A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors

Cho, Byoung Chul; Han, Ji‐Youn; Lee, Ki Hyeong; Cho, Eun Kyung; Lee, Yun‐Gyoo; Kim, Dong-Wan; Kim, Joo-Hang; Lee, Gyeong‐Won; Lee, Jong-Seok; Shim, Byoung Yong; Chun, Sang Hoon; Lee, Sung Sook; Kim, Hye Ryun; Hong, Min Hee; Ahn, Jin Seok; Sun, Jong‐Mu; Lee, Young‐Joo; Lee, Dong Hoon; Kang, Ji Ah; Lee, Nami; Kwon, Mijung; Espenschied, Carin R.; Yablonovitch, Arielle; Ahn, Myung‐Ju

doi:10.1016/j.jtho.2021.11.025

Cited by 59 publications

(60 citation statements)

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“…With the progresses of drug development, third-generation TKIs, including osimertinib, aumolertinib and furmonertinib, have been recommended as the first-line setting for EGFR mutant NSCLC patients, 1 , 2 , 3 as salvage treatment for T790M mutation-positive patients after resistance to first- and second-generation EGFR TKIs 4 , 5 , 6 , 7 and as adjuvant therapy for post-surgery EGFR-mutant NSCLCs. 8 Other developing third-generation TKIs, including lazertinib, 9 abivertinib, 10 and rezivertinib 11 have shown powerful anti-tumor potentials in T790M-positive NSCLC patients. However, with widespread clinical applications of osimertinib and other third-generation TKIs, acquired resistance is a growing clinical challenge.…”

Section: Introductionmentioning

confidence: 99%

Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via suppressing M2 macrophages polarization

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via suppressing M2 macrophages polarization

et al. 2022

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“…However, other clinical studies have shown that the effect of H2RAs on gastric pH elevation reaches a plateau in 3–4 days after continuous multiple dosing [ 30 , 31 ]. Therefore, this analysis was performed assuming that the elevation of gastric pH was sufficiently expressed after about 4 days of multiple dosing of H2RA and PPI, which were the criteria for classifying the ARA group and non-ARA group [ 8 , 19 ]. In the non-ARA group, no one took ARAs for 1, 2, or 3 days during the 4 days immediately before evaluation of the PK parameters of lazertinib.…”

Section: Discussionmentioning

confidence: 99%

“…PK data of lazertinib and co-administration information with ARAs from the LASER201 study were used in this analysis. Detailed information about the methods and results of the LASER201 study has been described previously [ 8 , 19 ]. In brief, the study was an open-label, multicenter, phase 1/2 study to evaluate the efficacy, pharmacokinetics, and safety of lazertinib in patients with EGFR mutation-positive advanced NSCLC.…”

Section: Methodsmentioning

confidence: 99%

Effects of Acid-Reducing Agents on the Pharmacokinetics of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer

et al. 2022

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Introduction Lazertinib is an irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Co-administration of TKIs with acid-reducing agents (ARAs) can lead to potential drug–drug interactions, which decreases solubility and absorption of TKIs and is ultimately associated with reduced efficacy of TKIs. This retrospective analysis evaluated the effect of ARAs on the pharmacokinetics of lazertinib using data obtained from patients with advanced EGFR mutation-positive non-small-cell lung cancer. Methods In a total of 234 patients with lazertinib pharmacokinetics observed at steady state, dose-normalized (DN) area under the concentration–time curve (AUC ss ), maximum concentration ( C max,ss ), and/or trough concentration on day 15 ( C D15 ) were compared between a group receiving ARA concomitantly for at least 4 days (ARA group) and another group not receiving ARA (non-ARA group) in a dose-proportional range. Additionally, a comparison of pharmacokinetic parameters at a therapeutic dose of 240 mg once daily was evaluated. Results Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of ARA group to non-ARA group for DNAUC ss , DNC max,ss , and DNC D15 at 40 mg to 320 mg once daily showing the dose proportionality were 0.8743 (0.7285–1.0493), 0.9035 (0.7482–1.0910), and 0.9126 (0.7364–1.1311), respectively. GMRs with 90% CIs for AUC ss , C max,ss , and C D15 at 240 mg were 0.9136 (0.6637–1.2576), 0.9012 (0.6703–1.2116), and 0.8850 (0.6463–1.2118), respectively. Conclusion All pharmacokinetic parameters were not significantly different between the two groups ( p values > 0.05), indicating that co-administered ARAs did not significantly affect the steady state pharmacokinetics of lazertinib. Therefore, no dose adjustment of lazertinib is required in patients receiving concomitant ARAs. ClinicalTrials.gov identifiers NCT03046992, NCT04075396. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-022-02286-z.

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“…LASER201 (ClinicalTrials.gov Identifier: NCT03046992 ), a multicenter, open-label, phase I/II study, was conducted to evaluate the efficacy of lazertinib in advanced NSCLC patients with activating EGFR mutations (L858R, 19del, G719X, and L861Q) who had progressed on first- or second-generation EGFR TKI. 17 18 The study consisted of three parts: part A (dose-escalation), part B (dose-expansion), and part C (dose-extension in first- and second-line cohorts). It was conducted across 17 centers in South Korea (Part D is being conducted in countries other than Korea, including Caucasians).…”

Section: Clinical Studymentioning

confidence: 99%

Lazertinib: on the Way to Its Throne

2022

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Lazertinib is an oral, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that forms an irreversible covalent bond to the Cys797 residue in the ATP-binding site of the EGFR kinase domain and exhibits a high selectivity for sensitizing and T790M EGFR mutations. In January 2021, it was first approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) patients with EGFR T790M who had previously received EGFR TKI therapy based on LASER201, a phase I/II trial. At a recommended dose of 240 mg, lazertinib achieved an encouraging anti-tumor activity in both extra- and intracranial lesions. With a high half-maximal inhibitory concentration for EGFR wildtype tumors, it is anticipated to pose a lower risk of skin and cardiac adverse events compared to osimertinib. Lazertinib is currently being investigated as a monotherapy in first-line treatment and in combination with amivantamab under various settings. In this review, we systematically summarize the preclinical and clinical data of lazertinib and discuss future perspectives on the treatment of EGFR-mutant NSCLC.

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A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors

Cited by 59 publications

References 22 publications

Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via suppressing M2 macrophages polarization

Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via suppressing M2 macrophages polarization

Effects of Acid-Reducing Agents on the Pharmacokinetics of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer

Lazertinib: on the Way to Its Throne

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