Journal of Thoracic Oncology最新文献

{"title":"Response to Letter to the Editor: “Refining Surgical Decision-Making for Elderly With Lung Cancer Patients: Recognized Risks, Unmet Needs”","authors":"Ian Bostock MD, MS, FACS, Adam Fox MD, MS, Kathryn Engelhart MD, MS, Farhood Farjah MD, Chi- Fu Jeffrey Yang MD, Robert Smith PhD, Barry Gibney DO, Gerard A. Silvestri MD, MS","doi":"10.1016/j.jtho.2025.02.024","DOIUrl":"10.1016/j.jtho.2025.02.024","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 5","pages":"Pages e63-e64"},"PeriodicalIF":21.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916705","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}

{"title":"The Use of Investigator-Assigned Subjective or Judgmental Efficacy and Toxicity Reporting in Early Phase Clinical Trials of Lung Cancer Treatments","authors":"William J. Phillips MD ,&nbsp;Alexander S. Watson MD, DPhil ,&nbsp;D. Ross Camidge MD, PhD","doi":"10.1016/j.jtho.2024.12.003","DOIUrl":"10.1016/j.jtho.2024.12.003","url":null,"abstract":"<div><h3>Introduction</h3><div>Investigator-assigned Subjective or Judgmental Efficacy and Toxicity (ISJET) reporting represents language used to contextualize efficacy or toxicity data in clinical trials that may be inappropriate or misleading. In addition, pooling of grade 1 and 2 adverse events (AEs) may reflect a practice based on acute chemotherapy treatments rather than the expansion of chronic treatments that are now commonplace for many patients with lung cancer. In this study, we set out to evaluate the use of ISJETs and combined grade 1 and 2 reporting in early phase clinical trials of lung treatments at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.</div></div><div><h3>Methods</h3><div>Phase I and II clinical trials of systemic treatments in adults with at least one patient with lung cancer presented at the 2024 ASCO Annual Meeting were reviewed. Baseline information and toxicity/efficacy reporting were collected. ISJETs were captured based on predefined phrases such as “tolerable,” “manageable,” “acceptable,” or “favorable.”</div></div><div><h3>Results</h3><div>A total of 100 eligible studies were identified. The median sample size was 43 (interquartile range 29–73), and 61 studies (61%) were phase I trials. Most studies reported any-grade (99%) and grade 3 (96%) AEs. Only 12% of the studies distinguished between grade 1 and 2 AEs. ISJETs were used to report toxicity in 88% and efficacy in 41% of the studies, respectively.</div></div><div><h3>Conclusion</h3><div>Most early phase lung cancer clinical trials presented at the 2024 ASCO Annual Meeting included ISJETs and did not distinguish between grade 1 and 2 AEs. Initiatives to increase objective efficacy and toxicity reporting language and more fit-for-purpose toxicity reporting are warranted.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 5","pages":"Pages 589-596"},"PeriodicalIF":21.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791957","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}

{"title":"Neoadjuvant and Adjuvant Osimertinib in Stage IA to IIIA, EGFR-Mutant NSCLC (NORA)","authors":"Jii Bum Lee MD, PhD ,&nbsp;Su-Jin Choi MS ,&nbsp;Hyo Sup Shim MD, PhD ,&nbsp;Byung Jo Park MD, PhD ,&nbsp;Chang Young Lee MD ,&nbsp;Sumedha Sudhaman PhD ,&nbsp;Sharlene Velichko PhD ,&nbsp;Min Hee Hong MD ,&nbsp;Byoung Chul Cho MD, PhD ,&nbsp;Sun Min Lim MD, PhD","doi":"10.1016/j.jtho.2024.12.023","DOIUrl":"10.1016/j.jtho.2024.12.023","url":null,"abstract":"<div><h3>Introduction</h3><div>Treatment with adjuvant osimertinib for three years is the standard-of-care for resected stage IB to IIIA NSCLC harboring <em>EGFR</em> mutations. The role of neoadjuvant osimertinib in the perioperative setting is yet to be elucidated in the NeoADAURA study (NCT04351555).</div></div><div><h3>Methods</h3><div>This is a single-center, pilot study of patients with clinical stage IA to IIIA NSCLC (American Joint Committee on Cancer eighth edition) harboring an activating <em>EGFR</em> mutation (Exon 19 deletion, L858R) (NCT04816838). Patients were treated with two 28-day cycles of neoadjuvant osimertinib followed by surgical resection and three years of adjuvant osimertinib. The primary endpoint was the objective response rate after two cycles of neoadjuvant treatment. Secondary endpoints included the pathologic complete response rate and major pathologic response rate. Exploratory objectives included the correlation of longitudinal circulating tumor DNA testing (Signatera) and response to neoadjuvant osimertinib.</div></div><div><h3>Results</h3><div>A total of 25 patients were enrolled and treated with neoadjuvant osimertinib, and all patients received surgical resection with R0 resection. The objective response rate was 44% (n = 11) all of which were partial responses. Fourteen patients (56%) reported stable disease after neoadjuvant osimertinib. The major pathologic response and pathologic complete response rates were 24% (n = 6) and 0%, respectively. None of the patients received adjuvant chemotherapy. The median disease-free survival was not reached at a median follow-up of 31 months (range: 13.8–38.6 mo). Six patients (30%) were circulating tumor DNA–positive at baseline and achieved clearance after 1 cycle of neoadjuvant osimertinib. There were no grade 3 adverse events during neoadjuvant treatment.</div></div><div><h3>Conclusions</h3><div>Two cycles of neoadjuvant osimertinib did not meet its primary endpoint of ORR. Neoadjuvant osimertinib is a feasible approach with a manageable safety profile in resectable <em>EGFR</em>-mutant NSCLC.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 5","pages":"Pages 641-650"},"PeriodicalIF":21.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895765","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}

