{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T12:11:45Z","timestamp":1778933505624,"version":"3.51.4"},"reference-count":54,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Adult ovarian granulosa cell tumours (GCT) are the most common subtype of ovarian sex cord\u2010stromal tumours. Forkhead transcription factor\n                      <jats:italic>FOXL2<\/jats:italic>\n                      is required for development and function of normal granulosa cells, including proliferation and ovarian hormone synthesis. A single somatic missense mutation in\n                      <jats:italic>FOXL2<\/jats:italic>\n                      , c.402C\u00a0&gt;\u00a0G (p.Cys134Trp), has previously been identified in the majority of GCT and is a pathognomonic marker for this tumour type. NOTCH activation contributes to GCT survival in preclinical models, and\n                      <jats:italic>NOTCH2<\/jats:italic>\n                      and\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      are critical for embryonic development of the ovary and function of the ovarian follicle. Nirogacestat is a potent, selective, noncompetitive inhibitor of gamma secretase, which inhibits NOTCH pathway signalling. Treatment of GCT with nirogacestat was predicted to inhibit granulosa cell survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A Phase II clinical trial was conducted to assess antitumour activity of nirogacestat in adult patients with relapsed\/refractory ovarian GCT (NCT05348356). This study enrolled 53 patients; all were evaluable for efficacy and safety. Endpoints included objective response rate by Response Evaluation Criteria in Solid Tumors v1.1 and 6\u2010month progression\u2010free survival (PFS6). Fresh or archival tumour samples were analysed for mutational profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients received a median of 5 prior lines of therapy (range, 1\u201313) and a median of 3.7 months of treatment (range, 0\u201320 months). A decrease in tumour burden was seen in 16 (30%) patients; however, there were no confirmed objective responses. Thirty\u2010one (58%) patients had stable disease; 18 (34%) had progressive disease. Eleven (21%) patients achieved PFS6. No correlations with disease stability were found with baseline clinical characteristics. All 3 patients who had an activating\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      mutation achieved PFS6.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In patients with heavily pretreated GCT, nirogacestat treatment resulted in durable disease stabilisation of at least 7\u00a0weeks for 58% of patients, with 21% achieving PFS6, including the 3 patients whose tumours had an activating\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      mutation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>This Phase II clinical trial of a rare tumour achieved its enrolment target in under 1 year and completed primary analysis within 2 years.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>87% (46 of 53 patients who received nirogacestat) had fresh or archival biopsies that were analysed by next\u2010generation sequencing for mutational profiling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Of the 3 patients with activating\n                            <jats:italic>NOTCH1<\/jats:italic>\n                            mutations, all achieved 6\u2010month progression\u2010free survival (PFS6); 8 other patients also achieved PFS6 but did not share a common mutation.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70568","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T09:35:12Z","timestamp":1768037712000},"source":"Crossref","is-referenced-by-count":0,"title":["Phase II clinical trial of nirogacestat in patients with relapsed ovarian granulosa cell tumours"],"prefix":"10.1002","volume":"16","author":[{"given":"Rachel N.","family":"Grisham","sequence":"first","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Hopp","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Froedtert Hospital and the Medical College of Wisconsin Milwaukee Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Pennington","sequence":"additional","affiliation":[{"name":"Division of Gynecologic Oncology University of Washington Medical Center  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Holloway","sequence":"additional","affiliation":[{"name":"Gynecologic Oncology Program AdventHealth Medical Group GYN Oncology at Orlando  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert M.","family":"Wenham","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology H. 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