Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors: ceritinib

2017 ◽  
Vol 13 (29) ◽  
pp. 2629-2644 ◽  
Author(s):  
Tommaso De Pas ◽  
Laura Pala ◽  
Chiara Catania ◽  
Fabio Conforti
Keyword(s):  
Clinical Features ◽  
Anaplastic Lymphoma Kinase ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Anaplastic Lymphoma

scholarly journals Therapeutic Sequencing in ALK+ NSCLC

2021 ◽  
Vol 14 (2) ◽  
pp. 80
Author(s):  
Mei Elsayed ◽  
Petros Christopoulos
Keyword(s):  
Disease Progression ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Fourth Generation ◽  
Cell Therapies ◽  
Anaplastic Lymphoma ◽  
Phase Ii Studies ◽  
Tumor Mutational Burden ◽  
Potential Clinical Utility

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.

Discovery of anaplastic lymphoma kinase inhibitors from natural product library: A holistic in silico approach

2020 ◽  
Author(s):  
Saranyadevi Subburaj ◽  
Tanvi Anand Nagrale ◽  
Mohd. Mustufa Khan ◽  
Nivya James ◽  
Ramanathan Karuppasamy ◽  
...  
Keyword(s):  
Natural Product ◽  
Anaplastic Lymphoma Kinase ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Anaplastic Lymphoma ◽  
Natural Product Library

scholarly journals Brigatinib versus other second-generation ALK inhibitors as initial treatment of anaplastic lymphoma kinase positive non-small cell lung cancer with deep phenotyping: study protocol of the ABP trial

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Petros Christopoulos ◽  
Farastuk Bozorgmehr ◽  
Lena Brückner ◽  
Inn Chung ◽  
Johannes Krisam ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Anaplastic Lymphoma Kinase ◽  
Second Generation ◽  
Search Query ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Link Type ◽  
Biomarker Analysis ◽  
Nsclc Patients

Abstract Background Availability of potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) has pushed the median survival of ALK+ non-smallcell lung cancer (NSCLC) patients to over five years. In particular, second-generation ALK TKI have demonstrated superiority compared to the first-generation compound crizotinib and are meanwhile standard first-line treatment. However, clinical courses of individual patients vary widely, with secondary development of drug resistance and intracranial progression remaining important problems. While these limitations highlight the need for better disease monitoring and additional therapeutic tools, molecular tumor features are increasingly recognized as crucial determinants of clinical outcome. This trial aims to optimize management of ALK+ NSCLC by analyzing the efficacy of second-generation ALK inhibitors in conjunction with deep longitudinal phenotyping across two treatment lines. Methods/design In this exploratory prospective phase II clinical trial, newly diagnosed ALK+ NSCLC patients will be randomized into two treatment arms, stratified by presence of brain metastases and ECOG performance status: brigatinib (experimental arm) vs. any other approved second-generation ALK TKI. Tumor tissue and blood samples will be collected for biomarker analysis at the beginning and throughout the study period to investigate baseline molecular tumor properties and analyze the development of acquired drug resistance. In addition, participating investigators and patients will have the possibility of fast-track molecular tumor and ctDNA profiling at the time of disease progression using state-of-the-art next-generation sequencing (NGS), in order to support decisions regarding next-line therapy. Discussion Besides supporting therapeutic decisions for enrolled patients, the ABP trial primarily aims to deepen the understanding of the underlying biology and facilitate development of a framework for individualized management of ALK+ NSCLC according to molecular features. Patients with low molecular risk and the perspective of a “chronic disease” will be distinguished from “high-risk” cases, molecular properties of which will be utilized to elaborate improved methods of non-invasive monitoring and novel preclinical models in order to advance therapeutic strategies. Trial registration Clinicaltrials.gov, NCT04318938. Registered March 182,020, https://www.clinicaltrials.gov/ct2/show/NCT04318938 Eudra-CT, 2019–001828-36. Registered September 302,019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-001828-36

scholarly journals Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

RSC Advances ◽  
2018 ◽  
Vol 8 (30) ◽  
pp. 16470-16493 ◽  
Author(s):  
Muhammad Latif ◽  
Zaman Ashraf ◽  
Sulman Basit ◽  
Abdul Ghaffar ◽  
Muhammad Sohail Zafar ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitors ◽  
Anaplastic Lymphoma ◽  
Orally Bioavailable

This review describes hit-to-drug evolution milestones, synthetic strategies and clinical significance of novel DAAPalogues discovered for ALK inhibition which are either progressing as investigational or preclinical candidates to treat the patients with ALK+-NSCLC.

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