Jean-Yves Blay, Quentin Devin, Florence Duffaud, Maud Toulmonde, Nelly Firmin, Olivier Collard, Emmanuelle Bompas, Benjamin Verret, Isabelle Ray-Coquard, Sebastien Salas, Clemence Henon, Charles Honoré, Mehdi Brahmi, Armelle Dufresne, Marc Pracht, Alice Hervieu, Nicolas Penel, Francois Bertucci, Maria Rios, Esma Saada-Bouzid, Pauline Soibinet, David Perol, Sylvie Chabaud, Antoine Italiano, Axel Le Cesne
{"title":"晚期胃肠道间质瘤患者停用与继续使用伊马替尼（BFR14）：一项开放标签、多中心、随机、3期试验的探索性长期随访。","authors":"Jean-Yves Blay, Quentin Devin, Florence Duffaud, Maud Toulmonde, Nelly Firmin, Olivier Collard, Emmanuelle Bompas, Benjamin Verret, Isabelle Ray-Coquard, Sebastien Salas, Clemence Henon, Charles Honoré, Mehdi Brahmi, Armelle Dufresne, Marc Pracht, Alice Hervieu, Nicolas Penel, Francois Bertucci, Maria Rios, Esma Saada-Bouzid, Pauline Soibinet, David Perol, Sylvie Chabaud, Antoine Italiano, Axel Le Cesne","doi":"10.1016/S1470-2045(24)00318-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial.</p><p><strong>Methods: </strong>BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861.</p><p><strong>Findings: </strong>Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib.</p><p><strong>Funding: </strong>Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.</p>","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"1163-1175"},"PeriodicalIF":41.6000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.\",\"authors\":\"Jean-Yves Blay, Quentin Devin, Florence Duffaud, Maud Toulmonde, Nelly Firmin, Olivier Collard, Emmanuelle Bompas, Benjamin Verret, Isabelle Ray-Coquard, Sebastien Salas, Clemence Henon, Charles Honoré, Mehdi Brahmi, Armelle Dufresne, Marc Pracht, Alice Hervieu, Nicolas Penel, Francois Bertucci, Maria Rios, Esma Saada-Bouzid, Pauline Soibinet, David Perol, Sylvie Chabaud, Antoine Italiano, Axel Le Cesne\",\"doi\":\"10.1016/S1470-2045(24)00318-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. 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引用次数: 0
摘要
背景：酪氨酸激酶抑制剂（TKI）停药对晚期胃肠道间质瘤（GIST）患者耐药性和生存期的长期影响尚不明确。我们报告了在BFR14试验中停用伊马替尼的晚期GIST患者的探索性长期疗效：BFR14是一项开放标签、随机3期试验，在法国17家综合癌症中心或医院进行。年龄在18岁或18岁以上的晚期GIST患者符合条件：东部合作肿瘤学组（Eastern Cooperative Oncology Group）表现为0-3级，既往未接受过伊马替尼治疗，既往未患恶性肿瘤。患者每天口服伊马替尼 400 毫克。根据《实体瘤反应评估标准》（1.0），在治疗开始后1年、3年和5年时获得完全或部分反应或病情稳定的患者将被随机分配（1:1）至中断治疗直至病情进展（中断组）或继续治疗直至病情进展（继续组）。随机分配由计算机集中生成，按参与中心和CT扫描有无残留疾病对2至6名患者进行分层。主要终点是无进展生存期。次要终点包括伊马替尼耐药时间和总生存期。在意向治疗的基础上，对所有未失去随访机会的随机分配患者进行了分析。该试验已在ClinicalTrial.gov网站注册，编号为NCT00367861：2003年5月12日至2004年3月16日，伊马替尼治疗一年后，32名患者被随机分配到中断治疗组，26名患者被随机分配到继续治疗组。2005年6月13日至2007年5月30日，伊马替尼治疗3年后，25名患者被随机分配到中断治疗组，25名患者被随机分配到继续治疗组。2007年11月9日至2010年7月12日，伊马替尼治疗5年后，14名患者被随机分配到中断治疗组，13名患者被随机分配到继续治疗组。随机分配1年后的中位随访时间为235-2个月（IQR 128-8-236-6），随机分配3年后的中位随访时间为200-9个月（190-2-208-4），随机分配5年后的中位随访时间为164-5个月（134-4-176-4）。服用伊马替尼1年后，中断组与继续服用组的中位无进展生存期分别为6-1个月（95% CI 2-5-10-1）对27-8个月（19-5-37-9；危险比[HR] 0-36[95% CI 0-20-0-64]，对数rank p=0-0003）；服用伊马替尼3年后，中断组与继续服用组的中位无进展生存期分别为7-0个月（3-5-11-7）对67-0个月（48-8-85-6；0-15[0-07-0-32]，对数rank pFunding：Centre Léon Bérard、INCa、CONTICANET、Ligue Contre le Cancer 和 Novartis。
Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.
Background: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial.
Methods: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861.
Findings: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib.
Funding: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
期刊介绍：
The Lancet Oncology is a trusted international journal that addresses various topics in clinical practice, health policy, and global oncology. It covers a wide range of cancer types, including breast, endocrine system, gastrointestinal, genitourinary, gynaecological, haematological, head and neck, neurooncology, paediatric, thoracic, sarcoma, and skin cancers. Additionally, it includes articles on epidemiology, cancer prevention and control, supportive care, imaging, and health-care systems.
The journal has an Impact Factor of 51.1, making it the leading clinical oncology research journal worldwide. It publishes different types of articles, such as Articles, Reviews, Policy Reviews, Personal Views, Clinical Pictures, Comments, Correspondence, News, and Perspectives. The Lancet Oncology also collaborates with societies, governments, NGOs, and academic centers to publish Series and Commissions that aim to drive positive changes in clinical practice and health policy in areas of global oncology that require attention.
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