{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:28:08Z","timestamp":1787128088631,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Med. Sci.","Medical Sciences"],"abstract":"<jats:p>Background\/Objectives: High-grade pulmonary neuroendocrine carcinoma (HGNEC-L), including SCLC and LCNEC, is aggressive and usually treated according to SCLC paradigms. The clinical relevance of de novo actionable genomic alterations (AGA) remains incompletely defined. Methods: We performed a retrospective multicenter analysis of advanced HGNEC-L with de novo AGA, assessing rwORR, rwDCR, rwPFS, and OS. Findings were contextualized by a structured literature review and exploratory pooled reconstructed-IPD Cox analysis, with targeted therapy modeled as a source-stratified time-dependent covariate. Results: Ten patients from four tertiary centers were included. Most were women (90.0%) and never-smokers (70.0%); histology was LCNEC in 60.0% and SCLC\/mixed SCLC in 40.0%. AGA included EGFR mutations (n = 6), EML4-ALK fusions (n = 2), KIF5B-RET fusion (n = 1), and KRAS p.G12C (n = 1). Targeted-containing regimens achieved rwORR 77.8%, rwDCR 88.9%, and median rwPFS 9.0 months (95% CI, 2.0\u201318.7), as opposed to 3.7 months for ICI-containing regimens and 2.6 months for chemotherapy alone. Median OS for the entire cohort was 17.2 months (95% CI, 4.8\u201336.3); overall survival did not differ significantly between patients with and without targeted-containing exposure (19.0 vs. 17.2 months; log-rank p = 0.50). In pooled reconstructed-IPD time-dependent Cox analysis (72 patients, 39 deaths), targeted therapy showed a favorable but non-significant OS association (HR, 0.89; 95% CI, 0.31\u20132.56; p = 0.831), maintained directionally in the age\/sex-adjusted subset (HR, 0.54; 95% CI, 0.16\u20131.77; p = 0.306). Conclusions: De novo AGA-positive HGNEC-L represents a clinically relevant subgroup with potential sensitivity to genotype-matched targeted therapy, supporting comprehensive molecular profiling and early targeted therapy consideration.<\/jats:p>","DOI":"10.3390\/medsci14040491","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:12:11Z","timestamp":1787069531000},"page":"491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["De Novo Actionable Genomic Alterations in High-Grade Pulmonary Neuroendocrine Carcinomas: Therapeutic Implications of Targeted Treatment"],"prefix":"10.3390","volume":"14","author":[{"given":"Ari","family":"Raphael","sequence":"first","affiliation":[{"name":"Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 4941492, Israel"},{"name":"Gray Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nir","family":"Peled","sequence":"additional","affiliation":[{"name":"Helmsley Cancer Center, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6226-2573","authenticated-orcid":false,"given":"Roni","family":"Gillis","sequence":"additional","affiliation":[{"name":"Helmsley Cancer Center, Shaare Zedek Medical Center, Jerusalem 9103102, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3411-800X","authenticated-orcid":false,"given":"Hovav","family":"Nechushtan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"},{"name":"Sharett Institute of Oncology, Hadassah Medical Center, Jerusalem 9112001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7570-4550","authenticated-orcid":false,"given":"Walid","family":"Shalata","sequence":"additional","affiliation":[{"name":"The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka University Medical Center, Beer-Sheva 8410101, Israel"},{"name":"Joyce & Irving Goldman Medical School, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6971-3576","authenticated-orcid":false,"given":"Elizabeth","family":"Dudnik","sequence":"additional","affiliation":[{"name":"Joyce & Irving Goldman Medical School, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"},{"name":"Lung Cancer Service, Assuta Medical Centers, Tel Aviv 6971028, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1016\/S1470-2045(24)00374-7","article-title":"Pulmonary neuroendocrine neoplasms: The molecular landscape, therapeutic challenges, and diagnosis and management strategies","volume":"26","author":"Sen","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1158\/1078-0432.CCR-17-1921","article-title":"Molecular subtypes of pulmonary large-cell neuroendocrine carcinoma predict chemotherapy treatment outcome","volume":"24","author":"Derks","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1158\/1078-0432.CCR-15-2946","article-title":"Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets","volume":"22","author":"Rekhtman","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/s41467-018-03099-x","article-title":"Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors","volume":"9","author":"George","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1158\/1078-0432.CCR-19-0556","article-title":"The prognostic and therapeutic role of genomic subtyping by sequencing tumor or cell-free DNA in pulmonary large-cell neuroendocrine