Glenn J Hanna,Nicole Scarfo,Kee-Young Shin,Anne O'Neill,Veronica Bedard,Michael J Dennis,Kartik Sehgal,Vickie Y Jo,Kristine Wong,Andrey Ugolkov,Andrew Mazar,Robert I Haddad
{"title":"Elraglusib是一种糖原合成酶激酶3β (GSK-3β)抑制剂,在复发性转移性唾液腺癌患者中联合化疗(或不联合免疫治疗)。","authors":"Glenn J Hanna,Nicole Scarfo,Kee-Young Shin,Anne O'Neill,Veronica Bedard,Michael J Dennis,Kartik Sehgal,Vickie Y Jo,Kristine Wong,Andrey Ugolkov,Andrew Mazar,Robert I Haddad","doi":"10.1158/1078-0432.ccr-25-2731","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nGSK-3b is a known therapeutic target in cancer. Aberrant nuclear GSK-3β (nGSK-3β) expression has been shown in some salivary gland cancers (SGC). Elraglusib is a small molecule GSK-3β inhibitor with immunomodulatory potential. We hypothesized that elraglusib plus platinum-based chemotherapy and immunotherapy priming would be a novel treatment approach for SGC.\r\n\r\nDESIGN\r\nThis phase 2, open-label trial enrolled patients with recurrent or metastatic SGC (adenoid cystic carcinoma [ACC] vs. other subtypes) with disease progression in the preceding year. Cohort 1 received elraglusib (15 mg/kg IV on days 1, 4) plus carboplatin (AUC 5) or cisplatin (75 mg/m2) every 21-days. Cohort 2 received 2-cycles of pembrolizumab (200 mg IV) every 21-days prior to the same regimen.\r\n\r\nPRIMARY ENDPOINT\r\nbest overall response rate (ORR) by RECIST 1.1 (>5/32 in response to detect 25% ORR).\r\n\r\nRESULTS\r\nThirty-two patients enrolled, 15 (47%) with ACC and 17 (53%) with non-ACC. Best ORR was 9.4% (3/32; 95%CI, 2-25) (3 partial responses, all non-ACC). Nineteen (59%) patients achieved stable disease. Median duration of response: 6.9 months. Common treatment-related adverse events: anemia (22, 69%), nausea (16, 50%), and neutropenia (14, 44%). At median follow-up of 18.3 months, median PFS: 6.4 months (95%CI, 2.3-8.8) and median OS: 18.6 months (95%CI, 9.7-29.4) overall. Median nGSK-3β expression was 50% vs. 2% for responders vs. non-responders.\r\n\r\nCONCLUSION(S)\r\nThe trial did not meet its primary endpoint, though 18% of non-ACC patients treated with immune priming followed by cisplatin plus elraglusib achieved response. Higher nGSK-3β expression was observed in tumor samples from responders.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"60 1","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Elraglusib, a glycogen synthase kinase-3β (GSK-3β) inhibitor, plus chemotherapy with or without immunotherapy in patients with recurrent, metastatic salivary gland carcinoma.\",\"authors\":\"Glenn J Hanna,Nicole Scarfo,Kee-Young Shin,Anne O'Neill,Veronica Bedard,Michael J Dennis,Kartik Sehgal,Vickie Y Jo,Kristine Wong,Andrey Ugolkov,Andrew Mazar,Robert I Haddad\",\"doi\":\"10.1158/1078-0432.ccr-25-2731\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND\\r\\nGSK-3b is a known therapeutic target in cancer. Aberrant nuclear GSK-3β (nGSK-3β) expression has been shown in some salivary gland cancers (SGC). Elraglusib is a small molecule GSK-3β inhibitor with immunomodulatory potential. We hypothesized that elraglusib plus platinum-based chemotherapy and immunotherapy priming would be a novel treatment approach for SGC.\\r\\n\\r\\nDESIGN\\r\\nThis phase 2, open-label trial enrolled patients with recurrent or metastatic SGC (adenoid cystic carcinoma [ACC] vs. other subtypes) with disease progression in the preceding year. Cohort 1 received elraglusib (15 mg/kg IV on days 1, 4) plus carboplatin (AUC 5) or cisplatin (75 mg/m2) every 21-days. Cohort 2 received 2-cycles of pembrolizumab (200 mg IV) every 21-days prior to the same regimen.