Anaplastic lymphoma kinase inhibitors
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Acquired resistance: case report A 39-year-old woman acquired resistance to alectinib, ceritinib, crizotinib and lorlatinib, while being treated for non small cell lung cancer (NSCLC) [dosages and routes not stated]. The woman, who was diagnosed with stage IV metastatic NSCLC, started receiving crizotinib in January 2017. However, she achieved a partial response in the lung primary tumour and stable disease at the metastatic sites after 5 months of therapy. Nine months post therapy initiation, her disease progressed with an increase in the number and size of the liver metastases. The woman’s therapy with crizotinib was discontinued in October 2017. From December 2017 to March 2018, she received ceritinib, and from April 2018 to May 2018, she received alectinib. She achieved very short duration of responses from both medications. From May 2018, she received 6 cycles of carboplatin and pemetrexed, which resulted in short-term disease stabilisation. A biopsy of the liver metastasis was done for ALK mutations in exons 22, 23 and 25, which revealed the presence of a G to A point mutation in exon 23 of the ALK gene that resulted in G1202R substitution of the ALK tyrosine kinase receptor. In August 2018, she received lorlatinib, which delayed disease progression for 5 months. In December 2018, therapy with lorlatinib was discontinued. During further disease progression, her plasma was sent for circulating free tumour DNA (cfDNA) analysis, and the isolated cfDNA was tested for mutation hotspot regions in 12 genes (EGFR, ERBB2, ALK, BRAF, KRAS, MAP2K1, MET, NRAS, PIK3CA, ROS1, RET and TP53), along with ALK, ROS1 and RET rearrangements. Liquid biopsy showed a new ALK point mutation, G1269A resulted from a G to C nucleotide change in exon 25, which was observed in 3.5% of reads. In addition to this, cfDNA testing verified the ongoing presence of the G1202R mutation at a frequency of 14.5%, along with the subsistence of the variant 3a/b EML4 (6)-ALK (20) translocation. Later, she succumbed to her disease. It was noted that the coexistence of G1202R and G1269A mutations following lorlatinib treatment presented as resistance mechanisms. Author comment: "[B]etween patients who carried either variant 1 or 3 and treated with ALK-[tyrosine kinase inhibitors], despite variant 3 being mostly associated with the development of G1202R resistant mutation, as also seen in our case." "The development of secondary mutations that render ALK-[tyrosine kinase inhibitors] ineffective is a typical resistance mechanism against these inhibitors." Kougioumtzi A, et al. Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: A case report and literature review. ESMO Open 4: e000561, No. 5, 25 Oct 2019. Available from: URL: http:// 803438885 doi.org/10.1136/esmoopen-2019-000561 - Greece
0114-9954/19/1783-0001/$14.95 Adis © 2019 Springer Nature Switzerland AG. All rights reserved
Reactions 14 Dec 2019 No. 1783
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