Journal of Thoracic Oncology最新文献

{"title":"Final Overall Survival and Long-Term Safety of Lorlatinib in Patients With ALK-Positive NSCLC From the Pivotal Phase 2 Study: A Brief Report.","authors":"Sai-Hong Ignatius Ou, Benjamin J Solomon, Benjamin Besse, Alessandra Bearz, Chia-Chi Lin, Rita Chiari, D Ross Camidge, Jessica J Lin, Antonello Abbattista, Francesca Toffalorio, Ross A Soo","doi":"10.1016/j.jtho.2024.11.021","DOIUrl":"10.1016/j.jtho.2024.11.021","url":null,"abstract":"<p><strong>Introduction: </strong>Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases with broad coverage of ALK resistance mutations. We present the overall survival (OS) and long-term safety of lorlatinib in patients with advanced ALK-positive NSCLC from the final analyses of the pivotal phase 2 study.</p><p><strong>Methods: </strong>Adults with ALK-positive NSCLC, enrolled in expansion cohorts (EXPs) on the basis of prior therapy (EXP1-5), received lorlatinib 100 mg orally once daily in continuous 21-day cycles. The primary endpoint was the objective response rate; secondary endpoints included OS and safety.</p><p><strong>Results: </strong>Thirty patients were enrolled in EXP1 (treatment naïve), 59 in EXP2-3A (disease progression after crizotinib ± chemotherapy), 28 in EXP3B (disease progression after one second-generation ALK tyrosine kinase inhibitor [TKI] ± chemotherapy), 111 in EXP4-5 (disease progression after ≥2 ALK TKIs ± chemotherapy), and 139 in EXP3B-5 (disease progression after ≥1 ALK TKI ± chemotherapy). Median OS was not reached (NR) (95% confidence interval [CI]: NR-NR) in EXP1, NR (95% CI: 51.5-NR) in EXP2-3A, 37.4 months (95% CI: 12.3-NR) in EXP3B, 19.2 months (95% CI: 15.4-30.2) in EXP4-5, and 20.7 months (95% CI: 16.1-30.3) in EXP3B-5. All-cause adverse events leading to dose reduction were reported in 77 patients (28%), temporary treatment discontinuation in 158 patients (57%), and permanent discontinuation in 35 patients (13%).</p><p><strong>Conclusions: </strong>After a minimum follow-up of five years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.</p><p><strong>Clinicaltrials: </strong>gov NCT01970865.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710553","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":"Differentiating Separate Primary Lung Adenocarcinomas From Intrapulmonary Metastases With Emphasis on Pathological and Molecular Considerations: Recommendations From the International Association for the Study of Lung Cancer Pathology Committee.","authors":"Teh-Ying Chou, Sanja Dacic, Ignacio Wistuba, Mary Beth Beasley, Sabina Berezowska, Yeun-Chung Chang, Jin-Haeng Chung, Casey Connolly, Yuchen Han, Fred R Hirsch, David M Hwang, Andrew Janowczyk, Philippe Joubert, Keith M Kerr, Dongmei Lin, Yuko Minami, Mari Mino-Kenudson, Andrew G Nicholson, Mauro Papotti, Natasha Rekhtman, Anja C Roden, J H von der Thüsen, William Travis, Ming-Sound Tsao, Yasushi Yatabe, Yi-Chen Yeh, Lukas Bubendorf, Wei-Chin Chang, Valeria Denninghoff, Fabio Rocha Fernandes Tavora, Takuo Hayashi, Paul Hofman, Deepali Jain, Tae-Jung Kim, Sylvie Lantuejoul, John Le Quesne, Fernando Lopez-Rios, Daisuke Matsubara, Masayuki Noguchi, Teodora Radonic, Anjali Saqi, Kurt Schalper, Hyo Sup Shim, Lynette Sholl, Annikka Weissferdt, Wendy A Cooper","doi":"10.1016/j.jtho.2024.11.016","DOIUrl":"10.1016/j.jtho.2024.11.016","url":null,"abstract":"<p><strong>Introduction: </strong>With the implementation of low-dose computed tomography screening, multiple pulmonary tumor nodules are diagnosed with increasing frequency and the selection of surgical treatments versus systemic therapies has become challenging on a daily basis in clinical practice. In the presence of multiple carcinomas, especially adenocarcinomas, pathologically determined to be of pulmonary origin, the distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is important for staging, management, and prognostication.</p><p><strong>Methods: </strong>We systemically reviewed various means that aid in the differentiation between SPLCs and IPMs explored by histopathologic evaluation and molecular profiling, the latter includes DNA microsatellite analysis, array comparative genomic hybridization, TP53 and oncogenic driver mutation testing and, more recently, with promising effectiveness, next-generation sequencing comprising small- or large-scale multi-gene panels.