Lung Cancer最新文献

{"title":"Safety assessment of KRAS (G12C) inhibitors based on the FDA Adverse Event Reporting System (FAERS) database: A real-world pharmacovigilance study","authors":"Maohua Chen ,&nbsp;Yaping Huang ,&nbsp;Shaojun Jiang ,&nbsp;Chengjie Ke","doi":"10.1016/j.lungcan.2024.107966","DOIUrl":"10.1016/j.lungcan.2024.107966","url":null,"abstract":"<div><h3>Objectives</h3><div><em>KRAS (G12C)</em> inhibitors (sotorasib and adagrasib) have approved treatment in patients with <em>KRAS (G12C)</em>-mutated non-small cell lung cancer (NSCLC). The post-marketing data concerning <em>KRAS (G12C)</em> inhibitors remain limited, and the outcomes of relevant studies are yet to yield conclusive evidence supporting the long-term safety of <em>KRAS (G12C)</em> inhibitors.</div></div><div><h3>Materials and methods</h3><div>This investigation comprehensively assessed adverse events (AEs) attributed to <em>KRAS (G12C)</em> inhibitors by employing advanced data mining techniques, utilizing the FDA Adverse Event Reporting System (FAERS). The dataset encompasses the period from the first quarter of 2021 to the first quarter of 2024. A disproportionality analysis was conducted to quantify the correlation between <em>KRAS (G12C)</em> inhibitors and AEs. The metrics employed for the evaluation of disproportionality comprise the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayesian geometric mean (EBGM).</div></div><div><h3>Results</h3><div>A total of 2,253 and 486 reports were identified as related to sotorasib and adagrasib, with the identification of 51 and 26 preferred terms, respectively. The most frequent AEs of sotorasib comprised diarrhoea (ROR 5.27), hepatotoxicity (ROR 38.09), alanine aminotransferase increased (ROR 17.41), aspartate aminotransferase increased (ROR 20.88), and hepatic function abnormal (ROR 19.88). The most common AEs of adagrasib included diarrhoea (ROR 4.21), nausea (ROR 3.84), vomiting (ROR 5.36), decreased appetite (ROR 4.79), and dehydration (ROR 7.00). A relatively reduced risk of hepatotoxicity but a increased risk of serious AEs in adagrasib compared to sotorasib (<em>P</em> &lt; 0.001).</div></div><div><h3>Conclusion</h3><div>Our findings would provide valued evidence for healthcare professionals to recognize AEs associated with <em>KRAS (G12C)</em> inhibitors and differences between sotorasib and adagrasib, and guide their clinical practice.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107966"},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The prediction of treatment outcome in NSCLC patients harboring an EGFR exon 20 mutation using molecular modeling","authors":"F. Zwierenga ,&nbsp;L. Zhang ,&nbsp;J. Melcr ,&nbsp;E. Schuuring ,&nbsp;B.A.M.H. van Veggel ,&nbsp;A.J. de Langen ,&nbsp;H.J.M. Groen ,&nbsp;M.R. Groves ,&nbsp;A.J. van der Wekken","doi":"10.1016/j.lungcan.2024.107973","DOIUrl":"10.1016/j.lungcan.2024.107973","url":null,"abstract":"<div><h3>Introduction</h3><div>The structural effect of uncommon heterogenous in-frame deletion and/or insertion mutations within exon 20 (EGFRex20+) in relation to therapy response is poorly understood. This study aims to elucidate the structural alterations caused by EGFRex20+ mutations and correlate these changes with patient responses.</div></div><div><h3>Material and method</h3><div>We selected EGFRex20+ mutations from advanced NSCLC patients in the Position20 and AFACET studies for computational analysis. Homology models representing both inactive and active conformations of these mutations were generated using the Swiss-Model server. Molecular docking studies with EGFR-TKIs was conducted using smina, followed by Molecular Dynamic (MD) simulations performed with GROMACS. These computational findings were compared with clinical outcomes to evaluate their potential in predicting patient response.