{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T11:11:58Z","timestamp":1788606718436,"version":"build-2803163510"},"reference-count":18,"publisher":"Oxford University Press (OUP)","issue":"9","funder":[{"name":"Center for Cancer Research, the Intramural Program of the NCI","award":["ZIA BC 011793"],"award-info":[{"award-number":["ZIA BC 011793"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Histologic transformation of EGFR-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is an aggressive resistance mechanism associated with poor outcomes and limited treatment options. Preclinical and clinical data suggest a rationale for combining PARP inhibition with immune checkpoint blockade in this setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted an open-label, single-arm phase II study of durvalumab 1500\u2009mg intravenously every 28\u2009days plus olaparib 300\u2009mg orally twice daily in patients with EGFR-mutant NSCLC transformed to SCLC. The primary endpoint was objective response rate by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study was terminated early because of slow accrual.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All enrolled patients were evaluable for efficacy and safety. Best overall response was stable disease in 1 patient and progressive disease in 3 patients, resulting in an objective response rate of 0% and disease control rate of 25%. Median PFS was 1.75\u2009months and median OS was 9.33\u2009months. Concurrent TP53 and RB1 alterations were identified in most patients, and all retained activating EGFR mutations, predominantly exon 19 deletions. Although formal criteria for hyperprogression were not met, 1 patient developed rapid multi-organ progression involving bone, liver, lung, and lymph nodes. Treatment was generally well tolerated with predominantly grade 1-2 adverse events and no grade 3 or higher treatment-related toxicities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Olaparib plus durvalumab demonstrated limited clinical activity in EGFR-mutant NSCLC transformed to SCLC despite a strong biologic rationale. ClinicalTrials.gov identifier: NCT04538378.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag328","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:12:28Z","timestamp":1786705948000},"source":"Crossref","is-referenced-by-count":0,"title":["Phase II study of olaparib plus durvalumab in EGFR-mutant NSCLC transformed to small cell lung cancer"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5825-3356","authenticated-orcid":false,"given":"Chirayu","family":"Mohindroo","sequence":"first","affiliation":[{"name":"Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD,","place":["United States"]},{"name":"Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa , Iowa City, IA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Nichols","sequence":"additional","affiliation":[{"name":"Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research , Frederick, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Pinkiert","sequence":"additional","affiliation":[{"name":"Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3293-3115","authenticated-orcid":false,"given":"Anish","family":"Thomas","sequence":"additional","affiliation":[{"name":"Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD,","place":["United States"]},{"name":"Robert H. Lurie Comprehensive Cancer Center and Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"2026090506265492500_oyag328-B1","doi-asserted-by":"publisher","first-page":"105326","DOI":"10.1016\/j.esmoop.2025.105326","article-title":"Correlation between treatments and outcomes of patients with EGFR-mutated non-small-cell lung cancer that transitioned into small-cell lung cancer: an international retrospective study","volume":"10","author":"Catania","year":"2025","journal-title":"ESMO Open"},{"key":"2026090506265492500_oyag328-B2","doi-asserted-by":"publisher","first-page":"5448","DOI":"10.1200\/jco.23.01435","article-title":"Systemic therapy for small-cell lung cancer: ASCO-Ontario Health (Cancer Care Ontario) guideline","volume":"41","author":"Khurshid","year":"2023","journal-title":"J Clin Oncol"},{"key":"2026090506265492500_oyag328-B3","doi-asserted-by":"publisher","first-page":"e20569","DOI":"10.1200\/JCO.2024.42.16_suppl.e20569","article-title":"Characteristics, treatment patterns, and prognostic factors in small cell lung cancer transformation of advanced non-small cell lung cancer with epidermal growth factor receptor mutation after tyrosine kinase inhibitor therapy","volume":"42","author":"Liao","year":"2024","journal-title":"J Clin Oncol"},{"key":"2026090506265492500_oyag328-B4","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1200\/jco.18.01585","article-title":"EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes","volume":"37","author":"Marcoux","year":"2019","journal-title":"J Clin