Efficacy of lorlatinib in lung carcinomas carrying distinct ALK translocation variants: The results of a single-center study

Background: Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use. Methods: This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 ( n = 5), 1 ( n = 26) or none ( n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program. Results: Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2021.101121

Authors: Sergey V. Orlov, Aglaya G. Iyevleva, Elena A. Filippova, Alexandra M. Lozhkina, Svetlana V. Odintsova, Tatiana N. Sokolova, Natalia V. Mitiushkina, Vladislav I. Tiurin, Elena V. Preobrazhenskaya, Alexandr A. Romanko, Alexandr S. Martianov, Alexandr O. Ivantsov, Svetlana N. Aleksakhina, Alexandr V. Togo, Evgeny N. Imyanitov.

Concomitance of a novel RMDN2-ALK fusion and an EML4-ALK fusion in a lung adenocarcinoma

Here, we present a lung adenocarcinoma with two ALK fusions, a novel RMDN2-ALK fusion accompanied by an EML4-ALK fusion, detected by a targeted next generation sequencing assay. The genomic translocation breakpoints of the RMDN2-ALK fusion were mapped to intron 2 for RMDN2 and exon 15 for ALK, and EML4-ALK breakpoints were mapped to intron 13 for EML4 and intron 19 for ALK. ALK break-apart FISH detected multiple ALK rearrangements, a gene fusion panel (NanoString) test confirmed the EML4-ALK fusion, and RNA-sequencing revealed two ALK fusions. The RMDN2 gene locates at the short arm of chromosome 2 between ALK and EML4 genes. The intact ALK kinase domain fused to RMDN2. Genome-wide copy number variants were found in multiple chromosome arms and the short arm of chromosome 2, suggestive of complex rearrangements. Further detailed analyses of breakpoints and copy number variants may shed light on mechanisms of their formation and pathogenesis in lung malignancies. READ ARTICLE

Cancer Genetics DOI: 10.1016/j.cancergen.2021.06.004

Authors: Liqun Jiang, Suping Chen, Victoria Stinnett, Lisa Haley, Laura Morsberger, Alison Shane, Melanie Hardy, Kirstin Smith, Christopher D. Gocke, Ming-Tseh Lin and Ying S. Zou,

Investigation on the prognostic impact of concurrent genomic alterations in crizotinib-treated EML4-ALK-rearranged advanced non-small cell lung cancer patients

Background: ... In our study, we investigated concurrent molecular factors that could contribute to the heterogeneity of their clinical outcomes to crizotinib therapy... Conclusion: Our study revealed that concurrent deleterious mutations, particularly copy number amplifications in oncogenic genes have prognostic implications in patients with EML4-ALK-rearranged NSCLC receiving crizotinib therapy. These observations advance the understanding of the heterogeneity of treatment responses among patients with EML4-ALK-rearranged tumors. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.05.026

Authors: Jing Zheng, Yanping Zhu, Ke Sun, Qian Shen, Yuehong Wang, He Cao, Analyn Lizaso, Bing Yu, Jing Lin, Songan Chen, Jianya Zhou, Jianying Zhou

Case StudyKirk SmithAugust 1, 2020ALK fusion, ALK rearrangements, EML4-ALK, Crizotinib, Lung cancer

The repertoire of genetic alterations in salivary duct carcinoma including a novel HNRNPH3-ALK rearrangement

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy with limited treatment options and poor outcome. Twenty-nine primary resected SDC, including 15 SDC de novo (SDCDN), and 14 SDC ex pleomorphic adenoma (SDCXPA) were subjected to the massive parallel sequencing assay (MSK-IMPACT) targeting 287 to 468 cancer-related genes. TP53 was the most frequently altered gene (69%). TP53 mutations and ERBB2 amplification were more frequent in SDCXPA than in SDCDN (P = .0007 and P = .01, respectively). Potentially targetable mutations were detected in 79% (23/29) of SDC involving ERBB2 (31%), PIK3CA (28%), HRAS (21%), ALK (7%) and BRAF (3%), and 22% (5/23) of those cases harbored possible primary resistance mutations involving CCNE1, NF1 and PTEN. A novel HNRNPH3-ALK rearrangement was found in one SDCDN. In another case, EML4-ALK fusion detected in the primary tumor was associated with ALK G1202R secondary resistance mutation in the post-treatment metastasis. A germline analysis of the DN..... READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2019.03.004

Authors: Snjezana Dogan, Charlotte K. Y. Ng, Bin Xu, Rahul Kumar, Lu Wang, Marcia Edelweiss, Sasinya N. Scott, Ahmet Zehir, Alexander Drilon, Luc, G. T. Morris, Nancy Y. Lee,Cristina R. Antonescu, Alan L. Ho, Nora Katabi, Michael F. Berger, Jorge S. Reis-Filho

Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma

A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. READ ARTICLE

Molecular Cancer Research DOI:10.1158/1541-7786.MCR-18-1075

Authors: Lara E. Davis, Kevin D. Nusser, Joanna Przybyl, Janét Pittsenbarger, Nicolle E. Hofmann, Sushama Varma, Sujay Vennam, Maria Debiec-Rychter, Matt van de Rijn and Monika A. Davare

Case StudyKirk SmithMarch 1, 2019leiomyosarcoma, ALK rearrangements, KANK2-ALK, ACTG2-ALK, Lorlatinib