{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:36:25Z","timestamp":1791336985196,"version":"4.3.1"},"reference-count":21,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Well-differentiated grade 3 neuroendocrine tumors (NETs) have recently been described as a distinct category, and randomized data regarding efficacy of therapy for these patients are scarce. In the phase 3 CABINET trial, cabozantinib improved PFS compared with placebo in patients with advanced, previously treated, progressive extra-pancreatic NETs (epNETs) and pancreatic NETs (pNETs) of all grades. Here, we evaluate if these results remain consistent in a subgroup of patients with well-differentiated G3 NETs. Patients with locally advanced or metastatic epNETs or pNETs were randomized 2:1 in independent cohorts to receive cabozantinib 60 mg daily vs placebo. We analyzed outcomes of the subset of patients with G3 NETs (Ki-67 &amp;gt; 20%), combining patients in the pNET and epNET cohorts due to small sample sizes. Twenty-four patients had G3 NETs, 16 randomized to cabozantinib and 8 to placebo. Primary sites included pancreas (n = 12), GI tract (n = 7), unknown primary sites (n = 3), and lung\/thymus (n = 2). Median PFS for patients with G3 NETs treated with cabozantinib was 7.9 vs 3 months with placebo (HR = 0.15, 95% CI: 0.04\u20130.57, 1-sided log-rank P = 0.0034). The confirmed overall radiographic response rate was 25% (4\/16) with cabozantinib vs 0% (0\/8) with placebo. Safety outcomes were consistent with published data for the trial as a whole. Subset analysis of the CABINET trial showed improved PFS associated with cabozantinib vs placebo for G3 NETs of pancreatic and extra-pancreatic origin. Despite limited numbers, these results suggest that cabozantinib can be an effective option for patients with advanced G3 NETs.<\/jats:p>\n                    <jats:p>ClinicalTrials.gov Identifier: NCT03375320.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/erc-25-0415","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T14:47:53Z","timestamp":1768229273000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":4,"title":["Cabozantinib for advanced grade 3 neuroendocrine tumors: subgroup analysis of the phase 3 CABINET trial (Alliance A021602)"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8405-218X","authenticated-orcid":true,"given":"Jonathan R","family":"Strosberg","sequence":"first","affiliation":[{"name":"1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Zemla","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Geyer","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Pulsipher","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Shu","family":"Ou","sequence":"additional","affiliation":[{"name":"2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer","family":"Behr","sequence":"additional","affiliation":[{"name":"3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1385-9995","authenticated-orcid":true,"given":"Nitya","family":"Raj","sequence":"additional","affiliation":[{"name":"4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namrata","family":"Vijayvergia","sequence":"additional","affiliation":[{"name":"5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5271-9744","authenticated-orcid":true,"given":"Arvind","family":"Dasari","sequence":"additional","affiliation":[{"name":"6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen M","family":"O\u2019Reilly","sequence":"additional","affiliation":[{"name":"4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A","family":"Meyerhardt","sequence":"additional","affiliation":[{"name":"7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M","family":"Wolin","sequence":"additional","affiliation":[{"name":"8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorvardur R","family":"Halfdanarson","sequence":"additional","affiliation":[{"name":"9"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A","family":"Chan","sequence":"additional","affiliation":[{"name":"7"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"2026070909440866200_bib1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO classification of neuroendocrine neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr Pathol"},{"key":"2026070909440866200_bib2","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/s41416-025-03054-w","article-title":"Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study","volume":"133","author":"Sorbye","year":"2025","journal-title":"Br J Cancer"},{"key":"2026070909440866200_bib3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.thorsurg.2014.04.001","article-title":"Pathology and diagnosis of neuroendocrine tumors: lung neuroendocrine","volume":"24","author":"Travis","year":"2014","journal-title":"Thorac Surg Clin"},{"key":"2026070909440866200_bib4","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s41379-019-0248-2","article-title":"Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices","volume":"32","author":"Rekhtman","year":"2019","journal-title":"Mod Pathol"},{"key":"2026070909440866200_bib5","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1056\/NEJMoa1316158","article-title":"Lanreotide in metastatic enteropancreatic neuroendocrine tumors","volume":"371","author":"Caplin","year":"2014","journal-title":"N