</div></div><div><h3>Results</h3><div>Our docking studies of 29 EGFRex20+ mutations revealed that the binding energies of afatinib, osimertinib, zipalertinib, and sunvozertinib, compared to the wild type, do not significantly impact either TKI’s efficacy. MD simulations for eight EGFRex20+ mutations (A763_Y764insFQEA, A767_V769dup, S768_D770dup, D770_N771insG, D770_P772dup, N771_H773dup, H773_V774insY and H773_V774delinsLM) revealed varying degrees of instability. For six variants, predicted activation based on the αC-helix stability and orientation, as well as TKI sensitivity, aligned well with clinical observations from the Position20 and AFACET studies. Two mutations (D770_N771insG and N771_H773dup) predicted as poor to moderate responders, showed minimal activation of the αC-helix region, warranting further investigation.</div></div><div><h3>Conclusion</h3><div>In conclusion, MD simulations can effectively predict patient outcomes by connecting computational results with clinical data and advancing our understanding of EGFR mutations and their therapeutic responses.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107973"},"PeriodicalIF":4.5,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MTAP as an emerging biomarker in thoracic malignancies","authors":"Magdalena M. Brune ,&nbsp;Spasenija Savic Prince ,&nbsp;Tatjana Vlajnic ,&nbsp;Obinna Chijioke ,&nbsp;Luca Roma ,&nbsp;David König ,&nbsp;Lukas Bubendorf","doi":"10.1016/j.lungcan.2024.107963","DOIUrl":"10.1016/j.lungcan.2024.107963","url":null,"abstract":"<div><div>S-methyl-5′-thioadenosine phosphorylase (MTAP) deficiency is an emerging biomarker in non-small cell lung cancer (NSCLC) and beyond. The <em>MTAP</em> gene is located in the chromosomal region <em>9p21.3</em>, which shows one of the most common homozygous deletions across all human cancers (<em>9p21</em> loss). Loss of <em>9p21</em> is found in the majority of pleural mesotheliomas, where it serves as an established diagnostic marker. Until recently, fluorescence <em>in situ</em> hybridization (FISH) was the gold standard for the detection of <em>9p21</em> losses, but loss of MTAP expression by immunohistochemistry (IHC) gains increasing importance as an easy to apply and cost-effective diagnostic surrogate marker. Besides, <em>MTAP</em> loss, which has been reported in 13% of NSCLC, is becoming an emerging predictive biomarker in two different scenarios in NSCLC and other cancer types: 1) <em>MTAP</em> loss seems to negatively predict the response to immune checkpoint inhibitor (ICI) treatment via silencing of the tumor microenvironment, and 2) <em>MTAP</em> loss serves as a predictive biomarker for novel targeted treatment strategies. MTAP deficiency leads to an impaired function of the protein arginine methyltransferase 5 (PRMT5) due to its partial inhibition by MTAP’s accumulating substrate methylthioadenosine (MTA). This process leaves MTAP deficient tumor cells heavily dependent on the remaining function of PRMT5, making it a perfect target for synthetic lethality. Indeed, MTA-cooperative PRMT5-inhibitors are now tested in several clinical trials with promising early results in solid malignancies. With its emergence as a predictive biomarker, the implementation of MTAP IHC into diagnostic routine for NSCLC and other tumors is likely to take place soon. In this review article, we summarize the current literature on the role of MTAP in thoracic tumors and evaluate different testing methods, including IHC, FISH and next generation sequencing.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107963"},"PeriodicalIF":4.5,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic review and network meta-analysis of lorlatinib with comparison to other anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) as first-line treatment for ALK-positive advanced non-smallcell lung cancer (NSCLC)","authors":"Sai-Hong Ou ,&nbsp;Hannah Kilvert ,&nbsp;Jane Candlish ,&nbsp;Ben Lee ,&nbsp;Anna Polli ,&nbsp;Despina Thomaidou ,&nbsp;Hannah Le","doi":"10.1016/j.lungcan.2024.107968","DOIUrl":"10.1016/j.lungcan.2024.107968","url":null,"abstract":"<div><h3>Background</h3><div>Next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) (alectinib, brigatinib, and lorlatinib) demonstrate superior progression-free survival (PFS) over chemotherapy or crizotinib as first-line (1L) treatment of ALK-positive advanced non-smallcell lung cancer (NSCLC).