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The impact of clinical stage on the effectiveness of osimertinib for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) remains unexamined. We investigated osimertinib therapeutic efficacy variation between stage IVA or lower and stage IVB EGFR mutation-positive lung cancers, focusing on differences in pretreatment co-occurring genetic alterations in circulating tumor DNA. This was a secondary analysis of the ELUCIDATOR study, a multicenter prospective observational study in Japan that assessed the mechanisms underlying resistance to osimertinib as a first-line treatment for advanced NSCLC with EGFR mutations. We compared the progression-free survival (PFS), overall survival (OS), and pretreatment co-occurring genetic alterations detected in plasma between patients with stages IVA (n = 83) and IVB disease (n = 84). Multivariate analysis of PFS and OS revealed that stage IVB was associated with a poor prognosis (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.36-3.04, p < 0.001, HR: 2.35, 95% CI: 1.45-3.90, p < 0.001, respectively). Pre-osimertinib treatment, significantly more TP53- (52.4% vs. 27.7%, p = 0.002), EGFR amplification- (58.3% vs. 23.2%, p < 0.001), and MET amplification-positive cases (22.6% vs. 7.2%, p = 0.008) were found among stage IVB than among stage IVA or lower cases. Patients with EGFR-positive NSCLC in stage IVB exhibited significantly shorter PFS and OS than those in earlier stages when treated with first-line osimertinib. The prevalence of baseline TP53 mutations, EGFR amplification, and MET amplification in plasma were significantly higher in stage IVB cases, implicating them in the worse outcomes of this group., Competing Interests: Declarations. Ethical approval and consent to participate: This prospective observational study was registered on December 10, 2018, in the Japanese Register of Clinical Trials (JRCT; Clinical Trial Number: jRCTs031180051). Written informed consent was obtained from all patients before the study began, and the National Hospital Organization Review Board for Clinical Trials approved this protocol prior to the start of the study. Consent for publication: Not applicable. Competing interests: Taniguchi Y has received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, and MSD. Tamiya A received honoraria from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Amgen, Taiho Pharmaceutical, Kyowa-Kirin, MSD, Takeda Pharmaceutical, Nihon-Kayaku, Novartis, Thermo Fischer, Amgen, Tsumura, Daiich-Sankyo, and Merck BioFarma, and research funding from Daiichi-Sankyo, Beigene, and AstraZeneca. Oki M has received Honoraria from AMCO, AstraZeneca, Canon Medical Systems, Chugai Pharmaceutical, Fujifilm Toyama Chemical, Kaneka Medix, Merit Medical Japan, Novartis Pharma, Olympus and Sanofi, and research funding from AbbVie, AstraZeneca, Chugai Pharmaceutical, Fujifilm Toyama Chemical, GlaxoSmithKline, Janssen Pharmaceutical, MSD, Ono Pharmaceutical, Parxel International, Pfizer, Sanofi. Mori M received honoraria from AstraZeneca, Boehringer Ingelheim, MSD, Eli Lilly, Novartis, Chugai Pharmaceutical, Taiho Pharmaceutical, Kyowa-kirin, Ono Pharmaceutical, Otsuka, Nihon-kayaku, Pfizer, Daiici-Sankyo, Takeda Pharmaceutical, and Shionogi and research funding from Chugai Pharmaceutical, Ono Pharmaceutical, MSD, and Delt-fly. Koh Y has received honoraria from Chugai Pharmaceutical, Guardant Health, Amgen, Takeda Pharmaceutical, and Tosoh Corporation and has received consulting or advisory roles from Tosoh Corporation and research funding from Boehringer Ingelheim, AstraZeneca, Chugai Pharmaceutical, Tosoh Corporation, Daiichi Sankyo, Zeon Corporation, Amgen, and Takeda Pharmaceutical. The other co-authors received no honoraria or research funding., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recognizing rare molecular variants of driver mutations poses a challenge in precision oncology, particularly for treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to determine whether Oncomine Dx Target Test Multi-CDx System (ODxTT), the most widely used genetic test for NSCLC in Japan, potentially overlooks druggable EGFR mutations., Materials and Methods: Among 418 patients who underwent molecular testing using ODxTT at our hospital, 267 were diagnosed with adenocarcinoma. No mutations were reported in 82 of these cases. For these 82 cases, we searched for EGFR mutations in exons 18-21 by examining the binary alignment map file. Once a mutation was identified, its pathological significance was evaluated using the ClinVar database to determine whether ODxTT had overlooked any actionable EGFR mutations., Results: Mutations in EGFR exons 19 and 18 were identified in six and four cases, respectively. Three, six, and none of these variants were detectable using the Cobas EGFR Mutation Test v2, Lung Cancer Compact Panel, and Amoy Dx, respectively. Of the 10 patients, five were subsequently treated with EGFR TKI; three showed partial response, one had stable disease, and one had progressive disease., Conclusions: ODxTT failed to identify 10 actionable EGFR mutations, accounting for 12.2% (10/82) of the cases initially