{"title":"In Situ Detection of Programmed Cell Death Protein 1 and Programmed Death Ligand 1 Interactions as a Functional Predictor for Response to Immune Checkpoint Inhibition in NSCLC","authors":"Amanda Lindberg MSc ,&nbsp;Lars Muhl PhD ,&nbsp;Hui Yu MSc ,&nbsp;Louise Hellberg BSc ,&nbsp;Rebecca Artursson MSc ,&nbsp;Jakob Friedrich MD ,&nbsp;Max Backman MD, PhD ,&nbsp;Neda Hekmati MSc ,&nbsp;Johanna Mattsson PhD ,&nbsp;Cecilia Lindskog PhD ,&nbsp;Hans Brunnström MD, PhD ,&nbsp;Johan Botling MD, PhD ,&nbsp;Artur Mezheyeuski MD, PhD ,&nbsp;Erika Broström MD ,&nbsp;Miklos Gulyas MD, PhD ,&nbsp;Klas Kärre MD, PhD ,&nbsp;Johan Isaksson MD, PhD ,&nbsp;Patrick Micke MD, PhD ,&nbsp;Carina Strell PhD","doi":"10.1016/j.jtho.2024.12.026","DOIUrl":"10.1016/j.jtho.2024.12.026","url":null,"abstract":"<div><h3>Introduction</h3><div>Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)–PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes.</div></div><div><h3>Methods</h3><div>We applied a second-generation in situ proximity ligation assay to detect PD1–PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms.</div></div><div><h3>Results</h3><div>In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1–PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1–PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1–PD-L1 interactions exhibited additional expression of stromal immune mediators (<em>EOMES, HAVCR1</em>/TIM-1, <em>JAML, FCRL1</em>).</div></div><div><h3>Conclusion</h3><div>Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 5","pages":"Pages 625-640"},"PeriodicalIF":21.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915251","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}