</div></div><div><h3>Methods</h3><div>We conducted network meta-analyses (NMAs) comparing the relative efficacy of lorlatinib with other ALK TKIs in this indication. Evidence identified from a systematic literature review and subsequent updates formed the basis of our evidence. The primary analysis investigated PFS by independent review committee (IRC) in the intent-to-treat (ITT) population. Secondary outcomes included PFS among subgroups, intracranial time to progression (IC TTP), adverse events, and discontinuation due to adverse events. For each of the outcomes, Bayesian proportional hazards NMAs estimated the relative treatment effects.</div><div>Additionally, we compared the design and results of eight published NMAs conducted for 1L ALK + advanced NSCLC to date.</div></div><div><h3>Results</h3><div>We formed a network of 10 trials, allowing indirect treatment comparisons. Two trials directly compared alectinib (600 mg twice daily) to crizotinib and one trial directly compared lorlatinib to crizotinib. The results of the NMA show that the hazard ratios (95 % credible interval [CrI]) for ITT PFS IRC were 0.61 (95 % CrI: 0.39, 0.97) when comparing lorlatinib with alectinib (600 mg twice daily) and 0.57 (95 % CrI: 0.35, 0.93) when comparing lorlatinib with brigatinib.</div><div>In the review of published NMAs, HRs for lorlatinib versus alectinib (600 mg twice daily) and brigatinib were compared. This comparison confirmed that each published NMA yielded similar results.</div></div><div><h3>Conclusions</h3><div>Our NMA analysis adds to existing findings and supplements data gaps from other published NMAs. Findings from eight published NMAs consistently supported lorlatinib as a clinically effective 1L treatment for ALK + advanced NSCLC patients compared to other TKIs.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107968"},"PeriodicalIF":4.5,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of alcohol with lung cancer risk in men with different growth hormone receptor genotypes","authors":"Randi Chen ,&nbsp;Timothy A. Donlon ,&nbsp;Brian J. Morris ,&nbsp;Richard C. Allsopp ,&nbsp;Bradley J. Willcox ,&nbsp;Kamal H. Masaki","doi":"10.1016/j.lungcan.2024.107971","DOIUrl":"10.1016/j.lungcan.2024.107971","url":null,"abstract":"<div><h3>Objective</h3><div>To test whether genetic variants of the growth hormone receptor gene (<em>GHR</em>) modulate the effect of lifestyle variables on lung cancer (LC) risk.</div></div><div><h3>Materials and methods</h3><div>This population-based cohort study involved 6,439 men from the Japan-Hawaii Cancer study drawn from the Kuakini Honolulu Heart Program who were cancer-free at baseline examination (1965–1968; age 45–68 years) and followed-up until December 1999. We determined the association of <em>GHR</em> SNP <em>rs4130113</em> genotypes <em>GHR</em>-<em>AA</em> (common allele <em>A</em> homozygotes) and <em>GHR</em>-<em>G</em> (minor allele <em>G</em> carriage) with alcohol drinking, BMI, physical activity and cigarette smoking in relation to LC and non-small cell LC (NSCLC). Results were expressed as hazard ratios and 95 % CIs estimated from Cox proportional hazard models.</div></div><div><h3>Results</h3><div>Over mean 26.7 ± 7.4 SD years follow-up, 190 LC cases, including 133 NSCLC cases, were diagnosed. After adjusting for age, education, alcohol intake, BMI, physical activity, cigarette smoking, green tea consumption and dietary saturated fat, main-effect Cox models showed that compared with <em>GHR</em>-<em>AA</em>, <em>GHR</em>-<em>G</em> was associated with protection against LC: HR = 0.75 (95 % CI, 0.56–1.00). Full Cox models showed <em>GHR</em>-<em>G</em> interacted with alcohol intake only (β = 1.171; p = 0.0003; drinks per week: β = 0.279; P = 0.0024). Stratified analyses showed that for <em>GHR-AA</em>, drinkers had reduced LC risk (HR = 0.54; 95 % CI, 0.35–0.85), and that &lt;2 drinks/week had the strongest protection (HR = 0.38; 95 % CI, 0.18–0.83). In contrast, for <em>GHR</em>-<em>G,</em> alcohol drinkers had increased LC risk (HR = 1.70; 95 % CI, 1.07–2.69) which was dose-dependent (P for trend = 0.005). Results for NSCLC were similar.