Mechanisms of resistance after crizotinib or second-generation ALK therapy in advanced non-small cell lung cancer

Remón, Jordi; Esteller, Laura; Hendriks, Lizza

doi:10.21037/pcm-20-33

Cited by 2 publications

(2 citation statements)

References 28 publications

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“…Most patients will develop progressive disease after response to first- and second-line therapy. The mechanism of acquired resistance after targeted drug treatment has attracted increasing attention ( 18 ). However, the subsequent treatment is less hopeful and a clear standard has not been established ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

Cost-effectiveness analysis of anlotinib as a third-line or further treatment for advanced non-small cell lung cancer in China

Zhu,

Ni,

Guan

2023

Transl Lung Cancer Res

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Background The health expenditure on treatment of advanced non-small cell lung cancer (NSCLC) is enormous, especially in third-line or further therapy. Cost-effectiveness analysis for the treatment of advanced NSCLC is particularly important. Anlotinib has been approved by the China Food and Drug Administration (CFDA) for the third-line or further treatment of advanced NSCLC. The price of anlotinib in China fell in 2022. Thus, this study evaluated the cost-effectiveness of anlotinib in the third-line or further treatment of patients with advanced NSCLC based on the newest price from the Chinese health-care system perspective. Methods A Markov model was developed to compare the lifetime costs and effectiveness of anlotinib and a placebo in the third-line or further treatment of patients with advanced NSCLC based on outcome data from the ALTER 0303 phase-3 randomized clinical trial, which included 437 patients with advanced NSCLC and investigated the efficacy of anlotinib. The lifetime costs and quality-adjusted life years (QALYs) were estimated. One-way and probabilistic sensitivity analyses were performed to evaluate the model uncertainty. Results Anlotinib provided an additional 0.1161 QALYs compared to the placebo. The corresponding incremental cost was ¥22,729. The incremental cost-effectiveness ratio (ICER) of anlotinib compared to the placebo was ¥195,768 per QALY. From the perspective of the Chinese health-care system, anlotinib was found to be cost-effective compared to the placebo in the third-line or further treatment of patients with advanced NSCLC at a willingness-to-pay (WTP) threshold of ¥242,928 per QALY. Moreover, 1-way sensitivity analysis found that the results were sensitive to the utility of progressive disease (PD). The lower this parameter was, the higher the probability of ICER for anlotinib not being cost-effective. The cost-effectiveness acceptability curves showed that the base-case analysis results were relatively stable. Conclusions Considering the clinical efficacy, safety, and cost-effectiveness of anlotinib, it may be a valuable third-line or further treatment for advanced NSCLC in China.

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Section: Discussionmentioning

confidence: 99%

Cost-effectiveness analysis of anlotinib as a third-line or further treatment for advanced non-small cell lung cancer in China

Zhu,

Ni,

Guan

2023

Transl Lung Cancer Res

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“…The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of these drugs in advanced ALK-positive NSCLC treatment. These ALK TKIs include crizotinib (first generation), ceritinib, brigatinib, alectinib, and ensartinib (second generation), and lorlatinib (third generation) ( Remon et al, 2022 ; Rijavec et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations

Balasundaram,

Doss

2024

Front. Mol. Biosci.

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Background: In non-small-cell lung cancer (NSCLC), a pivotal factor in promoting cancer development is the rearrangement in the anaplastic lymphoma kinase ALK gene, resulting in elevated ALK protein expression. F1174C/L/V is the acquired secondary resistant mutation in ALK. Significant survival improvements have been seen while tyrosine kinase inhibitors specifically target ALK. Nevertheless, the emergence of drug resistance hinders the clinical effectiveness of these drugs.Objective: This research sought to find the binding affinity/inhibitory effects of the existing drug lorlatinib (LOR) and upcoming TPX-0131 (zotizalkib/TPX) and repotrectinib (TPX-0005/REP) inhibitors against ALK F1174C/L/V mutations using computational approaches to identify potential strategies over resistance.Methods: We conducted molecular docking, molecular dynamics simulation, and MMPBSA calculations to investigate how compact macrocyclic inhibitors, such as TPX-0131 and repotrectinib, fit within the ATP-binding boundary and differ from LOR.Results: Our results demonstrated that TPX-0131 and repotrectinib contributed to higher binding energy in F1174C and F1174L mutations than LOR. Repotrectinib showed greater binding energy in the F1174V mutation, whereas LOR and TPX-0131 exhibited similar binding energy. However, all three inhibitors showed significant binding energy toward F1174C/L/V mutations found in NSCLC.Conclusion: This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.

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Mechanisms of resistance after crizotinib or second-generation ALK therapy in advanced non-small cell lung cancer

Cited by 2 publications

References 28 publications

Cost-effectiveness analysis of anlotinib as a third-line or further treatment for advanced non-small cell lung cancer in China

Cost-effectiveness analysis of anlotinib as a third-line or further treatment for advanced non-small cell lung cancer in China

A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations

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