</p><p><strong>Results: </strong>Comprehensive histologic evaluation may suffice to differentiate between SPLCs and IPMs. Nevertheless, molecular profiling using larger-scale next-generation sequencing typically provides superior discriminatory power, allowing for more accurate classification. On the basis of the literature review and expert opinions, we proposed a combined four-step histologic and molecular classification algorithm for addressing multiple pulmonary tumor nodules of adenocarcinoma histology that encourages a multidisciplinary approach. It is also noteworthy that new technologies combining machine learning and digital pathology may develop into valuable diagnostic tools for distinguishing SPLCs from IPMs in the future.</p><p><strong>Conclusions: </strong>Although histopathologic evaluation is often adequate to differentiate SPLCs from IPMs, molecular profiling should be performed when possible, especially in cases with tumors exhibiting similar morphology. This manuscript summarized the previous efforts in resolving the current challenges and highlighted the recent progress in the differentiation methods and algorithms used in categorizing multiple lung adenocarcinomas into SPLCs or IPMs, which are becoming more and more critical in precision lung cancer management.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695332","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":"Low Dose Computed Tomography for Lung Cancer Screening in Tuberculosis Endemic Countries: A Systematic Review and Meta-Analysis.","authors":"Vikram Damaraju, Juhu Kiran Krushna Karri, Gayathri Gandrakota, Yamini Marimuthu, Adimulam Ganga Ravindra, Rajeev Aravindakshan, Navneet Singh","doi":"10.1016/j.jtho.2024.11.020","DOIUrl":"10.1016/j.jtho.2024.11.020","url":null,"abstract":"<p><strong>Introduction: </strong>Lung cancer screening (LCS) using low-dose computed tomography (LDCT) reduces mortality. Nevertheless, in high tuberculosis-burden countries (HTBC), there are concerns about high false-positive rates due to persistent lung lesions from prior tuberculosis (TB) infections. This study aims to evaluate the screen-positive rate (SPR) of LDCT screening in HTBC.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis to identify studies utilizing LDCT for LCS in HTBC and reported SPR from inception to December 6, 2023. The primary outcome was the SPR, and the secondary outcome was the lung cancer detection rate (LCDR). The summary data was pooled using a random-effects model, and factors influencing the SPR were analyzed using multivariable meta-regression analysis.</p><p><strong>Results: </strong>A total of 44 studies with 477,424 individuals (59.3% men) were included in the systematic review. Lung Imaging Reporting and Data System (Lung-RADS) (31%, 14 studies) and National Lung Screening Trial (NLST) criteria (non-calcified nodule ≥ 4 mm; 10 studies) were the most common criteria used for assessing SPR. The pooled SPR and LCDR were 18.36% (95% confidence interval [CI]: 14.6-22.1) and 0.94% (95% confidence interval: 0.75-1.15), respectively. Although SPR was significantly higher with NLST criteria than Lung-RADS criteria (25.6% versus 10.4%, p < 0.0001), the LCDR remained similar (0.91% versus 0.95%, p = 0.92). Studies using NLST criteria had a higher SPR in multivariable meta-regression analysis. Nevertheless, the analysis is limited by significant statistical heterogeneity and publication bias.</p><p><strong>Conclusion: </strong>Lung cancer screening by LDCT in HTBC demonstrates comparable SPR and LCDR to regions with lower TB incidence rates. Lung-RADS criteria are preferable to NLST criteria for LCS in HTBC to mitigate false-positive rates.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710558","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":"Identification of Defined Molecular Subgroups on the Basis of Immunohistochemical Analyses and Potential Therapeutic Vulnerabilities of Pulmonary Carcinoids.","authors":"Daphne J G Leunissen, Laura Moonen, Jan H von der Thüsen, Michael A den Bakker, Lisa M Hillen, Tijmen J J van Weert, Axel Zur Hausen, Thierry P P van den Bosch, Lisa M V Lap, Ronald A Damhuis, Niki L Reynaert, Esther C van den Broek, Lynnette Fernandez-Cuesta, Matthieu Foll, Nicolas Alcala, Alexandra Sexton-Oates, Anne-Marie C Dingemans, Ernst-Jan M Speel, Jules L Derks","doi":"10.1016/j.jtho.2024.11.018","DOIUrl":"10.1016/j.jtho.2024.11.018","url":null,"abstract":"<p><strong>Introduction: </strong>Multi-omic studies have identified three molecular separated pulmonary carcinoid (PC) subgroups (A1, A2, B) with distinctive mRNA expression profiles (e.g., orthopedia homeobox protein [OTP], achaete-scute homolog [ASCL1], and hepatocyte nuclear factor 1 homeobox A [HNF1A]). We aimed to establish an immunohistochemical (IHC) biomarker panel that enables subgroup identification, and assessment of its potential clinical relevance.