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PMID (34548910)
Authors Kemper M, Evers G, Schulze AB, Sperveslage J, Schülke C, Lenz G, Herold T, Hartmann W, Schildhaus HU, Bleckmann A
Title Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition.
Journal Oncotarget
Vol 12
Issue 19
Date 2021 Sep 14
URL
Abstract Text Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK-fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off-target KRAS-mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS mutant clone and clinical tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive tumor disease also for ALK-positive NSCLC to personalize treatment in a subgroup of ALK-positive patients.

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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 A1200_G1201delinsW indel unknown ALK A1200_G1201delinsW results in deletion of an alanine (A) and a glycine (G) from aa 1200 to aa 1201 in the protein kinase domain of the Alk protein, combined with the insertion of a tryptophan (W) at the same site (UniProt.org). A1200_G1201delinsW has been associated with secondary drug resistance to some ALK inhibitors (PMID: 34548910), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2022). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK A1200_G1201delinsW lung adenocarcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical case study, post treatment biopsy analysis of a lung adenocarcinoma patient initially harboring EML4-ALK who developed progressive disease after 20 months of Alecensa (alectinib) treatment revealed acquisition of ALK A1200_G1201delinsW (PMID: 34548910). 34548910
EML4 - ALK ALK A1200_G1201delinsW lung adenocarcinoma predicted - sensitive Brigatinib Case Reports/Case Series Actionable In a clinical case study, a lung adenocarcinoma patient harboring EML4-ALK who developed resistance to Alecensa (alectinib) following acquisition of ALK A1200_G1201delinsW demonstrated symptom improvement and stable disease for 4 months with Alunbrig (brigatinib) treatment (PMID: 34548910). 34548910