Reference Detail

Ref Type

Journal Article

PMID

(38623748)

Authors

Leporati R, Miliziano D, Beninato T, Mazzeo L, Manglaviti S, Brambilla M, Occhipinti M, Prelaj A, Proto C, Lo Russo G

Title

Response to lorlatinib rechallenge in a case of ALK-rearranged metastatic NSCLC with a resistance mutation to second generation TKIs.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Tumori			2024 Apr 16	3008916241246659	Tumori

URL

Abstract Text

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. With the increasing number of target therapies available, the optimal sequence is yet to be defined, as resistance profiles may evolve over time and in response to sequential ALK inhibitors. Therefore, ALK-targeted strategies may be personalized based upon the presence of specific ALK resistance mutations.Here, we report on the case of a patient who has been treated with a sequence of three ALK TKIs after receiving diagnosis of ALK-rearranged metastatic NSCLC in 2015 and gained further benefit upon lorlatinib rechallenge after the acquisition of the G1202R resistance mutation to second generation TKIs.In this case, the first ALK resistance mutation detected after progression on first line TKI, the I1171N, is a common resistance mutation after alectinib and confers sensitivity to brigatinib, that the patient received afterwards with a long-term disease stability. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.

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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 I1171N	lung adenocarcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK I1171N was identified at the time of progression in a patient with metastatic lung adenocarcinoma harboring EML4-ALK who previously demonstrated a partial response on Alecensa (alectinib) treatment (PMID: 38623748).	38623748
EML4 - ALK ALK I1171N	lung adenocarcinoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a partial response in all lesions including lesions within the CNS with a progression-free survival of 14 months in a patient with metastatic lung adenocarcinoma harboring EML4-ALK and ALK I1171N (PMID: 38623748).	38623748
EML4 - ALK ALK I1171N	lung adenocarcinoma	predicted - sensitive	Brigatinib	Case Reports/Case Series	Actionable	In a clinical case study, Alunbrig (brigatinib) treatment resulted in stable disease with a progression-free survival of 17 months in a patient with metastatic lung adenocarcinoma harboring EML4-ALK and ALK I1171N (PMID: 38623748).	38623748