Pub Date : 2025-04-02DOI: 10.1016/j.jtho.2025.03.045
Seshiru Nakazawa, Federica Pecci, Biagio Ricciuti, Felix H Gottlieb, Francesco Facchinetti, Guilherme Harada, Monica F Chen, Matteo Repetto, Flavia Giacomini, Jie Jiang, Marie-Anaïs Locquet, Maisam Makarem, Joao V Alessi, Alessandro Di Federico, Mihaela Aldea, Edoardo Garbo, Malini M Gandhi, Arushi Saini, Danielle Haradon, Magda Bahcall, William W Feng, Jessica K Lee, Alexa B Schrock, Alexander Drilon, Mark M Awad, Pasi A Jänne
Introduction: MET tyrosine kinase domain (TKD) mutations have recently been characterized as de novo oncogenic drivers in non-small cell lung cancer (NSCLC). However, whether activating MET TKD mutations can confer resistance to targeted therapy in non-MET, oncogene-driven NSCLCs remains unclear.
Material and methods: To characterize the genomic features of tumors with MET TKD mutations in oncogene-driven NSCLC, we performed tumor genomic profiling on two different cohorts of patients with NSCLC. Preclinical models of the most frequently observed MET TKD mutations were generated to determine the effect on sensitivity to targeted therapy. Treatment strategies to overcome MET TKD mutation-mediated resistance were further explored.
Results: Genomic profiling from >115,000 patients with NSCLC demonstrated that activating MET TKD mutations are prevalent in 0.15% of cases, and that about half of them co-occur with another oncogenic driver, with a differential pattern in co-occurring MET TKD mutations according to the oncogenic alteration. A review of eight cases with sequential genomic testing revealed that MET TKD mutation was acquired after systemic therapy in 88% of cases, with a potential contribution of APOBEC mutagenesis underlying this process. In vitro, MET TKD mutation conferred resistance to targeted therapy in diverse oncogene-driven models, which could be overcome by combinatorial treatment against both the primary oncogene and the MET TKD mutation.
Conclusions: MET TKD mutation can act as an off-target mechanism of resistance in diverse oncogene-driven NSCLC. Combination therapy with an effective MET-targeted therapy can potentially overcome MET TKD mutation-mediated resistance.
{"title":"Activating mutations in the MET kinase domain co-occur with other driver oncogenes and mediate resistance to targeted therapy in NSCLC.","authors":"Seshiru Nakazawa, Federica Pecci, Biagio Ricciuti, Felix H Gottlieb, Francesco Facchinetti, Guilherme Harada, Monica F Chen, Matteo Repetto, Flavia Giacomini, Jie Jiang, Marie-Anaïs Locquet, Maisam Makarem, Joao V Alessi, Alessandro Di Federico, Mihaela Aldea, Edoardo Garbo, Malini M Gandhi, Arushi Saini, Danielle Haradon, Magda Bahcall, William W Feng, Jessica K Lee, Alexa B Schrock, Alexander Drilon, Mark M Awad, Pasi A Jänne","doi":"10.1016/j.jtho.2025.03.045","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.03.045","url":null,"abstract":"<p><strong>Introduction: </strong>MET tyrosine kinase domain (TKD) mutations have recently been characterized as de novo oncogenic drivers in non-small cell lung cancer (NSCLC). However, whether activating MET TKD mutations can confer resistance to targeted therapy in non-MET, oncogene-driven NSCLCs remains unclear.</p><p><strong>Material and methods: </strong>To characterize the genomic features of tumors with MET TKD mutations in oncogene-driven NSCLC, we performed tumor genomic profiling on two different cohorts of patients with NSCLC. Preclinical models of the most frequently observed MET TKD mutations were generated to determine the effect on sensitivity to targeted therapy. Treatment strategies to overcome MET TKD mutation-mediated resistance were further explored.