</p><p><strong>Methods: </strong>All patients with resected pulmonary carcinoids (2003-2012) were identified from the Dutch Cancer/Pathology Registry, and tumors were revised. The IHC expression of OTP, ASCL1, and HNF1A was scored in a blinded fashion in a mRNA-profiled (n = 5 per subgroup) and national carcinoid cohort (N = 478). The expression of potential therapeutic targets (somatostatin receptor type 2a [SSTR2A] and delta-like canonical Notch ligand 3 [DLL3]) was assessed. Immunohistochemistry was assessed using H-scoring.</p><p><strong>Results: </strong>OTP, ASCL1, and HNF1A reported similar IHC and mRNA expression patterns in the matched primary samples. In the national cohort, IHC separated PCs into subgroups A1 (n = 224 [53%], OTP^high-ASCL1^high-HNF1A^low), A2 (n = 161 [38%], OTP^high-ASCL1^low-HNF1A^high), and B (n = 37 [9%], OTP^low-ASCL1^low-HNF1A^high). In 12% of PCs, no distinct classification could be provided. Patients with A1 were enriched for older age (83% > 50 y), female individuals (83%), and peripheral location (55%) with low SSTR2A (median = 10) and high DLL3 (median = 52) expression. A2 included younger patients (34% < 40 y) and endobronchial/central (87%) tumors with high SSTR2A (median = 160), but low DLL3 (median 0) expression. Group B included more male individuals (59%) and recurrence was more frequent (19%) than in groups A1 (8%) and A2 (6%). Neuroendocrine cell hyperplasia was enriched in A1 (25%) compared with A2 (3%) and B (0%).</p><p><strong>Conclusions: </strong>An OTP, ASCL1, and HNF1A IHC panel enables the identification of molecular-defined pulmonary carcinoid subgroups with distinct clinical phenotypes and diverging therapeutic vulnerabilities that require further prospective evaluation.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710555","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":"Erratum to 'Critical Evaluation of Methodologic Approaches in ALK Tyrosine Kinase Inhibitor Research: Addressing Confounding Factors and Statistical Robustness' [Journal of Thoracic Oncology Vol 19 Issue 11 (2024) e64-e65].","authors":"Wenqin Wang, Xiangzhi Li, Dan Shan","doi":"10.1016/j.jtho.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.jtho.2024.11.002","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682075","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":"Safety, Efficacy, and Biomarker Analysis of Deulorlatinib (TGRX-326) in Anaplastic Lymphoma Kinase-Positive NSCLC: A Multicenter, Open-Label, Phase 1/1b Trial.","authors":"Shen Zhao, Huaqiang Zhou, Nong Yang, Zhehai Wang, Wenjian Jin, Yuxiang Ma, Jinhui Xue, Xingya Li, Yunpeng Liu, Rui Meng, Jianying Zhou, Ying Cheng, Yongsheng Wang, Zhuang Yu, Yu Cao, Yuanyuan Zhao, Yan Huang, Wenfeng Fang, Yang Zhang, Shaodong Hong, Bo Wu, Yanxia Shi, Jingrong Cao, Mingyan Xu, Xiaoni Zhang, Longyu Hu, Bo Peng, Yunpeng Yang, Li Zhang, Hongyun Zhao","doi":"10.1016/j.jtho.2024.11.010","DOIUrl":"10.1016/j.jtho.2024.11.010","url":null,"abstract":"<p><strong>Introduction: </strong>Patients with anaplastic lymphoma kinase (ALK)-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy, and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.</p><p><strong>Methods: </strong>This three-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in the People's Republic of China (ClinicalTrials.gov, NCT05441956). Patients who were eligible had advanced ALK/ROS1-positive NSCLC. Patients enrolled in dose-escalation/dose-expansion parts were previously treated with one or more second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive) and received deulorlatinib 5 to 125 mg once per day. Patients enrolled in cohort-expansion parts were either crizotinib-treated, second-generation tyrosine kinase inhibitor (TKI)-treated, or TKI-naïve; and received deulorlatinib at the recommended phase 2 dose (RP2D). The primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in patients who were ALK-positive.</p><p><strong>Results: </strong>Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive = 171, ROS1-positive = 27). The most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%), and weight gain (53.0%). 40.4% of patients had grade 3 or higher TRAEs. Meanwhile, TRAE-associated dose interruptions, reduction, and discontinuation occurred in 11.1%, 3.0%, and 1.5% of patients, respectively. The RP2D was set at 60 mg once per day. A total of 144 patients who were ALK-positive were treated at RP2D. For crizotinib-treated (n = 14), second-generation TKI-treated (n = 97), and TKI-naïve (n = 33) patients, the objective response rate to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial objective response rate was 50%, 70.4%, and 75%, respectively. The median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for patients who were crizotinib-treated and TKI-naïve. Biomarker analyses identified undetectable ALK alterations at baseline and ALK circulating tumor DNA clearance at week 6 as potential predictive biomarkers.