Journal of Thoracic Oncology最新文献

{"title":"Immune Composition and Immunotherapy Outcomes of Mesothelioma with BAP1, CDKN2A, MTAP, and NF2 Alterations.","authors":"Ibiayi Dagogo-Jack, Owen Mitchell, Elizabeth Codd, Annie Li, Dawn Mitchell, Samantha E Flynn, Nanna Sivamanoharan, Patrick Reeves, Mark Poznansky, Ivan Valiev, Artem Kosmin, Beow Y Yeap, Grace Hambelton, A John Iafrate, Jochen K Lennerz, Yin P Hung, Hedy Kindler","doi":"10.1016/j.jtho.2025.06.018","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.06.018","url":null,"abstract":"<p><strong>Background: </strong>First-line mesothelioma treatment paradigms prioritize histology without integrating molecular features. Findings from other thoracic cancers suggest that tumor immune microenvironment (TME) composition and immunotherapy efficacy are informed by genomic profile. Mesothelioma studies exploring the relationship between molecular alterations, immune infiltrate, and immunotherapy outcomes are needed.</p><p><strong>Methods: </strong>Exome and transcriptomic sequencing and multiplex immunofluorescence were performed on pleural and peritoneal mesotheliomas annotated for BAP1, CDKN2A, MTAP, and NF2 (merlin) status to infer immune cell abundance and TME composition. Progression-free survival (PFS) and overall survival (OS) on ipilimumab + nivolumab was retrospectively determined according to molecular profile.</p><p><strong>Results: </strong>Transcriptional analysis segregated 113 mesothelioma specimens (n=85 epithelioid, n=28 non-epithelioid) into four predefined TME groups: fibrotic (n=14), immune desert (n=52), immune-enriched fibrotic (n=13), and immune-enriched non-fibrotic (n=34). The composition of the immune infiltrate was similar when tumors with BAP1 alterations were compared to BAP1 wildtype tumors. In contrast, specimens with MTAP or CDKN2A loss had global decrease in immune populations with predominance of the immune desert phenotype. There was non-significant increase in T lymphocytes in NF2-altered tumors. Multiplex immunofluorescence similarly demonstrated increased T lymphoid infiltrate in mesotheliomas with merlin loss, including regulatory T cells. On ipilimumab + nivolumab, patients with BAP1 alterations had improved survival whereas those with NF2 and CDKN2A alterations had shorter survival.</p><p><strong>Conclusions: </strong>Composition of the immune infiltrate may be distinct for mesotheliomas with loss of 9p21 genes (i.e., MTAP, CDKN2A) and NF2 alterations. Overall immune infiltrate abundance did not align with immunotherapy outcomes. Future immunotherapy biomarker development strategies should consider molecular background and functional characterization of mesothelioma tumor-immune interactions.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512112","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":"Surgical Outcomes with Neoadjuvant Durvalumab Plus Chemotherapy Followed by Adjuvant Durvalumab in Resectable NSCLC.","authors":"Tetsuya Mitsudomi, John V Heymach, Martin Reck, Janis M Taube, Shugeng Gao, Yoshitsugu Horio, Jian You, Gaofeng Li, Dinh Van Luong, Somcharoen Saeteng, Fumihiro Tanaka, Stefan B Watzka, Laszlo Urban, Zsuzsanna Szalai, Hiroaki Akamatsu, Jin Hyoung Kang, Francisco J Orlandi, Guzel Z Mukhametshina, Andreas Pircher, Carlos Henrique Andrade Teixeira, Mike Aperghis, Gary J Doherty, Ruth Doake, Tamer M Fouad, David Harpole","doi":"10.1016/j.jtho.2025.06.015","DOIUrl":"10.1016/j.jtho.2025.06.015","url":null,"abstract":"<p><strong>Introduction: </strong>In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival and pathological complete response (primary endpoints; modified ITT [mITT] population, which excluded patients with known EGFR/ALK aberrations) with a manageable safety profile in patients with resectable (R)-NSCLC. Here, we report surgical outcomes from AEGEAN.</p><p><strong>Methods: </strong>Patients with treatment-naïve R-NSCLC (stage II-IIIB[N2]) and ECOG PS 0/1 were randomized (1:1) to platinum-based chemotherapy plus durvalumab or placebo IV (Q3W, 4 cycles) before surgery, followed by durvalumab or placebo (Q4W, 12 cycles). Surgical outcomes were summarized for the mITT population using descriptive statistics.