</div></div><div><h3>Conclusion</h3><div>In men with the <em>GHR</em>-<em>AA</em> genotype, alcohol drinking at a low dose poses significantly less risk of LC compared with non-drinkers and higher alcohol consumption., the overall relationship being U-shaped. In contrast, in <em>GHR</em> minor allele carriers, alcohol posed a progressively greater risk of LC as amount consumed increased.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"198 ","pages":"Article 107971"},"PeriodicalIF":4.5,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined analysis of circulating tumor DNA and tumor tissue to overcome osimertinib resistance (OSIRIS); the second line osimertinib cohort","authors":"J.W.T. van der Wel ,&nbsp;M. Jebbink ,&nbsp;D. van den Broek ,&nbsp;L.C. Steinbusch ,&nbsp;W.S.M.E. Theelen ,&nbsp;G. Ruiter ,&nbsp;W. Buikhuisen ,&nbsp;J.A. Burgers ,&nbsp;P. Baas ,&nbsp;M. Vermeulen ,&nbsp;V. van der Noort ,&nbsp;S.M.S. Hashemi ,&nbsp;L.J.W. Bosch ,&nbsp;K. Monkhorst ,&nbsp;E.F. Smit ,&nbsp;M.C. Boelens ,&nbsp;A.J. de Langen","doi":"10.1016/j.lungcan.2024.107972","DOIUrl":"10.1016/j.lungcan.2024.107972","url":null,"abstract":"<div><h3>Introduction</h3><div>Osimertinib resistance inevitably occurs in EGFR mutated NSCLC. We aimed to identify resistance mechanisms (RM) using paired plasma and tumor samples in patients that progressed on 2nd/3rd line osimertinib.</div></div><div><h3>Methods</h3><div>From 09 – 2019 to 02 – 2021, 51 patients were enrolled. Plasma sequencing used AVENIO Expanded Panel (research use only), tumor biopsies underwent DNA and RNA sequencing and histological evaluation. Sequencing was regarded successful when the driver mutation was confirmed with a variant allele frequency of ≥0.10%. Concordance between modalities was calculated for the driver mutation and RMs covered in both modalities. The Molecular Tumor Board formulated a treatment advice.</div></div><div><h3>Results</h3><div>The driver mutation was detected in 42/51 plasma samples (82%) and in 50/51 tumor samples (98%), concordance rate was 80%. In 41/51 (80%) patients ≥1 RM was identified. Thirty-two RMs covered in both modalities were found in plasma (61.5%), 39 in tumor (75%), nineteen in both. RM concordance rate was 36.5%.</div></div><div><h3>Conclusion</h3><div>Combined analysis of plasma and tumor samples post 2nd/3rd line osimertinib identifies additional RMs regardless of the comparative approach used. Plasma sequencing identified 61.5% of RMs, tumor analysis identified 75%. Combined, they provide a superior overview of osimertinib resistance, enabling more tailored treatment options.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"198 ","pages":"Article 107972"},"PeriodicalIF":4.5,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142652704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-effectiveness of next-generation sequencing for advanced EGFR/ALK-negative non-small cell lung cancer","authors":"Dong-Won Kang ,&nbsp;Sun-Kyeong Park ,&nbsp;Sokbom Kang ,&nbsp;Eui-Kyung Lee","doi":"10.1016/j.lungcan.2024.107970","DOIUrl":"10.1016/j.lungcan.2024.107970","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to evaluate the cost-effectiveness of next-generation sequencing (NGS) versus sequential single-gene testing (SGT), including the long-term costs and survival outcomes of relevant treatments for advanced EGFR/ALK-negative non-small cell lung cancer (NSCLC).