</p><p><strong>Conclusions: </strong>Deulorlatinib reported desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648457","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":"Prophylactic Cranial Irradiation for Patients With SCLC-A New Perspective in the Immunotherapy Era.","authors":"Antonin Levy, Chad G Rusthoven, Paul D Brown, Cécile Le Péchoux, Corinne Faivre-Finn","doi":"10.1016/j.jtho.2024.11.011","DOIUrl":"10.1016/j.jtho.2024.11.011","url":null,"abstract":"<p><p>Prophylactic cranial irradiation (PCI) has long been used for SCLC to reduce the risk of brain metastases and potentially improve overall survival. Nevertheless, recent immunotherapy trials have provided limited data on its impact, as few patients were treated with PCI. The ADRIATIC trial reported improved outcomes with consolidation immunotherapy in limited-stage SCLC, and PCI was a stratification factor. Notably, patients receiving PCI in both arms had better outcomes than those who did not. Ongoing studies, such as EORTC-1901 PRIMALung (NCT04790253) and SWOG 1827-MAVERICK (NCT04155034), are further investigating PCI's role in the era of immunotherapy, highlighting its potential importance in evolving treatment strategies.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648400","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":"Predicted Effect of Incidental Pulmonary Nodule Findings on NSCLC Mortality.","authors":"S Tuminello, R Flores, M Untalan, T Ivic-Pavlicic, C I Henschke, R Yip, D F Yankelevitz, Emanuela Taioli","doi":"10.1016/j.jtho.2024.11.009","DOIUrl":"10.1016/j.jtho.2024.11.009","url":null,"abstract":"<p><strong>Introduction: </strong>Despite the reduction in mortality by low-dose computed tomography lung cancer screening, the uptake is still low. Patients undergo chest imaging for several other medical reasons, and this is a unique opportunity to detect lung nodules.</p><p><strong>Methods: </strong>In a cohort of patients with NSCLC from the Surveillance, Epidemiology, and End Results-Medicare-linked data, tumor size at previous imaging was calculated as follows: volume doubling time = [(T₂-T₁)·ln2]/ln(V₂/V₁), solving for the diameter of V₁. V₁ and V₂ are tumor volume at times T₁ (previous imaging) and T₂ (diagnostic procedure) according to three different growth models. The 10-year lung cancer-specific mortality was calculated as follows: lung cancer survival rate = (-0.0098 × maximum tumor diameter) + 1.</p><p><strong>Results: </strong>A total of 1007 patients who had a chest imaging performed up to 1 year before lung cancer diagnosis were included in this study. The median size of the tumor at diagnosis was 25 mm, and the predicted median tumor size at previous imaging was 12.16 mm, 17.3 mm, and 20.42 mm under the fast, medium, and slow growth model, respectively. Under the fast growth model, a detection of the nodule at previous imaging would have yield a decrease in mortality of 7.79%; the corresponding value for the medium growth model is 4.5% and for the slow growth model 2.45%.</p><p><strong>Conclusions: </strong>Identifying malignant lung nodules in imaging performed for other clinical reasons can help decrease the burden of NSCLC, especially for patients not eligible for low-dose computed tomography and the medically vulnerable. We reveal here that clinical benefits, especially among patients with aggressive disease, can be considerable.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621845","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":"DSTYK Inhibition Sensitizes NSCLC to Taxane-Based Chemotherapy.","authors":"Mirari Echepare, Beñat Picabea, Andrea Arricibita, Álvaro Teijeira, Andrea Pasquier, Carolina Zandueta, Nerea Otegui, Enrique Santamaría, Joaquín Fernández-Irigoyen, Octavio Romero, Montse Sanchez-Cespedes, Fernando Lecanda, Javier Hernández, Enriqueta Felip, Alberto Cruz-Bermúdez, Mariano Provencio, Marco Gentili, Federica Facchinetti, Luca Roz, Luis M Montuenga, Karmele Valencia","doi":"10.1016/j.jtho.2024.11.003","DOIUrl":"10.1016/j.jtho.2024.11.003","url":null,"abstract":"<p><strong>Introduction: </strong>Chemotherapy continues to be the standard treatment for patients noneligible for targeted or immune-based therapies; nevertheless, treatment resistance remains a major clinical challenge. We previously found that expression levels of DSTYK, a poorly explored dual serine/threonine and tyrosine kinase frequently amplified in cancer, identified patients with lung cancer exhibiting poor response to immune checkpoint inhibitors, and found that its inhibition sensitizes to immunotherapy. Seeking to explore the potential of DSTYK targeting in additional indications, we investigated the functional relevance and actionability of DSTYK in lung cancer chemoresistance.