Reference Detail

Ref Type

Journal Article

PMID

(39188081)

Authors

Wilson I, Qiu M, Itchins M, Wang B, Huang ML, Grimison P

Title

Metastatic Non-Myofibroblastic Sarcoma Harbouring EML4-ALK Fusion-Dramatic Response to ALK Tyrosine Kinase Inhibitors and Development of Resistance Mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer reports (Hoboken, N.J.)	7	8	2024 Aug	e2164	Cancer Rep (Hoboken)

URL

Abstract Text

Anaplastic lymphoma kinase (ALK) rearrangements are rare in non-myofibroblastic sarcoma and there is limited data on the efficacy of ALK tyrosine kinase inhibitors (TKIs) and mechanisms of resistance in these patients.A 58 year-old man with metastatic non-myofibroblastic sarcoma was found to have an EML4-ALK fusion on molecular sequencing. After progression on first line systemic therapy with doxorubicin, the patient received alectinib, a second generation ALK inhibitor, and had a marked clinical and radiological response. He progressed after 5 months of treatment. Repeat lung biopsy identified the emergence of an ALK I1171N resistance mutation. He was then treated with lorlatinib, again with rapid clinical improvement and significant partial radiological response. He progressed after 4 months, at which time a repeat lung biopsy identified a new ALK kinase domain mutation G1202R. The patient was subsequently treated with chemotherapy, though unfortunately died shortly after due to rapidly progressive disease.This case report adds to a body of evidence demonstrating the potential transformative response to targeted therapy in non-lung solid organ tumours harbouring ALK fusions. This is the first description tracking the development of resistance mutations in a patient with non-myofibroblastic sarcoma and questions the utility of the presence of G1202R mutation as a marker of lorlatinib sensitivity in non-lung ALK rearranged tumours, contrary to experience in lung cancer.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK G1202R	sarcoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with metastatic non-myofibroblastic sarcoma harboring EML4-ALK (e2:e20) and ALK I1171N experienced progressive disease on treatment with Lorbrena (lorlatinib) and was found to have lost ALK I1171N and acquired ALK G1202R (PMID: 39188081).	39188081
EML4 - ALK	sarcoma	predicted - sensitive	Alectinib	Case Reports/Case Series	Actionable	In a Phase II trial, Alecensa (alectinib) treatment resulted in a partial response in a patient with metastatic non-myofibroblastic sarcoma harboring EML4-ALK (e2:e20) (PMID: 39188081).	39188081
EML4 - ALK ALK I1171N	sarcoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a partial response in a patient with metastatic non-myofibroblastic sarcoma harboring EML4-ALK (e2:e20) and ALK I1171N (PMID: 39188081).	39188081
EML4 - ALK ALK I1171N	sarcoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a Phase II trial, ALK I1171N was identified on post-progression biopsy in a patient with metastatic non-myofibroblastic sarcoma harboring EML4-ALK (e2:e20), who previously achieved a partial response on Alecensa (alectinib) treatment (PMID: 39188081).	39188081