Engl J Med"},{"key":"2026070909440866200_bib6","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/onco.13633","article-title":"Somatostatin analogs for pancreatic neuroendocrine tumors: any benefit when Ki-67 is \u226510%?","volume":"26","author":"Merola","year":"2021","journal-title":"Oncologist"},{"key":"2026070909440866200_bib7","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1007\/s00432-018-2636-2","article-title":"Sunitinib shrinks NET-G3 pancreatic neuroendocrine neoplasms","volume":"144","author":"Mizuno","year":"2018","journal-title":"J Cancer Res Clin Oncol"},{"key":"2026070909440866200_bib8","doi-asserted-by":"crossref","DOI":"10.1016\/j.annonc.2023.09.717","article-title":"Safety and efficacy of everolimus (EVE) as second-line treamtent in neuroendocrine neoplasms G3 (NEN G3): an AIO phase II study (EVINEC)","volume":"34","author":"Pavel","year":"2023","journal-title":"Ann Oncol"},{"key":"2026070909440866200_bib9","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.3390\/cancers13081936","article-title":"Multicenter analysis of treatment outcomes for systemic therapy in well differentiated grade 3 neuroendocrine tumors (NET G3)","volume":"13","author":"Apostolidis","year":"2021","journal-title":"Cancers"},{"key":"2026070909440866200_bib10","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1530\/ERC-21-0109","article-title":"Treatment outcomes of advanced digestive well-differentiated grade 3 NETs","volume":"28","author":"de Mestier","year":"2021","journal-title":"Endocr Relat Cancer"},{"key":"2026070909440866200_bib11","doi-asserted-by":"crossref","first-page":"29","DOI":"10.6004\/jnccn.2021.7017","article-title":"Efficacy and toxicity analysis of capecitabine and temozolomide in neuroendocrine neoplasms","volume":"20","author":"Al-Toubah","year":"2021","journal-title":"J Natl Compr Canc Netw"},{"key":"2026070909440866200_bib12","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1002\/onco.13923","article-title":"Temozolomide in grade 3 gastroenteropancreatic neuroendocrine neoplasms: a multicenter retrospective review","volume":"26","author":"Chan","year":"2021","journal-title":"Oncologist"},{"key":"2026070909440866200_bib13","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1097\/MPA.0000000000000659","article-title":"Oxaliplatin-fluoropyrimidine chemotherapy plus bevacizumab in advanced neuroendocrine tumors: an analysis of 2 phase II trials","volume":"45","author":"Kunz","year":"2016","journal-title":"Pancreas"},{"key":"2026070909440866200_bib14","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/onco.13611","article-title":"Efficacy of FOLFOX in patients with aggressive pancreatic neuroendocrine tumors after prior capecitabine\/temozolomide","volume":"26","author":"Al-Toubah","year":"2021","journal-title":"Oncologist"},{"key":"2026070909440866200_bib15","doi-asserted-by":"crossref","first-page":"R67","DOI":"10.1530\/ERC-19-0400","article-title":"PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3)","volume":"27","author":"Sorbye","year":"2020","journal-title":"Endocr Relat Cancer"},{"key":"2026070909440866200_bib16","doi-asserted-by":"crossref","DOI":"10.1111\/jne.13443","article-title":"PRRT in high-grade digestive neuroendocrine neoplasms (NET G3 and NEC)","volume":"37","author":"Sorbye","year":"2025","journal-title":"J Neuroendocrinol"},{"key":"2026070909440866200_bib17","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1016\/S0140-6736(24)00701-3","article-title":"[(177)Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study","volume":"403","author":"Singh","year":"2024","journal-title":"Lancet"},{"key":"2026070909440866200_bib18","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1056\/NEJMoa2403991","article-title":"Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors","volume":"392","author":"Chan","year":"2025","journal-title":"N Engl J Med"},{"key":"2026070909440866200_bib19","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur J Cancer"},{"key":"2026070909440866200_bib20","volume-title":"Common terminology criteria for adverse events (CTCAE) v 5.0, 2017","author":"National Institutes of Health, National Cancer Institute","year":"2017"},{"key":"2026070909440866200_bib21","article-title":"Peptide receptor radionuclide therapy in G3 gastroenteropancreatic neuroendocrine tumors: a missed opportunity for European patients?","volume":"55","author":"Panzuto","year":"2025","journal-title":"Lancet Reg Health Eur"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/33\/1\/ERC-25-0415.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/33\/1\/ERC-25-0415.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0415\/506016\/erc-25-0415.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0415\/506016\/erc-25-0415.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:44:15Z","timestamp":1783604655000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/33\/1\/e250415\/75508\/Cabozantinib-for-advanced-grade-3-neuroendocrine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,1]]},"references-count":21,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-25-0415","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2026,1,1]]},"article-number":"e250415"}}