</p><p><strong>Methods: </strong>In silico analysis to study the differential sensitivity to paclitaxel, carboplatin, pemetrexed, and cisplatin drugs was performed using pan-cancer human cancer cell line DSTYK CN data downloaded from Depmap portal (https://depmap.org/portal/depmap/). Two cohorts of patients with lung cancer were used. An adjuvant cohort composed of patients with advanced IV-stage lung adenocarcinoma treated with carboplatin plus paclitaxel or carboplatin plus pemetrexed in the first line from VHIO; A neoadjuvant cohort including resectable stage IIIA or IIIB NSCLC tumor samples of patients from NADIM I and NADIM II clinical trials perioperative treated with nivolumab plus chemotherapy (carboplatin + paclitaxel). DSTYK CN was assessed by fluorescence in situ hybridization and quantitative reverse transcription-polymerase chain reaction. Proteomics and bioinformatic analyses were performed to study differentially expressed protein signatures. Functional in vitro experiments (adhesion, migration, and invasion) in both murine and human systems, and in vivo lung orthotopic, intracardiac, and intratibial xenograft and syngeneic models complete the study.</p><p><strong>Results: </strong>We show that DSTYK depletion specifically sensitizes lung cancer cells to taxane-based chemotherapy, particularly in combination with carboplatin. Mechanistically, DSTYK ablation remodels the cytoskeleton and impairs distant invasion and metastatic outgrowth in vivo. DSTYK downregulation sensitizes both primary and metastatic lung tumors to chemoimmunotherapy treatment leading to tumor regression in mouse models. Consistently, clinical data of patients with early and advanced lung cancer-in the neoadjuvant and adjuvant settings-show a strong correlation between DSTYK amplification and taxane resistance, underscoring the clinical significance of our findings to inform treatment decision-making.</p><p><strong>Conclusions: </strong>Collectively, our data indicates that DSTYK amplification may be a predictor of resistance to taxane-based treatments and represents an actionable target for these patients.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635770","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":"Durvalumab Versus Chemotherapy as First-line Treatment for Metastatic NSCLC With Tumor PD-L1 Expression of 25% or Higher: Results From the Randomized Phase 3 PEARL Study.","authors":"Shun Lu, Lin Wu, Qiming Wang, Ziping Wang, Dongqing Lv, Rui Ma, Bo Zhu, Ngoc van Tran, Liyan Jiang, Kejun Nan, Konstantin Laktionov, Stephen Clarke, Minghao Song, Helen Mann, Yinglei Liu, Xiaojin Shi, Yi-Long Wu","doi":"10.1016/j.jtho.2024.10.024","DOIUrl":"10.1016/j.jtho.2024.10.024","url":null,"abstract":"<p><strong>Introduction: </strong>PEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic NSCLC (mNSCLC [EGFR/ALK wild type]) with programmed cell death ligand 1 (PD-L1) tumor cell (TC) membrane expression status of 25% or higher. We report the final analysis of PEARL.</p><p><strong>Methods: </strong>Adults (N = 669) with previously untreated stage IV mNSCLC were randomized (1:1) to durvalumab 20 mg/kg every four weeks or chemotherapy every three weeks for four to six cycles. The dual primary endpoints were overall survival (OS) in the population with PD-L1 TC of 25% or higher and OS in the population at low risk of early mortality (LREM) with PD-L1 TC of 25% or higher.</p><p><strong>Results: </strong>Durvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the 25% and higher PD-L1 TC population (OS hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.71-0.99, p = 0.037; median OS 14.6 months, 95% CI: 12.2-16.9 versus 12.8 months, 95% CI: 10.1-14.7, respectively). In the 25% and higher PD-L1 TC low risk of early mortality population the OS hazard ratio for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79-1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6-17.2) versus 15.0 months (95% CI: 13.1-16.8), respectively. In the safety population, the incidence of grade 3 or 4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy).</p><p><strong>Conclusions: </strong>Durvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and 25% and higher PD-L1 TC. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621699","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}