challenges of EGFR-TKIs in NSCLC and the potential role of herbs and active compounds: From mechanism to clinical practice

Challenges of EGFR-TKIs in NSCLC and the potential role of herbs and active compounds: From mechanism to clinical practice

ASK120067 (limertinib) exerts pre-clinical anti-tumor activity by inhibiting EGFR exon20 insertion

Effect of Food on the Pharmacokinetics of Limertinib (ASK120067) and its Main Metabolite in Healthy Chinese Volunteers

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