</p><p><strong>Results: </strong>737/740 mITT patients received treatment, 366 and 371 in the durvalumab and placebo arms, respectively; 80.6% and 80.7% underwent surgery, 77.6% and 76.7% completed surgery, and, of the 295 and 302 patients who underwent surgery, 17.3% and 22.2% had delayed surgery. Median time from last neoadjuvant dose to surgery was 34.0 days in both arms. Of patients who underwent surgery, similar proportions had open (49.2% vs 50.7%) and minimally invasive (49.2% vs 47.0%) procedures; lobectomy was the most common procedure (88.1% vs 85.4%). R0 resection rates were numerically higher in the durvalumab versus placebo arm (94.7% vs 91.3%). Median time from surgery to first adjuvant dose was 50.0 versus 52.0 days. In exploratory analyses, a numerically higher proportion of patients in the durvalumab versus placebo arm with baseline N2 nodal status had downstaging from N2 to N0 (47.3% vs 40.2%) or, with baseline N1 nodal status, from N1 to N0 (53.6% vs 46.2%) after surgery. Similar proportions had surgical complication(s) (59.1% vs 60.1%), primarily grade 1/2 (53.0% vs 51.8%, modified safety analysis set).</p><p><strong>Conclusion: </strong>The addition of durvalumab to neoadjuvant chemotherapy had no detrimental effect on the feasibility, approach, type, or timing of surgery and was associated with a tolerable surgical safety profile, versus neoadjuvant chemotherapy alone.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT03800134.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368938","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":"Targeting WEE1 to overcome ARID1A mutation-driven osimertinib resistance in EGFR-mutant lung cancer.","authors":"Koji Fukuda, Shigeki Nanjo, Shinji Takeuchi, Turja Chakrabarti, Tyiesha Brown, Sharon Wesley Dev Sahadevan, Sachiko Arai, Shigeki Sato, Hiroshi Kotani, Akihiro Nishiyama, Hiroyuki Sakaguchi, Koushiro Ohtsubo, Hiroaki Taniguchi, Collin M Blakely, Trever G Bivona, Seiji Yano","doi":"10.1016/j.jtho.2025.06.007","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.06.007","url":null,"abstract":"<p><strong>Introduction: </strong>Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). However, despite its efficacy, resistance remains a major clinical challenge with unknown underlying mechanisms. This study aimed to investigate the mechanisms driving osimertinib resistance and identify therapeutic strategies.</p><p><strong>Methods: </strong>Using a mouse model of leptomeningeal carcinomatosis (LMC), we induced osimertinib resistance and performed next-generation sequencing to characterize resistance-associated mutations. We also analyzed clinical samples to correlate ARID1A status with progression-free survival (PFS) and overall survival (OS) in patients receiving osimertinib.</p><p><strong>Results: </strong>Mutations in the AT-rich interacting domain-containing protein 1A (ARID1A) gene were the most prevalent in resistant cells. Functional assays revealed that ARID1A knockout in parental cells and wild-type ARID1A gene expression in resistant cells were critical in conferring osimertinib resistance. A CRISPR-Cas9 knockout screen identified WEE1 kinase as a potent enhancer of apoptosis in ARID1A-mutant osimertinib-resistant cells. Mechanistically, ARID1A-mutant cells exhibited reduced expression of genes involved in cell cycle regulation and DNA repair, rendering them particularly sensitive to WEE1 inhibition. In the LMC mouse model, the combined inhibition of EGFR and WEE1 significantly suppressed tumor growth. Clinically, patients with ARID1A mutations treated with osimertinib had significantly shorter median PFS (6.25 vs. 18.0 months, p=0.0036) and OS (17.0 vs. 34.0 months, p=0.024) than those with wild-type ARID1A.</p><p><strong>Conclusions: </strong>These findings suggest that ARID1A mutations are critical biomarkers for osimertinib resistance and highlight WEE1 inhibition as a promising therapeutic approach for ARID1A-mutant osimertinib-resistant NSCLC.