A Arance, M-A Berciano-Guerrero, J Guo, M S Carlino, P A Ascierto, M Burotto, L Mortier, P Queirolo, V Chiarion-Sileni, J Schachter, X Zhang, J Martin-Liberal, M Del Vecchio, C E Okpara, C Dutcus, J Zhang, S J Diede, T Neff, G V Long
{"title":"随机、双盲、III期leap003研究：一线Lenvatinib + Pembrolizumab与安慰剂+ Pembrolizumab治疗不可切除或转移性黑色素瘤","authors":"A Arance, M-A Berciano-Guerrero, J Guo, M S Carlino, P A Ascierto, M Burotto, L Mortier, P Queirolo, V Chiarion-Sileni, J Schachter, X Zhang, J Martin-Liberal, M Del Vecchio, C E Okpara, C Dutcus, J Zhang, S J Diede, T Neff, G V Long","doi":"10.1016/j.annonc.2025.08.008","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti-PD-(L)1 therapy in LEAP-004. Here, we report results from LEAP-003 (NCT03820986) which evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in unresectable advanced melanoma.</p><p><strong>Participants and methods: </strong>Participants with unresectable stage III or IV melanoma, previously untreated with PD-1 or PD-L1 checkpoint inhibitors, were randomly assigned 1:1 to pembrolizumab 200 mg intravenously every 3 weeks plus either lenvatinib 20 mg or placebo orally once daily. Dual primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review and overall survival (OS). PFS was formally tested at the first interim analysis; OS at the final analysis. An external data monitoring committee regularly reviewed safety and efficacy. Three interim analyses and a final analysis were planned.</p><p><strong>Results: </strong>Overall, 674 participants were assigned to lenvatinib plus pembrolizumab (n = 334) or placebo plus pembrolizumab (n = 340). Median PFS at first interim analysis was 8.4 months for lenvatinib plus pembrolizumab versus 4.0 months for placebo plus pembrolizumab (HR, 0.72; 95% CI, 0.59-0.88; P = 0.0008). This benefit was not maintained at final analysis (HR, 0.83; 95% CI, 0.69-1.00). Median OS at final analysis was 25.8 months for lenvatinib plus pembrolizumab versus 39.5 months for placebo plus pembrolizumab (HR, 1.20; 95% CI, 0.97-1.48; P = 0.9521). Grade 3-5 treatment-related adverse events occurred in 58.7% of participants receiving lenvatinib plus pembrolizumab versus 29.0% receiving placebo plus pembrolizumab.</p><p><strong>Conclusion: </strong>Lenvatinib plus pembrolizumab did not provide additional benefit versus placebo plus pembrolizumab in participants with unresectable advanced melanoma. Thus, the trial was terminated early, and the third interim analysis became the final analysis. Immunotherapy remains the standard of care for advanced melanoma.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":65.4000,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Randomized, Double-Blind, Phase III LEAP-003 Study of First-Line Lenvatinib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab for Unresectable or Metastatic Melanoma.\",\"authors\":\"A Arance, M-A Berciano-Guerrero, J Guo, M S Carlino, P A Ascierto, M Burotto, L Mortier, P Queirolo, V Chiarion-Sileni, J Schachter, X Zhang, J Martin-Liberal, M Del Vecchio, C E Okpara, C Dutcus, J Zhang, S J Diede, T Neff, G V Long\",\"doi\":\"10.1016/j.annonc.2025.08.008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti-PD-(L)1 therapy in LEAP-004. Here, we report results from LEAP-003 (NCT03820986) which evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in unresectable advanced melanoma.</p><p><strong>Participants and methods: </strong>Participants with unresectable stage III or IV melanoma, previously untreated with PD-1 or PD-L1 checkpoint inhibitors, were randomly assigned 1:1 to pembrolizumab 200 mg intravenously every 3 weeks plus either lenvatinib 20 mg or placebo orally once daily. Dual primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review and overall survival (OS). PFS was formally tested at the first interim analysis; OS at the final analysis. An external data monitoring committee regularly reviewed safety and efficacy. Three interim analyses and a final analysis were planned.</p><p><strong>Results: </strong>Overall, 674 participants were assigned to lenvatinib plus pembrolizumab (n = 334) or placebo plus pembrolizumab (n = 340). Median PFS at first interim analysis was 8.4 months for lenvatinib plus pembrolizumab versus 4.0 months for placebo plus pembrolizumab (HR, 0.72; 95% CI, 0.59-0.88; P = 0.0008). This benefit was not maintained at final analysis (HR, 0.83; 95% CI, 0.69-1.00). Median OS at final analysis was 25.8 months for lenvatinib plus pembrolizumab versus 39.5 months for placebo plus pembrolizumab (HR, 1.20; 95% CI, 0.97-1.48; P = 0.9521). Grade 3-5 treatment-related adverse events occurred in 58.7% of participants receiving lenvatinib plus pembrolizumab versus 29.0% receiving placebo plus pembrolizumab.</p><p><strong>Conclusion: </strong>Lenvatinib plus pembrolizumab did not provide additional benefit versus placebo plus pembrolizumab in participants with unresectable advanced melanoma. Thus, the trial was terminated early, and the third interim analysis became the final analysis. Immunotherapy remains the standard of care for advanced melanoma.</p>\",\"PeriodicalId\":8000,\"journal\":{\"name\":\"Annals of Oncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":65.4000,\"publicationDate\":\"2025-08-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.annonc.2025.08.008\",\"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":"Annals of Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.annonc.2025.08.008","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Randomized, Double-Blind, Phase III LEAP-003 Study of First-Line Lenvatinib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab for Unresectable or Metastatic Melanoma.
Background: Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti-PD-(L)1 therapy in LEAP-004. Here, we report results from LEAP-003 (NCT03820986) which evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in unresectable advanced melanoma.
Participants and methods: Participants with unresectable stage III or IV melanoma, previously untreated with PD-1 or PD-L1 checkpoint inhibitors, were randomly assigned 1:1 to pembrolizumab 200 mg intravenously every 3 weeks plus either lenvatinib 20 mg or placebo orally once daily. Dual primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review and overall survival (OS). PFS was formally tested at the first interim analysis; OS at the final analysis. An external data monitoring committee regularly reviewed safety and efficacy. Three interim analyses and a final analysis were planned.
Results: Overall, 674 participants were assigned to lenvatinib plus pembrolizumab (n = 334) or placebo plus pembrolizumab (n = 340). Median PFS at first interim analysis was 8.4 months for lenvatinib plus pembrolizumab versus 4.0 months for placebo plus pembrolizumab (HR, 0.72; 95% CI, 0.59-0.88; P = 0.0008). This benefit was not maintained at final analysis (HR, 0.83; 95% CI, 0.69-1.00). Median OS at final analysis was 25.8 months for lenvatinib plus pembrolizumab versus 39.5 months for placebo plus pembrolizumab (HR, 1.20; 95% CI, 0.97-1.48; P = 0.9521). Grade 3-5 treatment-related adverse events occurred in 58.7% of participants receiving lenvatinib plus pembrolizumab versus 29.0% receiving placebo plus pembrolizumab.
Conclusion: Lenvatinib plus pembrolizumab did not provide additional benefit versus placebo plus pembrolizumab in participants with unresectable advanced melanoma. Thus, the trial was terminated early, and the third interim analysis became the final analysis. Immunotherapy remains the standard of care for advanced melanoma.
期刊介绍：
Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine.
The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings.
Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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