{"title":"Surveillance With Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of Patients With Stage I-to-III Lung Cancer After Completion of Curative treatment (SUPE_R): A Randomized Controlled Trial.","authors":"Kasper Foged Guldbrandsen, Martin Bloch, Kristin Skougaard, Lise Barlebo Ahlborn, Erik Jakobsen, Anette Højsgaard, Rene Horsleben Petersen, Lars Borgbjerg Møller, Morten Dahl, Boe Sandahl Sorensen, Malene Støchkel Frank, Jeanette Haar Ehlers, Martin Krakauer, Peter Michael Gørtz, Elisabeth Albrecht-Beste, Julie Marie Grüner, Zaigham Saghir, Joan Fledelius, Anne Lerberg Nielsen, Paw Christian Holdgaard, Søren Steen Nielsen, Mette Pøhl, Svetlana Borissova, Lotte Holm Land, Charlotte Kristiansen, Tine McCulloch, Lise Saksø Mortensen, Hanne Marie Nellemann, Malene Søby Christophersen, Ole Hilberg, Thor Lind Rasmussen, Signe Høyer Simonsen Schwaner, Christian B Laursen, Uffe Bodtger, Liza Sopina, Markus Nowak Lonsdale, Christian Niels Meyer, Oke Gerke, Jann Mortensen, Torben Riis Rasmussen, Barbara Malene Fischer","doi":"10.1016/j.jtho.2025.04.003","DOIUrl":"10.1016/j.jtho.2025.04.003","url":null,"abstract":"<p><strong>Introduction: </strong>Post-treatment surveillance is recommended for NSCLC owing to a high risk of recurrence, but evidence on the optimal surveillance method is lacking. This trial evaluates fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([¹⁸F]FDG PET/CT) versus contrast-enhanced CT (ceCT) for surveillance in patients with NSCLC.</p><p><strong>Methods: </strong>In this multicenter, randomized controlled trial (SUPE_R, ClinicalTrials.gov NCT03740126), patients with stage IA-to-IIIC NSCLC were randomized one-to-one to standard surveillance (ceCT) or surveillance with [¹⁸F]FDG PET/CT after completion of curative treatment. The primary outcome was the proportion of recurrences treated with curative intent. Secondary outcomes included time to recurrence (TTR) and overall survival (OS).</p><p><strong>Results: </strong>Between February 2019 and February 2022, 750 patients were randomized to PET/CT (n = 373) or CT (n = 377). Recurrences occurred in 164 patients (22%). The proportion of recurrences treated with curative intent was identical in the PET group (42/87) and CT group (37/77), both 48% (p = 0.98). More recurrences were detected through scheduled follow-up in the PET group (90%) than in the CT group (77%; p = 0.02). There were no significant differences in TTR (hazard ratio 1.12, 95% confidence interval 0.82-1.52, p = 0.48) or OS (hazard ratio 0.97, 95% confidence interval 0.66-1.43, p = 0.89) between groups.</p><p><strong>Conclusions: </strong>Surveillance with [¹⁸F]FDG PET/CT did not improve rates of curatively treated recurrences, TTR, or OS compared with ceCT in patients with NSCLC after curative treatment. These findings do not support the routine use of [¹⁸F]FDG PET/CT for post-treatment surveillance in this patient population.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016381","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}

{"title":"High-dose versus standard dose twice-daily thoracic radiotherapy in limited stage small-cell lung cancer: final survival data, long-term toxicity and relapse patterns in a randomised, open-label, phase II trial.","authors":"Bjørn Henning Grønberg, Kristin Toftaker Killingberg, Øystein Fløtten, Maria Moksnes Bjaanæs, Odd Terje Brustugun, Tesfaye Madebo, Seppo Wang Langer, Signe Lenora Risumlund, Tine Schytte, Nina Helbekkmo, Kirill Neumann, Øyvind Yksnøy, Jens Engleson, Sverre Fluge, Thor Naustdal, Liv Ellen Giske, Jan Nyman, Georgios Tsakonas, Tarje Onsøien Halvorsen","doi":"10.1016/j.jtho.2025.04.007","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.04.007","url":null,"abstract":"<p><strong>Introduction: </strong>Chemoradiotherapy is standard treatment for limited stage (LS) small-cell lung cancer (SCLC). A majority of patients relapse and there is a need for better treatment. We investigated whether twice-daily thoracic radiotherapy (TRT) of 60 Gy/40 fractions improve survival compared with the established schedule of 45 Gy/30 fractions. Here we report final survival data and long-term toxicity.</p><p><strong>Methods: </strong>Randomised, open-label, phase II trial. Eligible patients had PS 0-2, were ≥18 years, underwent FDG-PET/CT and brain MRI for staging and were randomised 1:1 to TRT of 60 or 45 Gy. Patients were to receive four courses of platinum/etoposide chemotherapy and responders were offered prophylactic cranial irradiation.</p><p><strong>Results: </strong>170 patients were randomized (60 Gy: n=89, 45 Gy: n=81). Median age was 65, 31% ≥70 years, 57% women, 89% had PS 0-1, 83% stage III disease, median planning target volume was 305 cm³, and 67% were treated with three-dimensional conformal radiotherapy (3D CRT). Median OS in the 60 Gy group was significantly longer (43.5 vs. 22.5 months, HR 0.68, 95% CI 0.48-0.98, p=0.037). The 60 Gy group did not experience more acute grade 3-4 esophagitis (60 Gy: 21%, 45 Gy: 18%, p=0.83) or pneumonitis (60 Gy: 3%, 45 Gy: 0%, p=0.39). Two patients, both in the 60 Gy group, developed oesophageal strictures, while eleven patients (60 Gy: n=5, 45 Gy: n=6) developed severe long-term eating and swallowing dysfunction.</p><p><strong>Conclusion: </strong>Twice-daily TRT of 60 Gy/40 fractions was well tolerated and prolonged survival compared with 45 Gy/30 fractions in LS SCLC patients.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031964","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}