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302386","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":"A pooled analysis of datopotamab deruxtecan in patients with EGFR-mutated NSCLC.","authors":"Myung-Ju Ahn, Aaron Lisberg, Yasushi Goto, Jacob Sands, Min Hee Hong, Luis Paz-Ares, Elvire Pons-Tostivint, Maurice Pérol, Enriqueta Felip, Shunichi Sugawara, Hidetoshi Hayashi, Byoung Chul Cho, George Blumenschein, Elaine Shum, Jong-Seok Lee, Rebecca S Heist, Robin Cornelissen, Wen-Cheng Chang, Dariusz Kowalski, Hong Zebger-Gong, Michael Chargualaf, Wen Gu, Lan Lan, Paul Howarth, Richard Joseph, Isamu Okamoto","doi":"10.1016/j.jtho.2025.06.002","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.06.002","url":null,"abstract":"<p><strong>Background: </strong>This exploratory analysis assessed datopotamab deruxtecan (Dato-DXd) in pretreated patients with advanced/metastatic NSCLC and EGFR mutations.</p><p><strong>Methods: </strong>Data were pooled from the phase II TROPION-Lung05 (NCT04484142) and phase III TROPION-Lung01 (NCT04656652) trials. Patients with EGFR-mutated advanced/metastatic NSCLC, who had received prior targeted therapies and platinum-based chemotherapy, received Dato-DXd 6 mg/kg (TROPION-Lung05) or were randomized to Dato-DXd 6 mg/kg or docetaxel 75 mg/m² (TROPION-Lung01) once every three weeks. Endpoints included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS), all per blinded independent central review, overall survival (OS), and safety.</p><p><strong>Results: </strong>In total, 117 patients with EGFR mutations who received Dato-DXd were included in the pool. The population was heavily pretreated (median three lines of prior therapies, range 1-5) and predominantly Asian (69%). The most common mutations were exon 19 deletion (51%), L858R (32%), and T790M (27%); more than one EGFR mutation could be present. The confirmed ORR was 43% (95% confidence interval [CI]: 34-52), including five complete responses (4%). Median DOR was 7.0 months (95% CI: 4.2-9.8). Median PFS and OS were 5.8 (95% CI: 5.4-8.2) and 15.6 months (95% CI: 13.1-19.0), respectively. The safety profile of Dato-DXd was consistent with the individual studies. No new safety signals were observed. Rates of grade ≥3 treatment-related adverse events and serious adverse events were 23% and 6%, respectively.</p><p><strong>Conclusion: </strong>Dato-DXd demonstrated meaningful clinical activity in patients with EGFR-mutated advanced/metastatic NSCLC who had progressed on EGFR-directed therapies and chemotherapy, with an acceptable safety profile.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293962","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":"Genomic profiles of pathogenic and moderate-penetrance germline variants associated with risk of early-onset lung adenocarcinoma.","authors":"Hourin Cho, Kouya Shiraishi, Kuniko Sunami, Yukihide Momozawa, Tatsuya Yoshida, Shingo Matsumoto, Koichi Matsuda, Motonobu Saito, Akiteru Goto, Takayuki Honda, Akifumi Mochizuki, Masahiro Torasawa, Yataro Daigo, Kimihiro Shimizu, Hideo Kunitoh, Yukihiro Yoshida, Makoto Hirata, Yoko Shimada, Michiko Ueki, Hanako Ono, Masahiro Gotoh, Yukiko Shimoda Igawa, Akiko Tateishi, Yoh Yamaguchi, Ryoko Inaba Higashiyama, Erika Machida, Motoki Iwasaki, Yosuke Kawai, Hiroyuki Yasuda, Junko Hamamoto, Issei Imoto, Hirokazu Matsushita, Sadaaki Takata, Tomomi Aoi, Syuzo Kaneko, Aya Kuchiba, Akihiko Shimomura, Maki Fukami, Kotaro Hattori, Kouichi Ozaki, Yoshihiro Asano, Biobank Japan Project, Atsushi Takano, Masashi Kobayashi, Yohei Miyagi, Kazumi Tanaka, Hiroyuki Suzuki, Takumi Yamaura, Teruhiko Yoshida, Yasushi Goto, Hidehito Horinouchi, Yasunari Miyazaki, Hidemi Ito, Toshiteru Nagashima, Yoichi Ohtaki, Kazuhiro Imai, Yoshihiro Minamiya, Kenichi Okubo, Johji Inazawa, Yuichi Shiraishi, Katsushi Tokunaga, Yoichiro Kamatani, Yasushi Yatabe, Koichi Goto, Masahiro Tsuboi, Shun-Ichi Watanabe, Yuichiro Ohe, Yoshinori Murakami, Keitaro Matsuo, Ryuji Hamamoto, Takahshi Kohno","doi":"10.1016/j.jtho.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.06.005","url":null,"abstract":"<p><strong>Introduction: </strong>Up to 54% of all lung adenocarcinoma (LADC) cases in Asian populations occur in never-smoking women, suggesting that the impact of smoking and other environmental factors on the risk of early-onset LADC is minimal. Genetic factors may play a crucial role in disease development.