{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T14:01:41Z","timestamp":1762783301658,"version":"build-2065373602"},"reference-count":21,"publisher":"Harborside Press, LLC","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:p>\n                    <jats:italic>ALK<\/jats:italic>\n                    gene rearrangements represent a targetable driver in non\u2013small cell lung cancer (NSCLC), but rare fusion variants remain poorly characterized and their sensitivity to\n                    <jats:italic>ALK<\/jats:italic>\n                    inhibitors is uncertain. This report describes a 67-year-old woman with stage IV lung adenocarcinoma in whom comprehensive genomic profiling (CGP) identified a rare\n                    <jats:italic>EML4-ALK<\/jats:italic>\n                    (E6;A18) fusion, subsequently confirmed by immunohistochemistry (IHC). Following first-line therapy with lorlatinib, the patient demonstrated rapid clinical improvement, radiologic tumor regression, and a complete metabolic response, including resolution of central nervous system metastases. No significant adverse effects were observed during treatment. This case provides the first evidence of complete and durable response with lorlatinib in a patient with NSCLC harboring the rare\n                    <jats:italic>EML4-ALK<\/jats:italic>\n                    (E6;A18) fusion. This report underscores the importance of integrating CGP with IHC for accurate molecular diagnosis and therapeutic decision-making in the context of atypical\n                    <jats:italic>ALK<\/jats:italic>\n                    fusions. It also highlights the clinical activity of next-generation\n                    <jats:italic>ALK<\/jats:italic>\n                    inhibitors against uncommon fusion variants, suggesting that even structurally distinct fusions may be sensitive to targeted therapy. Further research is warranted to validate treatment strategies in these rare genomic contexts.\n                  <\/jats:p>","DOI":"10.6004\/jnccn.2025.7099","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:40:44Z","timestamp":1759941644000},"source":"Crossref","is-referenced-by-count":0,"title":["Complete Response to Lorlatinib in Lung Adenocarcinoma With EML4-ALK Fusion Variant (E6;A18): Case Report and Literature Review"],"prefix":"10.6004","volume":"23","author":[{"given":"Antonio","family":"Vitale","sequence":"first","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"De Paolis","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Molecular and Personalized Diagnostics, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacopo","family":"Russo","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Horn","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"Stefani","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Scala","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Cancellieri","sequence":"additional","affiliation":[{"name":"Pathology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"D\u2019Argento","sequence":"additional","affiliation":[{"name":"Radiology and Neuroradiology Unit, Diagnostic Imaging and Oncological Radiotherapy Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Minucci","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Molecular and Personalized Diagnostics, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rocco","family":"Trisolini","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"},{"name":"Interventional Pulmonology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Margaritora","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"},{"name":"Thoracic Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilio","family":"Bria","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"},{"name":"Medical Oncology, Ospedale Isola Tiberina\u2014Gemelli Isola, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giampaolo","family":"Tortora","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"},{"name":"Faculty of Medicine and Surgery, Universita\u0300 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ettore","family":"D\u2019Argento","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"4047","reference":[{"key":"B1","series-title":"Cell Mol Life Sci","first-page":"1209","article-title":"Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs","volume":"73","author":"Bayliss R","year":"2016","unstructured":"Bayliss R, Choi J, Fennell DA,  Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs. Cell Mol Life Sci 2016;73:1209\u20131224."