Reference Detail

Ref Type

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	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	12	19	2021 Sep 14	1946-1952	Oncotarget

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, Aug 2024).	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 - 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
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