</p><p><strong>Methods: </strong>The prevalence of germline pathogenic variants (GPVs) of 454 hereditary cancer and DNA repair genes was examined by whole-exome and whole-genome sequencing of 350 early-onset LADC (aged < 40 years) and 1,441 later-onset LADC (aged ≥ 41 years) cases. A case-control study comprising 10,672 LADC cases and 7,898 healthy controls was performed to identify moderate-risk genetic factors for the disease. Analysis of somatic mutations in 1,280 LADC patients, including 31 patients with GPVs, was also performed.</p><p><strong>Results: </strong>The frequency of GPVs of TP53 and BRCA2 was significantly higher in those with early-onset LADC than in those with later-onset LADC. The detection rates for TP53 and BRCA2 GPVs were 2.9% and 1.7%, respectively, in patients with early-onset LADC, and 0.14% and 0.21%, respectively, in patients with later-onset LADC. Patients with BRCA1 GPVs showed a high incidence of concurrent TP53 somatic mutations. Patients with BRCA2 GPVs showed deficient homologous recombination in tumors via loss of the wild-type allele. A germline ALKBH2 variant, p.Glu35Alafs*54, was associated with the risk of early-onset LADC, and patients with a deleterious variant showed a correlation between SBS4-related somatic mutations and the Brinkman index.</p><p><strong>Conclusions: </strong>TP53 and BRCA2 GPVs and the ALKBH2 novel variant are associated with early-onset LADC in Asians.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293963","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 or Perioperative Chemoimmunotherapy Treatment in Patients with Resectable NSCLC: Still an Open Question. Comments on Marinelli et al. J Thorac Oncol. 2025;20:285-295.","authors":"Urania Dafni, Zoi Tsourti, Aikaterini Vervita, Panagiota Zygoura, Solange Peters","doi":"10.1016/j.jtho.2025.05.007","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.05.007","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216240","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":"Updated Efficacy and Safety From the Phase 2 PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic NSCLC‒A Brief Report.","authors":"Gregory J Riely, Myung-Ju Ahn, Jeffrey M Clarke, Ibiayi Dagogo-Jack, Raymond Esper, Enriqueta Felip, Francesco Gelsomino, Jonathan W Goldman, Maen Hussein, Melissa Johnson, Kristen A Marrone, Daniel Morgensztern, Ernest Nadal, Marcelo V Negrao, Michael Offin, Mariano Provencio, Suresh S Ramalingam, Logan Roof, Rachel E Sanborn, Egbert F Smit, Anne Tsao, Tiziana Usari, Ann Alcasid, Keith Wilner, Svitlana Tonkovyd, Xiaosong Zhang, Bruce E Johnson","doi":"10.1016/j.jtho.2025.05.023","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.05.023","url":null,"abstract":"<p><strong>Introduction: </strong>The PHAROS primary analysis showed robust antitumor activity and acceptable safety with encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report results after 18 months of additional follow-up.</p><p><strong>Methods: </strong>In this ongoing open-label, single-arm, phase 2 study, patients with BRAF V600E-mutant mNSCLC (59 treatment-naïve and 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily. Primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Results: </strong>At this data cutoff, median treatment duration with encorafenib plus binimetinib was 16.3 months in treatment-naïve and 5.5 months in previously treated patients; minimum follow-up was approximately 32 and 22 months, respectively. In treatment-naïve patients, the ORR was 75%, median DOR was 40.0 months, median PFS was 30.2 months, median OS was not estimable (NE; 95% CI: 31.3-NE), and the 3-year OS rate was 53%. In previously treated patients, the ORR was 46%, median DOR was 16.7 months, median PFS was 9.3 months, median OS was 22.7 months, and the 3-year OS rate was 29%. Overall, the most frequent treatment-related adverse events (TRAEs) were nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%). TRAEs led to dose reductions and permanent treatment discontinuations in 25 (26%) and 16 (16%) patients, respectively.