},{"key":"B2","series-title":"J Clin Oncol","first-page":"1105","article-title":"ALK in lung cancer: past, present, and future","volume":"31","author":"Shaw AT","year":"2013","unstructured":"Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31:1105\u20131111."},{"key":"B3","series-title":"J Thorac Oncol","first-page":"e126","article-title":"A case of lung adenocarcinoma resistant to crizotinib harboring a novel EML4-ALK variant, exon 6 of EML4 fused to exon 18 of ALK","volume":"11","author":"Anai S","year":"2016","unstructured":"Anai S, Takeshita M, Ando N,  A case of lung adenocarcinoma resistant to crizotinib harboring a novel EML4-ALK variant, exon 6 of EML4 fused to exon 18 of ALK. J Thorac Oncol 2016;11:e126\u2013128."},{"key":"B4","series-title":"J Natl Compr Canc Netw","first-page":"2","article-title":"A case of lung adenocarcinoma response to alectinib harboring a rare EML4-ALK variant, exon 6 of EML4 fused to exon 18 of ALK","volume":"20","author":"Liu L","year":"2021","unstructured":"Liu L, Hou F, Liu Y,  A case of lung adenocarcinoma response to alectinib harboring a rare EML4-ALK variant, exon 6 of EML4 fused to exon 18 of ALK. J Natl Compr Canc Netw 2021;20:2\u20136."},{"key":"B5","series-title":"N Engl J Med","first-page":"829","article-title":"Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer","volume":"377","author":"Peters S","year":"2017","unstructured":"Peters S, Camidge DR, Shaw AT,  Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829\u2013838."},{"key":"B6","series-title":"Lancet Respir Med","first-page":"354","article-title":"Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study","volume":"11","author":"Solomon BJ","year":"2023","unstructured":"Solomon BJ, Bauer TM, Mok TSK,  Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study. Lancet Respir Med 2023;11:354\u2013366."},{"key":"B7","series-title":"N Engl J Med","first-page":"2027","article-title":"Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer","volume":"379","author":"Camidge DR","year":"2018","unstructured":"Camidge DR, Kim HR, Ahn MJ,  Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 2018;379:2027\u20132039."},{"key":"B8","series-title":"Clin Lung Cancer","first-page":"e564","article-title":"Chr2 30297612-ALK, a novel intergenic fusion with exon18 of ALK, responds to crizotinib","volume":"21","author":"Chen X","year":"2020","unstructured":"Chen X, Zhao G, Zhong P,  Chr2 30297612-ALK, a novel intergenic fusion with exon18 of ALK, responds to crizotinib. Clin Lung Cancer 2020;21:e564\u2013566."},{"key":"B9","series-title":"Ann Oncol","first-page":"339","article-title":"Oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up","volume":"34","author":"Hendriks LE","year":"2023","unstructured":"Hendriks LE, Kerr KM, Menis J,  Oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34:339\u2013357."},{"key":"B10","series-title":"J Oncol Pract","first-page":"323","article-title":"Molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement Summary of the College of American Pathologists\/International Association for the Study of Lung Cancer\/Association for Molecular Pathology clinical practice guideline update","volume":"14","author":"Kalemkerian GP","year":"2018","unstructured":"Kalemkerian GP, Narula N, Kennedy EB. Molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement Summary of the College of American Pathologists\/International Association for the Study of Lung Cancer\/Association for Molecular Pathology clinical practice guideline update. J Oncol Pract 2018;14:323\u2013327."},{"article-title":"NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer","author":"Riely GJ","key":"B11","unstructured":"Riely GJ, Wood DE, Aisner DL, . NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Accessed July 20, 2025. To view the most recent version, visit https:\/\/www.nccn.org\/"},{"key":"B12","series-title":"Thorac Cancer","first-page":"2283","article-title":"Successful treatment of a non\u2010small\u2010cell lung cancer patient harboring HIP1-ALK (H28:A20) and CTNNB1 p.S45del with alectinib","volume":"15","author":"Longo V","year":"2024","unstructured":"Longo V, Pesola F, Lacalamita R,  Successful treatment of a non\u2010small\u2010cell lung cancer patient harboring HIP1-ALK (H28:A20) and CTNNB1 p.S45del with alectinib. Thorac Cancer 2024;15:2283\u20132287."