Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report

Our plain-English summary of Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report, by J. Hu, B. Zhang, F. Yao, et al (Therapeutic Advances in Respiratory Disease, 2020).

The study

• Authors: J. Hu, B. Zhang, F. Yao, Y. Fu, D. Chen, D. Li, N. Du, A. Lizaso, J. Song, L. Zhang, X. Li
• Journal: Therapeutic Advances in Respiratory Disease
• Published: 2020;14:1753466620935770
• Type of article: Case report
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection of EML4-ALK rearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.

In plain English

This case report described one patient in China: a 33-year-old non-smoking man with no family history of cancer and no known exposure to asbestos, diagnosed in 2018 with stage IIIB malignant pleural mesothelioma. Testing of fluid drained from around his lung with a 520-gene panel found a gene change called EML4-ALK (variant 3). After initial chemotherapy, he received the ALK-blocking drug alectinib. His tumor shrank (a partial response at 2 months), but progression was confirmed after 4.5 months in total. Blood testing then found two new ALK mutations, I1171N and L1196M. After two more chemotherapy regimens, he received lorlatinib. The main tumor shrank by about 34% within a month, but the disease progressed after 3.6 months. A third mutation, G1202R, then appeared on the same DNA strand as L1196M. He died in January 2019, with overall survival reported as 11.7 months. The authors described this as, to their knowledge, the first identification of EML4-ALK in pleural mesothelioma. They concluded that his resistance to both drugs was potentially caused by these multiple mutations. A single case shows one patient's course, not a rate.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report (single patient)
• Who was studied: One 33-year-old non-smoking man with no family history of cancer and no known asbestos exposure, treated at the Fourth Medical Center of Chinese PLA General Hospital, Beijing, from early 2018 until his death in January 2019; diagnosed with stage IIIB (cT4N2M0) malignant pleural mesothelioma
• Exposure: No known asbestos exposure. The study concerned treatment with the ALK inhibitors alectinib (600 mg twice daily, later raised to 900 mg twice daily) and lorlatinib, given after and between chemotherapy regimens
• Main results:
  • Targeted sequencing of pleural effusion fluid found an EML4-ALK rearrangement (variant 3), after which alectinib was started
  • On alectinib, CT after 2 months showed marked shrinkage of the main lesion, evaluated as partial response
  • Progressive disease was confirmed after a total of 4.5 months of alectinib, including a month at the higher 900 mg twice-daily dose
  • Blood (plasma) sequencing at alectinib progression showed two new ALK mutations, I1171N and L1196M
  • On lorlatinib, the main lesion shrank by about 34%, reaching partial response within a month
  • After a total of 3.6 months on lorlatinib the disease progressed, and plasma sequencing showed a new ALK G1202R mutation, confirmed to be on the same DNA strand (in cis) as L1196M
  • The patient died on 7 January 2019, with an overall survival of 11.7 months; brain progression was suspected but could not be checked by MRI because he was too weak
• The authors' conclusion: The authors stated that, to their knowledge, this was the first report of EML4-ALK rearrangement in a patient with malignant pleural mesothelioma. They concluded that his resistance to alectinib and then lorlatinib was potentially mediated by combined ALK mutations: I1171N with L1196M for alectinib, and I1171N, L1196M and G1202R for lorlatinib.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma.

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