</p><p><strong>Conclusions: </strong>With longer follow-up, encorafenib plus binimetinib showed durable and clinically meaningful antitumor activity, especially in treatment-naïve patients, with a manageable safety profile in patients with BRAF V600E-mutant mNSCLC.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248483","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":"LEAP-008: Lenvatinib Plus Pembrolizumab for Metastatic NSCLC That Has Progressed After an Anti-PD-(L)1 Plus Platinum Chemotherapy.","authors":"Natasha B Leighl, Luis Paz-Ares, Delvys Rodriguez Abreu, Rina Hui, Sofia Baka, Frédéric Bigot, Makoto Nishio, Alexey Smolin, Samreen Ahmed, Adam J Schoenfeld, Sameh Daher, Diego L Cortinovis, Vincenzo Di Noia, Helena Linardou, Justin F Gainor, Corina Dutcus, Chinyere E Okpara, Xuan Deng, Debra Kush, Ashwini Arunachalam, Andrew Song, Byoung Chul Cho","doi":"10.1016/j.jtho.2025.05.020","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.05.020","url":null,"abstract":"<p><strong>Background: </strong>LEAP-008 (NCT03976375) was an open-label, randomized, phase 3 study of lenvatinib plus pembrolizumab versus docetaxel for metastatic NSCLC that progressed on anti‒programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy and platinum-containing chemotherapy.</p><p><strong>Methods: </strong>Participants were randomized 4:4:1 to once-daily lenvatinib 20 mg plus pembrolizumab 200 mg every 3 weeks (maximum 35 cycles), docetaxel 75 mg/m² every 3 weeks, or once-daily lenvatinib 24 mg. Primary endpoints were overall survival (OS) and progression-free survival (PFS) per RECIST version 1.1 by central review. Superiority of lenvatinib plus pembrolizumab versus docetaxel was assessed at interim analysis 2 for PFS and at final analysis for OS.</p><p><strong>Results: </strong>Participants (N=422) were randomized to lenvatinib plus pembrolizumab (n=185), docetaxel (n=189), or lenvatinib monotherapy (n=48). Median (95% CI) PFS was 5.6 (4.2‒6.5) months with lenvatinib plus pembrolizumab and 4.2 (3.2‒5.2) months with docetaxel (hazard ratio [HR], 0.89 [95% CI, 0.70‒1.12]; P=0.164). Median (95% CI) OS was 11.3 (9.4‒13.2) versus 12.0 (9.6‒13.7) months (HR, 0.98 [95% CI, 0.78‒1.23]; P=0.434). Rates of treatment-related adverse events (AEs) were 91.7%, 91.0%, and 89.4% with lenvatinib plus pembrolizumab, docetaxel, and lenvatinib, respectively; rates of grade 3 to 5 treatment-related AEs were 59.7%, 48.6%, and 57.4%. Health-related quality of life scores were similar between treatment arms.</p><p><strong>Conclusion: </strong>Lenvatinib plus pembrolizumab did not improve efficacy versus docetaxel in participants with stage IV NSCLC that progressed on anti‒PD-1/PD-L1 therapy and platinum-containing chemotherapy. There were no unexpected safety signals. More effective therapies are needed for this patient population.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234465","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":"Treatment-Free Survival Over 6 Years of Follow-up in Patients With Metastatic Non-small Cell Lung Cancer Treated With First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in CheckMate 227 Part 1.","authors":"Solange Peters, Meredith M Regan, Luis G Paz-Ares, Martin Reck, Hossein Borghaei, Kenneth J O'Byrne, Julie R Brahmer, John R Penrod, Janice Li, LaRee Tracy, Yong Yuan, Judith Bushong, Adam Lee, Laura J Eccles, Saurabh Ray, Suresh S Ramalingam","doi":"10.1016/j.jtho.2025.05.019","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.05.019","url":null,"abstract":"<p><strong>Introduction: </strong>Treatment-free survival (TFS) characterizes periods of disease control and durable clinical benefit following treatment discontinuation in patients treated with immunotherapy. In CheckMate 227 Part 1, nivolumab plus ipilimumab showed long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic NSCLC. Here, we report updated long-term TFS results.