Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1–2 study

Ahn, Myung Ju; Han, Ji Youn; Lee, Ki Hyeong; Kim, Sang We; Kim, Dong Wan; Lee, Yun Gyoo; Cho, Eun Kyung; Kim, Joo Hang; Lee, Gyeong Won; Lee, Jong Seok; Min, Young Joo; Kim, Jin-Soo; Lee, Sung Sook; Kim, Hye Ryun; Hong, Min Hee; Ahn, Jin Seok; Sun, Jong Mu; Kim, Heung Tae; Lee, Dong Hoon; Kim, Sohee; Cho, Byoung Chul

doi:10.1016/s1470-2045(19)30504-2

Cited by 99 publications

(110 citation statements)

References 14 publications

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“…Myung-Ju et al have reported that lazaretinib, a third-generation EGFR-TKI, had intracranial response to a range of dosing schedules in 18 patients; however, no association to dosing was reported. 19 …”

Section: Discussionmentioning

confidence: 99%

Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases

Goldstein

Roisman

Keren-Rosenberg

et al. 2020

Neuro-Oncology Advances

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Background Osimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood brain barrier compared to previous EGFR TKIs and thus a 52% reduction in the risk of intracranial disease progression is seen when it is used as 1st line of therapy compared to gefitinib and erlotinib. It is also efficient as 2 nd line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report eleven patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either 1 st or 2 nd line setting. Methods This is a sub-cohort analysis from a larger non-randomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 to 160mg in EGFR mutated advanced NSCLC patients with intracranial progression in either 1 st (Arm A) or 2 nd line setting (Arm B for T790M+ and C for T790M-). Results Eleven patients, five in arm A, four in arm B and two in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4±8.9(6.6-30.7) months for arm A, 8.7±1.8(6.3-11.2) for arm B, and 14.5±7.8(6.7-22.3) for arm C. Intracranial response rate to dose-escalation was 54%(6/11) with 2/11 having intracranial stability. Median iPFS was 4.3±7.4(0.7-25.5) months; 3.8±6.4(1.8-18.9), 5.6±9.7(0.7-25.5) and 7.0±2.7(4.3-9.6) for arms A/B/C respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose limiting symptoms. Conclusions Osimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.

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Section: Discussionmentioning

confidence: 99%

Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases

Goldstein

Roisman

Keren-Rosenberg

et al. 2020

Neuro-Oncology Advances

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“…7,8 This led to the development of third-generation EGFR-TKIs, including osimertinib (Tagrisso, AZD9291), nazartinib, naquotinib, mavelertinib, avitinib, and lazertinib. [9][10][11] Among them, osimertinib is the only approved therapy worldwide, which was first approved in 2015 on the basis of targeting EGFR T790M resistance and then received an additional approval in 2018 as first-line therapy with improvement in progression-free survival (PFS) over a standard EGFR-TKI (gefitinib or erlotinib). 9,[12][13][14] Other candidates are in various stages of clinical development.…”

Section: Introductionmentioning

confidence: 99%

Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation

Shi

Zhang

et al. 2020

Journal of Thoracic Oncology

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Introduction: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of *Corresponding author. Disclosure: Ms. Jiang is an employee and shareholder at Shanghai Allist Pharmaceuticals Co., Ltd. The remaining authors declare no conflict of interest. Previously, part of the results of these studies have been presented as a poster at the World Conference on Lung Cancer (WCLC) 2017

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“…Clinical trials were also conducted on other third-generation TKIs. For example, lazertinib was tested in a clinical trial NCT03046992; the primary endpoints were safety and tolerability, and the phase II extension study is ongoing [ 30 ]. Abivertinib is a mutation-selective third-generation TKI, and its well-tolerated safety profile and anticancer activity were demonstrated in phase I/II studies (NCT02330367) [ 31 ].…”

Section: Acquired Resistance and Corresponding Strategiesmentioning

confidence: 99%

Current Strategies for Treating NSCLC: From Biological Mechanisms to Clinical Treatment

Kwok

2020

Cancers

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The identification of specific epidermal growth factor receptor (EGFR)-activating mutations heralded a breakthrough in non-small-cell lung cancer (NSCLC) treatments, with the subsequent development of EGFR-tyrosine kinase inhibitor (TKIs) becoming the first-line therapy for patients harboring EGFR mutations. However, acquired resistance to EGFR-TKIs inevitably occurs in patients following initial TKI treatment, leading to disease progression. Various mechanisms are behind the acquired resistance, and mainly include (1) target gene modification, (2) alternative parallel pathway activation, (3) downstream pathway activation, and (4) histological/phenotypic transformation. Approaches to combat the acquired resistance have been investigated according to these mechanisms. Newer generations of TKIs have been developed to target the secondary/tertiary EGFR mutations in patients with acquired resistance. In addition, combination therapies have been developed as another promising strategy to overcome acquired resistance through the activation of other signaling pathways. Thus, in this review, we summarize the mechanisms for acquired resistance and focus on the potential corresponding therapeutic strategies for acquired resistance.

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Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1–2 study

Cited by 99 publications

References 14 publications

Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases

Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases

Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation

Current Strategies for Treating NSCLC: From Biological Mechanisms to Clinical Treatment

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