</p><p><strong>Results: </strong>Genomic profiling from >115,000 patients with NSCLC demonstrated that activating MET TKD mutations are prevalent in 0.15% of cases, and that about half of them co-occur with another oncogenic driver, with a differential pattern in co-occurring MET TKD mutations according to the oncogenic alteration. A review of eight cases with sequential genomic testing revealed that MET TKD mutation was acquired after systemic therapy in 88% of cases, with a potential contribution of APOBEC mutagenesis underlying this process. In vitro, MET TKD mutation conferred resistance to targeted therapy in diverse oncogene-driven models, which could be overcome by combinatorial treatment against both the primary oncogene and the MET TKD mutation.</p><p><strong>Conclusions: </strong>MET TKD mutation can act as an off-target mechanism of resistance in diverse oncogene-driven NSCLC. Combination therapy with an effective MET-targeted therapy can potentially overcome MET TKD mutation-mediated resistance.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1016/j.jtho.2025.03.007
Dylan Yueyang Wang , Michela Ranieri , Fiona Sherman , Jiehui Deng , Kwok-Kin Wong , Elaine Shum , John T. Poirier
{"title":"OA05.01 Deep Mutational Scanning Reveals Novel EGFR Mutations Conferring Resistance to Osimertinib and BLU-945","authors":"Dylan Yueyang Wang , Michela Ranieri , Fiona Sherman , Jiehui Deng , Kwok-Kin Wong , Elaine Shum , John T. Poirier","doi":"10.1016/j.jtho.2025.03.007","DOIUrl":"10.1016/j.jtho.2025.03.007","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S2"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1016/j.jtho.2025.03.021
Brinda Gupta , Kieran Sweeney , Andrew Elliott , Jennifer Marks , Ari Vanderwalde , Sonam Puri , Misty D. Shields , Jorge J. Nieva , Heloisa P. Soares , Patrick C. Ma , Balazs Halmos , Stephen V. Liu
{"title":"PP01.14 Paired Sample Analyses of NSCLC After SCLC Transformation","authors":"Brinda Gupta , Kieran Sweeney , Andrew Elliott , Jennifer Marks , Ari Vanderwalde , Sonam Puri , Misty D. Shields , Jorge J. Nieva , Heloisa P. Soares , Patrick C. Ma , Balazs Halmos , Stephen V. Liu","doi":"10.1016/j.jtho.2025.03.021","DOIUrl":"10.1016/j.jtho.2025.03.021","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S8"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1016/j.jtho.2025.03.012
David Bracquemond , Maicol Mancini , Antonio Maraver
{"title":"PP01.04 Targeting the Minimal Residual Disease to Increase the Targeted Therapy Depth of Response in EGFR-Driven Lung Cancer","authors":"David Bracquemond , Maicol Mancini , Antonio Maraver","doi":"10.1016/j.jtho.2025.03.012","DOIUrl":"10.1016/j.jtho.2025.03.012","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S4"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1016/j.jtho.2024.11.025
Niels Heersche MD , Daan A.C. Lanser MD , M. Benthe Muntinghe-Wagenaar MD , Ma Ida Mohmaed Ali PharmD , Ezgi B. Ulas BSc , Tessa M.A. Trooster BSc , Evert de Jonge BSc , Esther Oomen-de Hoop PhD , Marthe S. Paats MD, PhD , Idris Bahce MD, PhD , Sander Croes PhD , Lizza E.L. Hendriks MD, PhD , Anthonie J. van der Wekken MD, PhD , Anne-Marie C. Dingemans MD, PhD , Alwin D.R. Huitema PhD , Ron H.N. van Schaik PhD , Ron H.J. Mathijssen MD, PhD , G.D. Marijn Veerman MD, PhD
Introduction
Alectinib, a small-molecule kinase inhibitor, is used as first-line treatment for ALK-positive (ALK+) NSCLC. Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity.
Methods
In this multicenter observational cohort study in patients with advanced ALK+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in ABCB1, CYP3A4, PPAR-α, POR, and CYP3A5. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals.
Results
Among 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; p = 0.001) and had +35% higher alectinib trough levels (p < 0.001). Homozygous carriers of the PPAR-α 209G>A variant exhibited a higher incidence of grade greater than or equal to 3 toxicity (38%) compared with patients who carried at least one wild-type allele (11%) (p = 0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95% confidence interval: 2.9%–36.6%; p = 0.019) higher trough levels.
Conclusions
Female patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. PPAR-α 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pretreatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.