</p><p><strong>Methods: </strong>This analysis included all randomized patients (tumor PD-L1 expression ≥1% and <1%). TFS was estimated as the restricted-mean survival time (between Kaplan-Meier curves for time to treatment discontinuation and time to subsequent systemic therapy/death) over 6-years post-randomization. TFS was further divided into periods with/without ongoing toxicity (grade ≥3 treatment-related adverse events [TRAEs]) and estimated over 2- and 6-years post-randomization.</p><p><strong>Results: </strong>At 6-years post-randomization (minimum follow-up: 73.5 months [∼6.1 years]), the estimated OS rate was 20% with nivolumab plus ipilimumab versus 11% with chemotherapy; 13% versus 2% of patients were treatment free. The 6-year mean TFS was 12.2 versus 5.0 (difference 7.2 [95% confidence interval (CI): 5.4-9.2]) months, with 17% versus 7% of the 6-year period spent in TFS. The 6-year mean TFS without grade ≥3 TRAEs was 11.6 versus 4.8 (difference, 6.9 [95% CI: 5.1-8.9]) months. The proportion of mean TFS time increased from 15% of 2-year to 17% of 6-year period with nivolumab plus ipilimumab but decreased from 14% to 7% with chemotherapy. Similar results were observed by tumor PD-L1 expression.</p><p><strong>Conclusions: </strong>Nivolumab plus ipilimumab improved TFS versus chemotherapy, regardless of tumor PD-L1 expression, supporting its use as an efficacious first-line treatment for metastatic NSCLC.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234467","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":"Quantitative and Dynamic ctDNA as a Biomarker of Response and Survival in Patients With Advanced Lung Squamous Cell Carcinoma Receiving Immunochemotherapy or Chemotherapy Alone.","authors":"Fei Zhou, Jiao Zhang, Shengxiang Ren, Jianhua Chen, Feifei Li, Ting Ma, Yong Fang, Qiming Wang, Wenxiu Yao, Renhua Guo, Dongqing Lv, Shundong Cang, Xiaorong Dong, Huijuan Wang, Nong Yang, Yun Fan, Jiuwei Cui, Ziping Wang, Jianxing He, Yu S Huang, Weizhi Chen, Li-Di Xu, Caicun Zhou","doi":"10.1016/j.jtho.2025.05.021","DOIUrl":"10.1016/j.jtho.2025.05.021","url":null,"abstract":"<p><strong>Introduction: </strong>Although circulating tumor DNA (ctDNA) dynamics have been widely explored for therapeutic response assessment, standardized methodologies remain elusive. Here, we developed MinerVa-Delta, a novel approach to quantify ctDNA dynamics by calculating weighted mutation changes in samples with multiple tracked variants.</p><p><strong>Methods: </strong>MinerVa-Delta was developed and analytically validated using serially diluted reference samples. The optimal cutoff was determined in a discovery cohort of 227 patients with advanced lung squamous cell carcinoma (LUSC) receiving programmed cell death protein 1 blockade plus chemotherapy or chemotherapy alone and further validated in an independent cohort of 97 patients with LUSC treated with chemotherapy alone. Variants were de novo called in pretreatment samples using a 769-gene next-generation sequencing panel, serving as a basis for personalized variant tracking in posttreatment plasma after two cycles of treatment. We applied MinerVa-Delta to evaluate prognosis and therapeutic response in advanced LUSC.</p><p><strong>Results: </strong>Patients classified as molecular responders (MinerVa-Delta <30%) exhibited significantly improved outcomes compared with nonresponders (MinerVa-Delta ≥30%), with superior progression-free survival (hazard ratio = 0.19, p < 0.001) and overall survival (hazard ratio = 0.24, p < 0.001). MinerVa-Delta displayed consistent prediction performance in the validation cohort. Furthermore, MinerVa-Delta accurately identified radiologic stable disease patients, a clinically heterogeneous population, who could benefit from initial treatment.</p><p><strong>Conclusions: </strong>Our findings suggest MinerVa-Delta is feasible for evaluating treatment response in patients with advanced LUSC. Integrating ctDNA profiling with conventional imaging could enhance response assessment, particularly in radiologic stable disease patients, enabling more precise therapeutic decision-making.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234466","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}