Karlijn Verkerk, Tijmen J W T van der Wel, Laurien J Zeverijn, Birgit S Geurts, Ilse A C Spiekman, Gijs F de Wit, Paul Roepman, Anne M L Jansen, Vincent van der Noort, Egbert F Smit, Ann Hoeben, Lizza E L Hendriks, Michel M van den Heuvel, Berber Piet, Gerarda J M Herder, Sayed M S Hashemi, Hans Gelderblom, Henk M W Verheul, Emile E Voest, Adrianus J de Langen
{"title":"克唑替尼治疗MET突变非小细胞肺癌的安全性、有效性和生物标志物分析--药物再发现方案的结果。","authors":"Karlijn Verkerk, Tijmen J W T van der Wel, Laurien J Zeverijn, Birgit S Geurts, Ilse A C Spiekman, Gijs F de Wit, Paul Roepman, Anne M L Jansen, Vincent van der Noort, Egbert F Smit, Ann Hoeben, Lizza E L Hendriks, Michel M van den Heuvel, Berber Piet, Gerarda J M Herder, Sayed M S Hashemi, Hans Gelderblom, Henk M W Verheul, Emile E Voest, Adrianus J de Langen","doi":"10.1158/1078-0432.CCR-24-1925","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse.</p><p><strong>Patients and methods: </strong>In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit [CB: RECIST v1.1 confirmed partial response, complete response (CR), or stable disease ≥16 weeks] and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage I and if ≥1/8 patients had CB, 24 patients in stage II. Whole-genome sequencing and RNA sequencing were performed on baseline biopsies.</p><p><strong>Results: </strong>Between September 2018 and October 2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, 13 (54.2%) partial response, and two (8.3%) stable disease. The CB rate was 70.8% [95% confidence interval (CI), 48.9-87.4], and the objective response rate was 62.5% (95% CI, 40.6-81.2). After 21.2-month median follow-up, median duration of response, progression-free survival, and overall survival were 9.3 (95% CI, 6.5-not available), 10.2 (95% CI, 6.0-20.1), and 13.0 months (95% CI, 9.0-not available), respectively. Twenty-three treatment-related grade ≥ 3 adverse events occurred in 12/30 patients (40%), causing treatment discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), and all other patients had MET exon 14 skipping mutations.</p><p><strong>Conclusions: </strong>Crizotinib is a valuable treatment option in METmut aNSCLC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5323-5332"},"PeriodicalIF":10.0000,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety, Efficacy, and Biomarker Analysis of Crizotinib in MET-Mutated Non-Small Cell Lung Cancer-Results from the Drug Rediscovery Protocol.\",\"authors\":\"Karlijn Verkerk, Tijmen J W T van der Wel, Laurien J Zeverijn, Birgit S Geurts, Ilse A C Spiekman, Gijs F de Wit, Paul Roepman, Anne M L Jansen, Vincent van der Noort, Egbert F Smit, Ann Hoeben, Lizza E L Hendriks, Michel M van den Heuvel, Berber Piet, Gerarda J M Herder, Sayed M S Hashemi, Hans Gelderblom, Henk M W Verheul, Emile E Voest, Adrianus J de Langen\",\"doi\":\"10.1158/1078-0432.CCR-24-1925\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse.</p><p><strong>Patients and methods: </strong>In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit [CB: RECIST v1.1 confirmed partial response, complete response (CR), or stable disease ≥16 weeks] and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage I and if ≥1/8 patients had CB, 24 patients in stage II. Whole-genome sequencing and RNA sequencing were performed on baseline biopsies.</p><p><strong>Results: </strong>Between September 2018 and October 2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, 13 (54.2%) partial response, and two (8.3%) stable disease. The CB rate was 70.8% [95% confidence interval (CI), 48.9-87.4], and the objective response rate was 62.5% (95% CI, 40.6-81.2). After 21.2-month median follow-up, median duration of response, progression-free survival, and overall survival were 9.3 (95% CI, 6.5-not available), 10.2 (95% CI, 6.0-20.1), and 13.0 months (95% CI, 9.0-not available), respectively. Twenty-three treatment-related grade ≥ 3 adverse events occurred in 12/30 patients (40%), causing treatment discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), and all other patients had MET exon 14 skipping mutations.</p><p><strong>Conclusions: </strong>Crizotinib is a valuable treatment option in METmut aNSCLC.</p>\",\"PeriodicalId\":10279,\"journal\":{\"name\":\"Clinical Cancer Research\",\"volume\":\" \",\"pages\":\"5323-5332\"},\"PeriodicalIF\":10.0000,\"publicationDate\":\"2024-12-02\",\"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-24-1925\",\"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-24-1925","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Safety, Efficacy, and Biomarker Analysis of Crizotinib in MET-Mutated Non-Small Cell Lung Cancer-Results from the Drug Rediscovery Protocol.
Purpose: To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse.
Patients and methods: In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit [CB: RECIST v1.1 confirmed partial response, complete response (CR), or stable disease ≥16 weeks] and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage I and if ≥1/8 patients had CB, 24 patients in stage II. Whole-genome sequencing and RNA sequencing were performed on baseline biopsies.
Results: Between September 2018 and October 2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, 13 (54.2%) partial response, and two (8.3%) stable disease. The CB rate was 70.8% [95% confidence interval (CI), 48.9-87.4], and the objective response rate was 62.5% (95% CI, 40.6-81.2). After 21.2-month median follow-up, median duration of response, progression-free survival, and overall survival were 9.3 (95% CI, 6.5-not available), 10.2 (95% CI, 6.0-20.1), and 13.0 months (95% CI, 9.0-not available), respectively. Twenty-three treatment-related grade ≥ 3 adverse events occurred in 12/30 patients (40%), causing treatment discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), and all other patients had MET exon 14 skipping mutations.
Conclusions: Crizotinib is a valuable treatment option in METmut aNSCLC.
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.
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