Alectinib是一种小分子激酶抑制剂，用于间变性淋巴瘤激酶阳性（ALK+）非小细胞肺癌（NSCLC）的一线治疗。尽管一般耐受性良好，但由于药物相关毒性，相当一部分患者需要调整剂量。与alectinib代谢相关基因的单核苷酸多态性（snp）可以预先识别有毒性风险的患者。方法：在接受阿勒替尼治疗的晚期ALK+ NSCLC患者的多中心观察队列研究中，我们研究了ABCB1、CYP3A4、PPAR-α、POR和CYP3A5的毒性、药代动力学和关键遗传变异之间的关系。从五家医院收集了人口统计学、不良事件和阿勒替尼低谷水平的数据。结果：215例患者中，47%出现严重毒性。女性经历了更严重的毒性反应(女性vs男性：56% vs 34%；p=0.001)，而且与携带至少一个野生型等位基因的患者（11%）相比，pA变异的≥3级毒性发生率（38%）更高（p=0.004）。这在Bonferroni修正后仍然很重要。出现严重毒性的患者为+18.5% (95%CI: 2.9-36.6%；P =0.019)较高的低谷水平。结论：女性患者因阿勒替尼暴露量较高，毒性更严重，值得进一步探讨。PPAR-α 209G>A显著增加了相关的阿勒替尼诱导的毒性，很可能是由于阿勒替尼暴露量的增加。治疗前基因变异检测和随后的剂量减少可以提供一种可行的方法来减少阿勒替尼相关的毒性。
{"title":"Sex and Common Germline Variants Affect the Toxicity Profile and Pharmacokinetics of Alectinib: A Nationwide Cohort Study in Patients With ALK-Positive NSCLC","authors":"Niels Heersche MD , Daan A.C. Lanser MD , M. Benthe Muntinghe-Wagenaar MD , Ma Ida Mohmaed Ali PharmD , Ezgi B. Ulas BSc , Tessa M.A. Trooster BSc , Evert de Jonge BSc , Esther Oomen-de Hoop PhD , Marthe S. Paats MD, PhD , Idris Bahce MD, PhD , Sander Croes PhD , Lizza E.L. Hendriks MD, PhD , Anthonie J. van der Wekken MD, PhD , Anne-Marie C. Dingemans MD, PhD , Alwin D.R. Huitema PhD , Ron H.N. van Schaik PhD , Ron H.J. Mathijssen MD, PhD , G.D. Marijn Veerman MD, PhD","doi":"10.1016/j.jtho.2024.11.025","DOIUrl":"10.1016/j.jtho.2024.11.025","url":null,"abstract":"<div><h3>Introduction</h3><div>Alectinib, a small-molecule kinase inhibitor, is used as first-line treatment for ALK-positive (<em>ALK</em>+) NSCLC. Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity.</div></div><div><h3>Methods</h3><div>In this multicenter observational cohort study in patients with advanced <em>ALK</em>+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in <em>ABCB1</em>, <em>CYP3A4</em>, <em>PPAR-α</em>, <em>POR</em>, and <em>CYP3A5</em>. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals.</div></div><div><h3>Results</h3><div>Among 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; <em>p</em> = 0.001) and had +35% higher alectinib trough levels (<em>p</em> < 0.001). Homozygous carriers of the <em>PPAR-α</em> 209G>A variant exhibited a higher incidence of grade greater than or equal to 3 toxicity (38%) compared with patients who carried at least one wild-type allele (11%) (<em>p</em> = 0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95% confidence interval: 2.9%–36.6%; <em>p</em> = 0.019) higher trough levels.</div></div><div><h3>Conclusions</h3><div>Female patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. <em>PPAR-α</em> 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pretreatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Pages 475-486"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1016/j.jtho.2025.03.009
Jaime L. Schneider , Yutong Dai , Ishita Dhiman , Jingpeng Chen , Shakchhi Joshi , Kiran Kurmi , Morgan Payne , Brandon Gassaway , Steven Gygi , Jessica J. Lin , Aaron Hata , Marcia Haigis
{"title":"PP01.01 Oncogenic Signaling is Rewired to Support Nucleotide Metabolism in Acquired Resistance to Targeted Therapies in NSCLC","authors":"Jaime L. Schneider , Yutong Dai , Ishita Dhiman , Jingpeng Chen , Shakchhi Joshi , Kiran Kurmi , Morgan Payne , Brandon Gassaway , Steven Gygi , Jessica J. Lin , Aaron Hata , Marcia Haigis","doi":"10.1016/j.jtho.2025.03.009","DOIUrl":"10.1016/j.jtho.2025.03.009","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S3"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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