carcinoma","volume":"26","author":"Zhuo","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1158\/1078-0432.CCR-16-0355","article-title":"Genomic profiling of large-cell neuroendocrine carcinoma of the lung","volume":"23","author":"Miyoshi","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e116","DOI":"10.1093\/oncolo\/oyab044","article-title":"Comprehensive Characterization of the Genomic Landscape in Chinese Pulmonary Neuroendocrine Tumors Reveals Prognostic and Therapeutic Markers (CSWOG-1901)","volume":"27","author":"Peng","year":"2022","journal-title":"Oncologist"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7717","DOI":"10.1038\/s41467-025-63091-0","article-title":"Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma","volume":"16","author":"Nassar","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJMc053610","article-title":"EGFR mutations in small-cell lung cancers in patients who have never smoked","volume":"355","author":"Zakowski","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1111\/j.1349-7006.2007.00600.x","article-title":"Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung","volume":"98","author":"Fukui","year":"2007","journal-title":"Cancer Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6092","DOI":"10.1158\/1078-0432.CCR-08-0332","article-title":"Epidermal growth factor receptor mutations in small cell lung cancer","volume":"14","author":"Tatematsu","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2500293","DOI":"10.1200\/PO-25-00293","article-title":"Actionable genomic alterations in large cell neuroendocrine carcinoma: A European case series of patients treated with a small molecule inhibitor","volume":"9","author":"Heijboer","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e686","DOI":"10.1016\/j.cllc.2021.01.004","article-title":"ALK rearrangement in lung neuroendocrine neoplasms: A case series of non-Asian patients with response to ALK inhibitors","volume":"22","author":"Doubre","year":"2021","journal-title":"Clin. Lung Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"a006234","DOI":"10.1101\/mcs.a006234","article-title":"Lorlatinib and compound mutations in ALK-positive large-cell neuroendocrine lung carcinoma: A case report","volume":"8","author":"Wiedemann","year":"2022","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_15","first-page":"100538","article-title":"Successful treatment of ALK-positive large-cell neuroendocrine carcinoma of the lung with sequential ALK inhibitors: A case report","volume":"4","author":"Kobayashi","year":"2023","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tashiro, T., Imamura, K., Tomita, Y., Tamanoi, D., Takaki, A., Sugahara, K., Sato, R., Saruwatari, K., Sakata, S., and Inaba, M. (2020). Heterogeneous tumor-immune microenvironments between primary and metastatic tumors in a patient with ALK rearrangement-positive large cell neuroendocrine carcinoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249705"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e0817","DOI":"10.1002\/rcr2.817","article-title":"Dramatic response to alectinib in an ALK-positive LCNEC patient with a poor performance status: A case report","volume":"9","author":"Masuda","year":"2021","journal-title":"Respirol. Case Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1200\/PO.20.00348","article-title":"Metastatic large-cell neuroendocrine lung carcinoma with ALK fusion oncogene with partial response to alectinib","volume":"5","author":"Leblanc","year":"2021","journal-title":"JCO Precis. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jiang, L., Yao, X., Cai, X., and Li, P. (2025). Case report: Evolution and targeted therapy of an EGFR-mutant large-cell neuroendocrine carcinoma. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1599765"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Akhoundova, D., Haberecker, M., Fritsch, R., H\u00f6ller, S., Kiessling, M.K., Rechsteiner, M., R\u00fcschoff, J.H., and Curioni-Fontecedro, A. (2022). Targeting ALK in neuroendocrine tumors of the lung. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.911294"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4991","DOI":"10.2147\/OTT.S172124","article-title":"ALK-rearrangement neuroendocrine carcinoma of the lung: A comprehensive study of a rare disease","volume":"11","author":"Zheng","year":"2018","journal-title":"Onco Targets Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e819","DOI":"10.1200\/JCO.2011.36.2251","article-title":"Large-cell neuroendocrine carcinoma of the lung harboring EGFR mutation and responding to gefitinib","volume":"29","author":"Giovannini","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/2049-6958-8-47","article-title":"Large-cell neuroendocrine carcinoma of lung with epidermal growth factor receptor gene mutation and co-expression of adenocarcinoma markers: A case report and review of the literature","volume":"8","author":"Sakai","year":"2013","journal-title":"Multidiscip. Respir. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1159\/000365413","article-title":"Tyrosine kinase inhibitors in EGFR-mutated large-cell neuroendocrine carcinoma of the lung? A case report","volume":"7","author":"Aroldi","year":"2014","journal-title":"Case Rep. