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Ref Type Journal Article
PMID (34890832)
Authors Tan DS, Thomas M, Kim DW, Szpakowski S, Urban P, Mehra R, Chow LQM, Sharma S, Solomon BJ, Felip E, Camidge DR, Vansteenkiste J, Petruzzelli L, Pantano S, Shaw AT
Title Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study.
Journal Vol Issue Date Pages Journal Short Title
Lung cancer (Amsterdam, Netherlands) 163 2022 01 7-13 Lung Cancer
URL
Abstract Text To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study.ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg.NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification.This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients.ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ALK E1129V missense unknown ALK E1129V lies within the protein kinase domain of the Alk protein (UniProt.org). E1129V has been identified in the scientific literature (PMID: 34890832, PMID: 36093526, PMID: 33161228), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK E1129V lung non-small cell carcinoma predicted - sensitive Ceritinib Case Reports/Case Series Actionable In a Phase I trial, Zykadia (ceritinib) treatment resulted in a partial response with a progression-free survival lasting at least 400 days in a patient with non-small cell lung cancer harboring EML4-ALK (e6:e20) and ALK E1129V (PMID: 34890832; NCT01283516). 34890832
EML4 - ALK ALK C1156Y lung non-small cell carcinoma conflicting Ceritinib Case Reports/Case Series Actionable In a Phase I trial, Zykadia (ceritinib) treatment resulted in a partial response in a patient with non-small cell lung cancer harboring EML4-ALK (e18:e20) and ALK C1156Y (PMID: 34890832; NCT01283516). 34890832
EML4 - ALK ALK I1171T ALK F1174V lung non-small cell carcinoma predicted - sensitive Ceritinib Case Reports/Case Series Actionable In a Phase I trial, Zykadia (ceritinib) treatment resulted in a partial response in a patient with non-small cell lung cancer harboring EML4-ALK (e13:e20), ALK F1174V, and ALK I1171T (PMID: 34890832; NCT01283516). 34890832
EML4 - ALK ALK L1196M lung non-small cell carcinoma sensitive Ceritinib Case Reports/Case Series Actionable In a Phase I trial, Zykadia (ceritinib) treatment resulted in 1 partial response and 1 patient with stable disease among 2 patients with non-small cell lung cancer harboring EML4-ALK (e13:e20) and ALK L1196M (PMID: 34890832; NCT01283516). 34890832