Dataset Information

Lorlatinib After Alectinib-Induced Pneumonitis: A Case Report.

ABSTRACT: ALK gene rearrangements are detected in approximately 3% to 5% of NSCLC. ALK tyrosine kinase inhibitors, such as third-generation lorlatinib, have exhibited remarkable efficacy in ALK-rearranged NSCLC; however, they have been associated with a low incidence of treatment-limiting and potentially fatal drug-induced interstitial lung disease (ILD). There is concern that this may represent a class effect, a theory that is supported by a number of case reports. Because of clinical trial exclusion criteria, there are limited prospective data to guide decision-making after ALK tyrosine kinase inhibitors-induced ILD. A systematic review of the literature was conducted and only identified four reported cases of lorlatinib safety in this context. Here, we report the successful sequencing of lorlatinib in a patient who discontinued alectinib secondary to grade 3 drug-induced ILD.

SUBMITTER: Fletcher JA

PROVIDER: S-EPMC10864325 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Lorlatinib After Alectinib-Induced Pneumonitis: A Case Report.

Fletcher James A JA Mullally William J WJ Ladwa Rahul R O'Byrne Kenneth J KJ

JTO clinical and research reports 20231019 2

ALK gene rearrangements are detected in approximately 3% to 5% of NSCLC. ALK tyrosine kinase inhibitors, such as third-generation lorlatinib, have exhibited remarkable efficacy in ALK-rearranged NSCLC; however, they have been associated with a low incidence of treatment-limiting and potentially fatal drug-induced interstitial lung disease (ILD). There is concern that this may represent a class effect, a theory that is supported by a number of case reports. Because of clinica ...[more]

PMID: 38357093

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Project description:BackgroundDrug resistance caused by G1202R/G1202del mutation in anaplastic lymphoma kinase (ALK) represents a great challenge in the clinic. The effect of other mutation(s) at G1202 on the available tyrosine kinase inhibitors (TKIs) in the clinic remains unknown.Case presentationA 50-year-old Chinese male non-smoker with lung adenocarcinoma progressed with spinal metastasis after receiving chest radiation together with Pemetrexed and Cisplatin as adjuvant chemotherapy. Targeted next generation sequencing (NGS) identified EML4-ALK gene fusion in the resected left lung tissue. Local radiation followed by Crizotinib were used in the following treatment and the spinal metastasis was found to shrink, but the progression free survival (PFS) only lasted for 2 months with the appearance of brain metastasis. Afterwards, the patient benefited from the therapy of Alectinib with a PFS of 8 months. Then he progressed with metastases in right lung and pleural, and did not show response to the chemotherapy with Docetaxel plus Bevacizumab. The targeted sequencing consistently identified EML4-ALK gene fusion in both plasma and pleural effusion (PE), as well as a novel ALK G1202K mutation (c.3604_3605delGGinsAA). Given the lack of established or known drug treatment for this novel mutation, we implemented molecular dynamics (MD) simulation-guided drug sensitivity prediction, which results suggested Lorlatinib remains potent against G1202K mutant ALK. Therefore, Lorlatinib was used as the fourth-line therapy, which lead to the considerable efficacy with improved performance status (PS) score and reduced lung metastases. The structural mechanism underlying G1202K-induced drug resistance to different ALK-TKIs was also discussed.ConclusionOur case suggested the ALK-G1202K mutation may serve as a novel mechanism underlying the resistance to Alectinib, and provide direct evidence to support its sensitization to Lorlatinib. Our work represented an example of integrating in silico predictions into clinical practice.

Dataset Information

Lorlatinib After Alectinib-Induced Pneumonitis: A Case Report.

Publications

Lorlatinib After Alectinib-Induced Pneumonitis: A Case Report.

Similar Datasets

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