Oncol"},{"key":"2026090506265492500_oyag328-B5","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/s43018-025-00996-1","article-title":"Advancing therapeutics in small-cell lung cancer","volume":"6","author":"Thomas","year":"2025","journal-title":"Nat Cancer"},{"key":"2026090506265492500_oyag328-B6","doi-asserted-by":"publisher","first-page":"109501","DOI":"10.1016\/j.lungcan.2026.109501","article-title":"Durvalumab plus etoposide\u2013platinum in patients with epidermal growth factor receptor (EGFR)-mutated advanced NSCLC and neuroendocrine transformation after first-line osimertinib: ORCHARD","volume":"218","author":"Okamoto","year":"2026","journal-title":"Lung Cancer"},{"key":"2026090506265492500_oyag328-B7","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.jtho.2019.04.026","article-title":"Durvalumab in combination with olaparib in patients with relapsed SCLC: results from a phase II study","volume":"14","author":"Thomas","year":"2019","journal-title":"J Thorac Oncol"},{"key":"2026090506265492500_oyag328-B8","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.lungcan.2022.11.016","article-title":"A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival","volume":"175","author":"Zhang","year":"2023","journal-title":"Lung Cancer"},{"key":"2026090506265492500_oyag328-B9","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.jtho.2024.10.021","article-title":"Phase II randomized study of maintenance atezolizumab versus atezolizumab plus talazoparib in patients with SLFN11 positive extensive-stage SCLC: S1929","volume":"20","author":"Karim","year":"2025","journal-title":"J Thorac Oncol"},{"key":"2026090506265492500_oyag328-B10","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.1158\/1078-0432.Ccr-19-3841","article-title":"Targeting DNA repair to drive immune responses: it\u2019s time to reconsider the strategy for clinical translation","volume":"26","author":"Takahashi","year":"2020","journal-title":"Clin Cancer Res"},{"key":"2026090506265492500_oyag328-B11","doi-asserted-by":"crossref","first-page":"eadj1415","DOI":"10.1126\/science.adj1415","article-title":"Lineage-specific intolerance to oncogenic drivers restricts histological transformation","volume":"383","author":"Gardner","year":"2024","journal-title":"Science"},{"key":"2026090506265492500_oyag328-B12","doi-asserted-by":"publisher","first-page":"8565","DOI":"10.1200\/JCO.2024.42.16_suppl.8565","article-title":"Osimertinib, platinum, etoposide as initial treatment for patients with EGFR mutant lung cancers with TP53 and RB1 alterations","volume":"42","author":"Chen","year":"2024","journal-title":"J Clin Oncol"},{"key":"2026090506265492500_oyag328-B13","doi-asserted-by":"publisher","first-page":"e2500538","DOI":"10.1200\/po-25-00538","article-title":"Multi-institution analysis of tarlatamab for the treatment of EGFR-mutant transformed small cell lung cancer","volume":"9","author":"Cooper","year":"2025","journal-title":"JCO Precis Oncol"},{"key":"2026090506265492500_oyag328-B14","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1158\/1078-0432.CCR-23-0536","article-title":"Targeting replication stress and chemotherapy resistance with a combination of sacituzumab govitecan and berzosertib: a phase I clinical trial","volume":"29","author":"Abel","year":"2023","journal-title":"Clin Cancer Res"},{"key":"2026090506265492500_oyag328-B15","doi-asserted-by":"publisher","first-page":"100807","DOI":"10.1016\/j.jtocrr.2025.100807","article-title":"Combination of lurbinectedin and osimertinib for treatment of EGFR-mutated transformed SCLC: a brief report","volume":"6","author":"Singh","year":"2025","journal-title":"JTO Clin Res Rep"},{"key":"2026090506265492500_oyag328-B16","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.197008","article-title":"EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy","volume":"11","author":"Ogino","year":"2026","journal-title":"JCI Insight"},{"key":"2026090506265492500_oyag328-B17","author":"NCCN"},{"key":"2026090506265492500_oyag328-B18","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1158\/2159-8290.CD-25-1454","article-title":"Blockade of tumor-intrinsic tgf-\u0392 signaling drives hyperprogression in small cell lung cancer","volume":"16","author":"Schroeder","year":"2026","journal-title":"Cancer Discov"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/oncolo\/advance-article-pdf\/doi\/10.1093\/oncolo\/oyag328\/70657436\/oyag328.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/31\/9\/oyag328\/70657436\/oyag328.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/31\/9\/oyag328\/70657436\/oyag328.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T10:26:59Z","timestamp":1788604019000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/doi\/10.1093\/oncolo\/oyag328\/8762013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":18,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,8,6]]}},"URL":"https:\/\/doi.org\/10.1093\/oncolo\/oyag328","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,8,6]]},"article-number":"oyag328"}}