</div></div><div><h3>Materials and Methods</h3><div>We developed a decision tree linked to a partitioned survival model to estimate the clinical outcomes and costs over the five-year analysis period. The decision tree consisted of treatment types based on molecular biomarker (ROS1, BRAF, NTRK, MET, RET, and KRAS alterations) test results. The probability of receiving each targeted therapy was estimated based on 1) the testing rate, 2) the proportion of alterations detected, and 3) the proportion of patients receiving treatment consistent with the testing results. We estimated the long-term overall survival and progression-free survival for each treatment using parametric estimation by reconstructing patient-level data from clinical trials. The costs of testing, drugs, administration, physician visits, monitoring, adverse events, post-progression, and end-of-life care were included. The utility values were obtained from a previous study. The incremental cost-effectiveness ratio (ICER) was used to evaluate the cost-effectiveness of NGS within a threshold of $38,701 (50,000,000 KRW) per quality-adjusted life year (QALY).</div></div><div><h3>Results</h3><div>The incremental life-years (LYs) and QALYs for the NGS group versus the SGT group were 0.028 and 0.023, respectively. The total medical cost for the NGS group was $8,375 higher than that for the SGT group. The difference in drug costs accounted for most of the differences in total medical costs. NGS was not cost-effective compared to sequential SGT, with an ICER of $300,233/LY and $359,405/QALY, respectively.</div></div><div><h3>Conclusions</h3><div>NGS is not cost-effective for advanced EGFR/ALK-negative NSCLC, but has a survival benefit over sequential SGT. Our findings provide a basis for decision-making regarding the coverage and clinical utilization of NGS in regions where EGFR alterations are prevalent.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107970"},"PeriodicalIF":4.5,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly sensitive and accurate detection of ALK-TKI resistance mutations by oligoribonucleotide interference-PCR (ORNi-PCR)-based methods","authors":"Chiori Tabe ,&nbsp;Toshitsugu Fujita ,&nbsp;Kageaki Taima ,&nbsp;Hisashi Tanaka ,&nbsp;Tomonori Makiguchi ,&nbsp;Masamichi Itoga ,&nbsp;Yoshiko Ishioka ,&nbsp;Sadatomo Tasaka ,&nbsp;Hodaka Fujii","doi":"10.1016/j.lungcan.2024.107969","DOIUrl":"10.1016/j.lungcan.2024.107969","url":null,"abstract":"<div><h3>Background</h3><div>Patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) are treated with ALK tyrosine kinase inhibitors (TKIs). Although most patients benefit from ALK-TKIs, the development of resistance mutations is common and results in NSCLC recurrence. To identify ALK-TKI-resistant NSCLC at the early recurrent phase, highly sensitive and accurate methods for the detection of mutations are essential.</div></div><div><h3>Objective</h3><div>The aim of this study was to establish highly sensitive, accurate, cost-effective, and clinically practical methods for the detection of two frequent ALK-TKI resistance mutations, ALK G1202R and L1196M, by liquid biopsy.</div></div><div><h3>Methods</h3><div>The efficacy of oligoribonucleotide interference-PCR (ORNi-PCR) was examined by first optimizing experimental conditions to specifically amplify the ALK-TKI resistance mutant DNA corresponding to ALK G1202R and L1196M mutations. ORNi-PCR was then combined with droplet digital PCR (ddPCR) or real-time PCR to detect these mutations in cell-free DNA (cfDNA) extracted from NSCLC patients.</div></div><div><h3>Results</h3><div>ORNi-PCR followed by ddPCR/real-time PCR detected 1–10 copy(s) of G1202R and L1196M DNA in model cfDNA. These mutations in patients’ cfDNA were identified using ORNi-PCR-based methods, whereas conventional ddPCR failed to detect them.</div></div><div><h3>Conclusion</h3><div>ORNi-PCR followed by ddPCR/real-time PCR enables highly sensitive and accurate detection of <em>ALK</em> mutations by liquid biopsy. Although the clinical data are limited, our results show that these methods are potentially useful for identifying ALK-TKI-resistant NSCLC at the early recurrent phase.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107969"},"PeriodicalIF":4.