{"title":"Misleading Interpretations of the MET Gene Acronym: Over 15 Years of Confusion in Scientific Publications and a Call for Reaffirming the Original Gene Nomenclature.","authors":"Piotr Religa, Marzena Łazarczyk, Michel-Edwar Mickael, Dominik S Skiba","doi":"10.1016/j.jtho.2025.03.044","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.03.044","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042281","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}

{"title":"Neoadjuvant Concurrent Chemo-Immuno-Radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage III N2 NSCLC: Primary Results From the SQUAT Trial (WJOG 12119L).","authors":"Akira Hamada, Junichi Soh, Akito Hata, Kiyoshi Nakamatsu, Mototsugu Shimokawa, Yasushi Yatabe, Jun Suzuki, Masahiro Tsuboi, Hidehito Horinouchi, Yuichi Sakairi, Masayuki Tanahashi, Shinichi Toyooka, Morihito Okada, Natusmi Matsuura, Hisayuki Shigematsu, Yasumasa Nishimura, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Tetsuya Mitsudomi","doi":"10.1016/j.jtho.2025.03.051","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.03.051","url":null,"abstract":"<p><strong>Introduction: </strong>Neoadjuvant chemo-immunotherapy is one of the standard treatment options for resectable stage II to III NSCLC. Nevertheless, this treatment yielded insufficient local control in the CheckMate 816 trial. We hypothesized that adding radiotherapy could improve local control, thereby improving survival outcomes.</p><p><strong>Methods: </strong>Eligible patients had clinical T1 to T3 or T4 (tumor size) N2 stage IIIA to B NSCLC (American Joint Committee on Cancer version 8), pathologically confirmed as N2 without extranodal invasion. Patients received concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m²] on days 1, 8, 15, 22, and 29, with 50 Gy radiation over 25 d) and durvalumab (1500 mg) on days 1 and 29, followed by surgical resection within two to six weeks. After surgery, durvalumab adjuvant therapy was administered for up to one year. The primary endpoint was major pathologic response (MPR: ≤10% viable tumor), with secondary endpoints being pathologic complete response, progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Results: </strong>From January 2020 through February 2022, 31 patients were enrolled from 10 Japanese institutions. The MPR rate was 63% (90% confidence interval: 47%-78%), which met the primary endpoint, and the pathologic complete response rate was 23%. At a median follow-up of 28 months, the two-year PFS and OS rates were 43% and 76%, respectively. Grade 3 or 4 adverse events occurred in 48% of cases, including one treatment-related death.</p><p><strong>Conclusions: </strong>Compared with recently published results of peri-operative chemo-immunotherapy trials, this treatment regimen had a higher MPR rate. Nevertheless, this benefit did not necessarily translate into improved PFS or OS.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971158","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}

{"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":"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 NSCLC. Nevertheless, whether activating MET TKD mutations can confer resistance to targeted therapy in non-MET, oncogene-driven NSCLCs remains unclear.</p><p><strong>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 of more than 115,000 patients with NSCLC found 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 the 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 resistance mechanism 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}

{"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 ,&nbsp;Daan A.C. Lanser MD ,&nbsp;M. Benthe Muntinghe-Wagenaar MD ,&nbsp;Ma Ida Mohmaed Ali PharmD ,&nbsp;Ezgi B. Ulas BSc ,&nbsp;Tessa M.A. Trooster BSc ,&nbsp;Evert de Jonge BSc ,&nbsp;Esther Oomen-de Hoop PhD ,&nbsp;Marthe S. Paats MD, PhD ,&nbsp;Idris Bahce MD, PhD ,&nbsp;Sander Croes PhD ,&nbsp;Lizza E.L. Hendriks MD, PhD ,&nbsp;Anthonie J. van der Wekken MD, PhD ,&nbsp;Anne-Marie C. Dingemans MD, PhD ,&nbsp;Alwin D.R. Huitema PhD ,&nbsp;Ron H.N. van Schaik PhD ,&nbsp;Ron H.J. Mathijssen MD, PhD ,&nbsp;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> &lt; 0.001). Homozygous carriers of the <em>PPAR-α</em> 209G&gt;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&gt;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}