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.3892\/ol.2015.3405","article-title":"A marked response to icotinib in a patient with large cell neuroendocrine carcinoma harboring an EGFR mutation: A case report","volume":"10","author":"Wang","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108936","DOI":"10.18632\/oncotarget.22426","article-title":"Therapeutic strategies and genetic profile comparisons in small cell carcinoma and large cell neuroendocrine carcinoma of the lung using next-generation sequencing","volume":"8","author":"Ito","year":"2017","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"713","DOI":"10.2169\/internalmedicine.9368-17","article-title":"Large cell neuroendocrine carcinoma harboring an ALK rearrangement with response to alectinib","volume":"57","author":"Hayashi","year":"2018","journal-title":"Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e220","DOI":"10.1016\/j.jtho.2018.05.035","article-title":"Identification of EML4-ALK Rearrangement and MET Exon 14 R988C Mutation in a Patient with High-Grade Neuroendocrine Lung Carcinoma Who Experienced a Lazarus Response to Crizotinib","volume":"13","author":"Ricciuti","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/pcmedi\/pbz005","article-title":"A case of large cell neuroendocrine carcinoma harboring rare ALK fusion with initial response to the ALK inhibitor crizotinib and acquired F1174L mutation after resistance","volume":"2","author":"Wang","year":"2019","journal-title":"Precis. Clin. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1159\/000511112","article-title":"Successful treatment of combined large cell neuroendocrine carcinoma harboring an EGFR mutation with EGFR-TKIs plus bevacizumab: A case report","volume":"13","author":"Muto","year":"2020","journal-title":"Case Rep. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Arora, A., Zaemes, J., Ozdemirli, M., and Kim, C. (2023). Response to selpercatinib in a patient with RET fusion-positive pulmonary large-cell neuroendocrine carcinoma: A case report. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1134151"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chen, Q., Zhang, J., Wang, X., Zong, W., Sun, L., Qin, J., and Yin, Y. (2023). Two case reports: EML4-ALK rearrangement large cell neuroendocrine carcinoma and literature review. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1227980"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2400257","DOI":"10.1200\/PO.24.00257","article-title":"Disease Course and Treatment Outcomes in Patients with De Novo Small-Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 20 Insertion: Two Case Reports","volume":"8","author":"Zullo","year":"2024","journal-title":"JCO Precis. Oncol."},{"key":"ref_34","first-page":"102116","article-title":"First-line selpercatinib for a patient with RET fusion-positive pulmonary large cell neuroendocrine carcinoma","volume":"50","author":"Eihuku","year":"2024","journal-title":"Respir. Med. Case Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e306","DOI":"10.1016\/j.cllc.2025.02.012","article-title":"Small cell lung cancer with de novo BRAF V600E mutation and durable response to targeted therapy: A case report","volume":"26","author":"Kulkarni","year":"2025","journal-title":"Clin. Lung Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"413","DOI":"10.21873\/anticanres.13127","article-title":"Use of ALK immunohistochemistry for optimal therapeutic strategy of pulmonary large-cell neuroendocrine carcinoma and identification of a novel KIF5B-ALK fusion oncokinase","volume":"39","author":"Shimizu","year":"2019","journal-title":"Anticancer. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e40","DOI":"10.1097\/JTO.0000000000000103","article-title":"A case of large-cell neuroendocrine carcinoma harboring an EML4-ALK rearrangement with resistance to the ALK inhibitor crizotinib","volume":"9","author":"Omachi","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1093\/annonc\/mdj114","article-title":"EGFR mutation in gefitinib-responsive small-cell lung cancer","volume":"17","author":"Okamoto","year":"2006","journal-title":"Ann. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/JTO.0b013e3181f94abb","article-title":"Epidermal growth factor receptor mutations in small cell lung cancer: A brief report","volume":"6","author":"Shiao","year":"2011","journal-title":"J. Thorac. Oncol."},{"key":"ref_40","first-page":"100098","article-title":"Successful Treatment of EGFR-Mutant Synchronous SCLC and Lung Adenocarcinoma with Osimertinib","volume":"2","author":"Batra","year":"2021","journal-title":"JTO Clin. Res. Rep."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/4\/491\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:16:42Z","timestamp":1787127402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/4\/491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["medsci14040491"],"URL":"https:\/\/doi.org\/10.3390\/medsci14040491","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]}}}