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer","authors":"David Planchard ,&nbsp;Jürgen Wolf ,&nbsp;Benjamin Solomon ,&nbsp;Martin Sebastian ,&nbsp;Martin Wermke ,&nbsp;Rebecca S. Heist ,&nbsp;Jong-Mu Sun ,&nbsp;Tae Min Kim ,&nbsp;Noemi Reguart ,&nbsp;Miguel F. Sanmamed ,&nbsp;Enriqueta Felip ,&nbsp;Pilar Garrido ,&nbsp;Armando Santoro ,&nbsp;Douglas Bootle ,&nbsp;Xuân-Mai Couillebault ,&nbsp;Anil Gaur ,&nbsp;Christina Mueller ,&nbsp;Teresa Poggio ,&nbsp;Jie Yang ,&nbsp;Michele Moschetta ,&nbsp;Christophe Dooms","doi":"10.1016/j.lungcan.2024.107964","DOIUrl":"10.1016/j.lungcan.2024.107964","url":null,"abstract":"<div><h3>Background</h3><div>Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib.</div></div><div><h3>Methods</h3><div>This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50–350 mg once daily [QD] or 300–600 mg twice daily [BID]) with rineterkib (100–300 mg QD) in patients with <em>KRAS</em>-/<em>BRAF</em>-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with <em>KRAS</em>-/<em>BRAF</em>-mutant NSCLC and <em>NRAS</em>-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics.</div></div><div><h3>Results</h3><div>Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with <em>KRAS</em>-mutant, two with <em>BRAF^non-V600</em>-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with <em>KRAS</em>-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in <em>DUSP6</em> mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively.</div></div><div><h3>Conclusions</h3><div>Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.</div><div><span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> identifier: NCT02974725.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107964"},"PeriodicalIF":4.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survival and recurrence rates following SBRT or surgery in medically operable Stage I NSCLC","authors":"Michael Snider ,&nbsp;Joseph K. Salama ,&nbsp;Matthew Boyer","doi":"10.1016/j.lungcan.2024.107962","DOIUrl":"10.1016/j.lungcan.2024.107962","url":null,"abstract":"<div><h3>Objectives</h3><div>Surgery is the standard of care for early-stage non-small cell lung cancer (NSCLC), with SBRT reserved for patients who are not surgical candidates. We hypothesized overall survival (OS), lung cancer-specific survival (LCSS), progression free survival (PFS), and recurrence rates following SBRT or surgery in medically operable patients with Stage I NSCLC from the Veterans’ Health Care System (VAHS) would be equivalent.</div></div><div><h3>Materials and methods</h3><div>Medically operable patients diagnosed with Stage I NSCLC between 2000–2020 from the VAHS, determined by an FEV1 or DLCO &gt; 60 % of predicted and Charlson comorbidity index (CCI) of 0 or 1, treated with SBRT or surgery were identified. SBRT patients were propensity score matched in a 1:1:1 ratio to those undergoing resection (SBRT:lobectomy:sub-lobar resection). OS, LCSS, and PFS and site of recurrence were determined.</div></div><div><h3>Results</h3><div>103 patients were included in each cohort. With a median follow-up of 7.9 years 5-year OS for all patients was 51 % (95 % CI 46–57 %). After propensity score matching, OS (HR 2.08, 1.59), LCSS (HR 2.28, 1.97), and PFS (1.97, 1.45) were significantly worse with SBRT compared to either lobectomy or sub-lobar resection, respectively, (p &lt; 0.05 for each comparison). Regional recurrence was significantly higher following SBRT (15.5 % vs 6.8 % or 4.9 %; <em>p</em> &lt; 0.05), but there was no significant difference in local (28.2 % vs 21.4 % or 21.4 %; <em>p</em> &gt; 0.05) or distant recurrence (10.7 % vs 9.7 % or 13.6 %; <em>p</em> &gt; 0.05) when compared to lobectomy or sub-lobar resection, respectively.</div></div><div><h3>Conclusion</h3><div>In medically operable patients, OS, LCSS, and PFS following either lobectomy or sub-lobar resection were superior to that for SBRT for Stage I NSCLC, likely due in part to higher regional recurrence following SBRT. This suggests that pulmonary function test results and CCI alone are insufficient to define a cohort of medically operable patients suited for SBRT. These data support strategies to overcome regional recurrences seen with SBRT.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107962"},"PeriodicalIF":4.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}