},{"key":"B13","series-title":"Lung Cancer","first-page":"107386","article-title":"A novel intergenic (between REG3A and CTNNA2-AS1)-ALK fusion responds to alectinib in lung adenocarcinoma","volume":"186","author":"Liu Z","year":"2023","unstructured":"Liu Z, Wu Q, Li W,  A novel intergenic (between REG3A and CTNNA2-AS1)-ALK fusion responds to alectinib in lung adenocarcinoma. Lung Cancer 2023;186:107386."},{"key":"B14","series-title":"J Cell Mol Med","first-page":"5326","article-title":"Lung adenocarcinoma with an uncommon CCDC85A\u2010ALK fusion responding to alectinib: a case report","volume":"26","author":"Lin J","year":"2022","unstructured":"Lin J, Wang W, Lin J,  Lung adenocarcinoma with an uncommon CCDC85A\u2010ALK fusion responding to alectinib: a case report. J Cell Mol Med 2022;26:5326\u20135329."},{"key":"B15","series-title":"JTO Clin Res Rep","first-page":"100015","article-title":"Catalog of 5\u2032 fusion partners in ALK-positive NSCLC circa 2020","volume":"1","author":"Ou SHI","year":"2020","unstructured":"Ou SHI, Zhu VW, Nagasaka M. Catalog of 5\u2032 fusion partners in ALK-positive NSCLC circa 2020. JTO Clin Res Rep 2020;1:100015."},{"key":"B16","series-title":"J Thorac Oncol","first-page":"1223","article-title":"Intergenic breakpoints identified by DNA sequencing confound targetable kinase fusion detection in NSCLC","volume":"15","author":"Li W","year":"2020","unstructured":"Li W, Liu Y, Li W,  Intergenic breakpoints identified by DNA sequencing confound targetable kinase fusion detection in NSCLC. J Thorac Oncol 2020;15:1223\u20131231."},{"key":"B17","series-title":"J Thorac Oncol","first-page":"404","article-title":"Potential unreliability of uncommon ALK, ROS1, and RET genomic breakpoints in predicting the efficacy of targeted therapy in NSCLC","volume":"16","author":"Li W","year":"2021","unstructured":"Li W, Guo L, Liu Y,  Potential unreliability of uncommon ALK, ROS1, and RET genomic breakpoints in predicting the efficacy of targeted therapy in NSCLC. J Thorac Oncol 2021;16:404\u2013418."},{"key":"B18","series-title":"J Clin Pathol","first-page":"405","article-title":"IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered?","volume":"75","author":"Batra U","year":"2022","unstructured":"Batra U, Nathany S, Sharma M,  IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered? J Clin Pathol 2022;75:405\u2013409."},{"key":"B19","series-title":"Nat Rev Cancer","first-page":"359","article-title":"ALK in cancer: from function to therapeutic targeting","volume":"25","author":"Voena C","year":"2025","unstructured":"Voena C, Ambrogio C, Iannelli F, Chiarle R. ALK in cancer: from function to therapeutic targeting. Nat Rev Cancer 2025;25:359\u2013378."},{"key":"B20","series-title":"JCO Precis Oncol","first-page":"e2400154","article-title":"ALK inhibition with alectinib for refractory metastatic renal cell carcinoma with ALK rearrangement: a rare case report and literature review","volume":"8","author":"Kathuria-Prakash N","year":"2024","unstructured":"Kathuria-Prakash N, Lopez LP, Raman S,  ALK inhibition with alectinib for refractory metastatic renal cell carcinoma with ALK rearrangement: a rare case report and literature review. JCO Precis Oncol 2024;8:e2400154."},{"key":"B21","series-title":"J Clin Oncol","first-page":"3105","article-title":"Efficacy and safety of alectinib in pediatric and adult patients with ALK altered advanced solid tumors: results from the TACKLE phase II trial, a MASTER KEY substudy (NCCH1712\/MK003)","volume":"43","author":"Okuma HS","year":"2025","unstructured":"Okuma HS, Arakawa A, Hirakawa A,  Efficacy and safety of alectinib in pediatric and adult patients with ALK altered advanced solid tumors: results from the TACKLE phase II trial, a MASTER KEY substudy (NCCH1712\/MK003). J Clin Oncol 2025;43(Suppl):Abstract 3105."}],"container-title":["Journal of the National Comprehensive Cancer Network"],"original-title":[],"link":[{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/23\/11\/article-e257099.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/23\/11\/article-e257099.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/23\/11\/article-e257099.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:56:45Z","timestamp":1762783005000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/23\/11\/article-e257099.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":21,"journal-issue":{"issue":"11"},"URL":"https:\/\/doi.org\/10.6004\/jnccn.2025.7099","relation":{},"ISSN":["1540-1405","1540-1413"],"issn-type":[{"type":"print","value":"1540-1405"},{"type":"electronic","value":"1540-1413"}],"subject":[],"published":{"date-parts":[[2025,11]]}}}