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

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.

Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report

“…Significantly, a case reported that the multiple ALK mutation, including I1171N, L1196M, and G1202R, mediated the resistance to lorlatinib in malignant pleural mesothelioma. However, in this case, we reported that the co-mutation of I1171N and G1202R was sensitive to lorlatinib (19). Our case with acquired multiple mutations respond differently to different ALK-TKIs, contributing to the understanding of complex ALK-TKI resistance mechanisms.…”

A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review

“…Both G1202R-paired or non–G1202R-paired mutations are identified, indicating multiple pathways leading to a common on-target phenotypic resistance to lorlatinib. 6 , 7 , 8 , 9 , 10 , 11 , 12 Indeed, even without a preexisting solvent-front mutation but with a common preexisting acquired resistance mutation to alectinib, such as I1171X, 13 subsequent treatment with lorlatinib despite its efficacy may lead to an increased risk of double mutations. Other less common acquired resistance mutations to crizotinib can also lead to double mutations when subsequently treated with lorlatinib.…”

“… 15 Owing to the pattern of use of lorlatinib on the basis of its approved indications (post-1L alectinib, post-1L ceritinib, and post-crizotinib and at least one other ALK TKI), most of the compound mutations that are resistant to lorlatinib have evolved from an existing solvent-front mutation ALK G1202R, with ALK G1202R plus ALK L1196M being the most frequent, followed by ALK G1202R plus ALK F1174L/C, ALK G1202R plus ALK L1198F, and ALK G1202R plus ALK G1269A. 6 , 7 , 8 , 9 , 10 , 11 , 12 A real-world study of lorlatinib revealed a decreasing median progression-free survival (PFS) with an increasing line of previous ALK TKI usage. 17 From three-dimensional modeling, we postulate two resistance mechanisms of ALK G1202R-based double mutations to lorlatinib.…”

Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC

“…Hu et al found that multiple mutations mediated lorlatinib resistance. 27 Therefore, the poor PFS of patient P6 may be related to the strong resistance of multiple mutations to lorlatinib. However, these were all advanced NSCLC patients who received long-term previous treatment with first-and/or second-generation ALK inhibitors after the detection of ALK rearrangement.…”

“…In addition to the L1196M/D1203N compound mutation, five other ALK mutations in baseline and one new occurred ALK mutation after progression on lorlatinib were detected in patient P6. Hu et al found that multiple mutations mediated lorlatinib resistance 27 . Therefore, the poor PFS of patient P6 may be related to the strong resistance of multiple mutations to lorlatinib.…”