\\r\\n\\r\\nPRIMARY ENDPOINT\\r\\nbest overall response rate (ORR) by RECIST 1.1 (>5/32 in response to detect 25% ORR).\\r\\n\\r\\nRESULTS\\r\\nThirty-two patients enrolled, 15 (47%) with ACC and 17 (53%) with non-ACC. Best ORR was 9.4% (3/32; 95%CI, 2-25) (3 partial responses, all non-ACC). Nineteen (59%) patients achieved stable disease. Median duration of response: 6.9 months. Common treatment-related adverse events: anemia (22, 69%), nausea (16, 50%), and neutropenia (14, 44%). At median follow-up of 18.3 months, median PFS: 6.4 months (95%CI, 2.3-8.8) and median OS: 18.6 months (95%CI, 9.7-29.4) overall. Median nGSK-3β expression was 50% vs. 2% for responders vs. non-responders.\\r\\n\\r\\nCONCLUSION(S)\\r\\nThe trial did not meet its primary endpoint, though 18% of non-ACC patients treated with immune priming followed by cisplatin plus elraglusib achieved response. Higher nGSK-3β expression was observed in tumor samples from responders.\",\"PeriodicalId\":10279,\"journal\":{\"name\":\"Clinical Cancer Research\",\"volume\":\"60 1\",\"pages\":\"\"},\"PeriodicalIF\":10.2000,\"publicationDate\":\"2025-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1078-0432.ccr-25-2731\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.ccr-25-2731","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Elraglusib, a glycogen synthase kinase-3β (GSK-3β) inhibitor, plus chemotherapy with or without immunotherapy in patients with recurrent, metastatic salivary gland carcinoma.
BACKGROUND
GSK-3b is a known therapeutic target in cancer. Aberrant nuclear GSK-3β (nGSK-3β) expression has been shown in some salivary gland cancers (SGC). Elraglusib is a small molecule GSK-3β inhibitor with immunomodulatory potential. We hypothesized that elraglusib plus platinum-based chemotherapy and immunotherapy priming would be a novel treatment approach for SGC.
DESIGN
This phase 2, open-label trial enrolled patients with recurrent or metastatic SGC (adenoid cystic carcinoma [ACC] vs. other subtypes) with disease progression in the preceding year. Cohort 1 received elraglusib (15 mg/kg IV on days 1, 4) plus carboplatin (AUC 5) or cisplatin (75 mg/m2) every 21-days. Cohort 2 received 2-cycles of pembrolizumab (200 mg IV) every 21-days prior to the same regimen.
PRIMARY ENDPOINT
best overall response rate (ORR) by RECIST 1.1 (>5/32 in response to detect 25% ORR).
RESULTS
Thirty-two patients enrolled, 15 (47%) with ACC and 17 (53%) with non-ACC. Best ORR was 9.4% (3/32; 95%CI, 2-25) (3 partial responses, all non-ACC). Nineteen (59%) patients achieved stable disease. Median duration of response: 6.9 months. Common treatment-related adverse events: anemia (22, 69%), nausea (16, 50%), and neutropenia (14, 44%). At median follow-up of 18.3 months, median PFS: 6.4 months (95%CI, 2.3-8.8) and median OS: 18.6 months (95%CI, 9.7-29.4) overall. Median nGSK-3β expression was 50% vs. 2% for responders vs. non-responders.
CONCLUSION(S)
The trial did not meet its primary endpoint, though 18% of non-ACC patients treated with immune priming followed by cisplatin plus elraglusib achieved response. Higher nGSK-3β expression was observed in tumor samples from responders.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.