Lorlatinib for the treatment of inflammatory myofibroblastic tumour with TPM4-ALK fusion following failure of entrectinib.

Published on Nov 1, 2020in Anti-Cancer Drugs2.26
· DOI :10.1097/CAD.0000000000000994
Han Hsi Wong3
Estimated H-index: 3
(Cambridge University Hospitals NHS Foundation Trust),
Helen Bentley1
Estimated H-index: 1
+ 4 AuthorsHelen Hatcher2
Estimated H-index: 2
Sources
Abstract
Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.
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References35
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#1Gonzalo Recondo (French Institute of Health and Medical Research)H-Index: 14
#2Laura MezquitaH-Index: 17
Last. Luc Friboulet (Université Paris-Saclay)H-Index: 28
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Purpose: Lorlatinib is a third-generation ALK tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setti...
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#1Jun Sakakibara-Konishi (Hokkaido University)H-Index: 11
#2Hidenori Kitai (Hokkaido University)H-Index: 7
Last. Naofumi Shinagawa (Hokkaido University)H-Index: 19
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10009Background: Entrectinib is a CNS-penetrant oral inhibitor of TrkA/B/C, ROS1 and ALK tyrosine kinases. We report the efficacy of entrectinib in children with recurrent/refractory solid or CNS t...
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#1Koutaroh Okada (JFCR: Japanese Foundation for Cancer Research)H-Index: 3
#2Mitsugu Araki (Kyoto University)H-Index: 9
Last. Ryohei Katayama (JFCR: Japanese Foundation for Cancer Research)H-Index: 34
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Abstract Background Alectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming ...
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: Receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) serves a crucial role in brain development. ALK is located on the short arm of chromosome 2 (2p23) and exchange of chromosomal segments with other genes, including nucleophosmin (NPM), echinoderm microtubule-associated protein-like 4 (EML4) and Trk-fused gene (TFG), readily occurs. Such chromosomal translocation results in the formation of chimeric X-ALK fusion oncoproteins, which possess potential oncogenic functions due to const...
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#1Sara Redaelli (University of Milano-Bicocca)H-Index: 23
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Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cell lines in vitro and in vivo to investigate the acquisition of resistance and its underlying mechanisms. ALCL cells acquired...
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Summary Background Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK -positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK -directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK -positive, advanced non-small-cell lung cancer. Methods In this ...
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Abstract Background Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non–small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. Methods In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC wh...
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ABSTRACT null null Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor of intermediate malignant potential that predominantly affects children, adolescents and young adults. IMT has a predilection for the lung, abdomen, pelvis, and retroperitoneum, however, can affect any part of the body. IMT is typically localized, and multifocal or metastatic disease is uncommon. Complete surgical resection is the treatment of choice when feasible. There is no established standard of care for...
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Here, we present the case of an adolescent with a rare metastatic Inflammatory myofibroblastic tumor (IMT) harboring a TFG-ROS1 fusion initially detected on tumor progression and retrospectively identified in the primary tumor after targeted RNA sequencing. The patient benefitted from sequential TKIs over a 5-year period with response to the third generation ALK/ROS inhibitor, lorlatinib leading to resection of the primary tumor. Detailed molecular analysis can identify targetable oncogenic kina...
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Soft tissue sarcomas are a group of rare mesenchymal tumors with more than 70 subtypes described. Treatment of these subtypes in an advanced setting is mainly according to a one-size-fits-all strategy indicating a high unmet need of new and more targeted therapeutic options in order to optimize survival. The introduction of advanced molecular techniques in cancer has led to better diagnostics and identification of new therapeutic targets, leading to more personalized treatment and improved progn...
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