reported as not carrying actionable mutations. Therefore, comprehensive genomic profiling should be actively performed early in cases with high clinical suspicion of EGFR mutations., (© 2025 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK + non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol). We identified phospholipid hydroperoxide glutathione peroxidase GPX4 as being involved in promoting the survival of DTP cells. GPX4 was found to be upregulated in DTP cells and to promote cell survival by suppressing reactive oxygen species (ROS) accumulation; GPX4 inhibitors blocked this upregulation and facilitated ROS-mediated cell death. Activated bypass signals involving epidermal growth factor receptor (EGFR)/receptor tyrosine-protein kinase erbB-3 (HER3) were also identified in DTP cells, and co-treatment with EGFR-TKI plus ALK-TKI enhanced ROS levels. Triple combination with an ALK-TKI plus a bypass pathway inhibitor plus a GPX4 inhibitor suppressed cell growth and induced intracellular ROS accumulation more greatly than did treatment with each agent alone. The combined inhibition of ALK plus inhibition of activated bypass signals plus inhibition of GPX4 may be a potent therapeutic strategy for patients with ALK + NSCLC to prevent the development of resistance to ALK-TKIs and lead to tumor eradication., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC)., Methods: Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m 2 once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points., Results: In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ≥3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively., Conclusion: Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.

Objectives: Programmed cell death ligand 1 (PD-L1) expression is widely used to predict the effectiveness of PD-(L)1 inhibitors despite its imperfection. Previous studies suggested the utilization of various serum biomarkers; nonetheless, findings are inconclusive because of limited sample sizes or the focus on a single biomarker in many of these studies. This study analyzed multiplex serum biomarkers to explore their predictive ability in a large cohort of patients with advanced non-small-cell lung cancer (NSCLC) treated with a PD-L1 inhibitor in a real-world setting., Materials and Methods: This was a sub-study of J-TAIL, a prospective observational study of atezolizumab monotherapy in pre-treated patients with advanced NSCLC. From April to October 2019, 262 patients were enrolled from 73 sites in Japan. Serum samples were collected at baseline and at the second dose of atezolizumab. Quantification of the 51 serum cytokines, chemokines, growth factors, and vascular endothelial growth factors was performed using the Luminex platform. Baseline values and fold changes of the time of the second dose to the baseline were examined in association with the effectiveness of atezolizumab., Results: Among the 51 proteins assessed, a higher baseline interleukin (IL)-12 level, a higher soluble CD40 ligand fold change, a lower IL-8 fold change were associated with higher objective response rate (ORR). Of these, only the lower IL-8 fold change was associated with better progression-free survival (PFS) (adjusted hazard ratio, 1.98; 95 % confidence interval, 1.45-2.70; P < 0.01). Multivariate analysis demonstrated that the lower IL-8 fold change was an independent factor for both the ORR and PFS. The IL-8 fold change was independent of the neutrophil/lymphocyte ratio, and durable PFS was observed in patients with both low., Conclusion: Comprehensive serum biomarker analysis revealed that a lower fold change in serum IL-8 was associated with better outcomes in pre-treated patients with advanced NSCLC receiving atezolizumab., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hiroaki Akamatsu has received grants or contracts from Amgen, Eli Lilly, and Chugai; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Amgen, Ono, AstraZeneca, Pfizer, Boehringer Ingelheim, Takeda, Bristol Myers Squibb, Taiho, Chugai, Eli Lilly, MSD, Nippon Kayaku, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Amgen and Janssen. Yasuhiro Koh has received grants or contracts from Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Takeda, Zeon, and Chugai; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Amgen, Takeda, Chugai, Guardant Health, CytoGen, Tosoh, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Tosoh. Makoto Nishio has received payment or honoraria for lectures from Ono, Chugai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. Yasushi Goto has received grants or contracts from AstraZeneca, and Pfizer; grants for the institution from AbbVie, Eli Lilly, Bristol Myers Squibb, Ono, Novartis, Kyorin, Daiichi Sankyo, Novartis, and Preferred Network; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Ono, Bristol Myers Squibb, Pfizer, MSD, Novartis, Merck, and Thermo Fisher; has participated in Data Safety Monitoring Boards or Advisory Boards for AstraZeneca, Chugai, Boehringer Ingelheim, Eli Lilly, Taiho, Pfizer, Novartis, Guardant Health, Illumina, Daiichi Sankyo, Ono, Bristol Myers Squibb, and MSD; and had a leadership or fiduciary role in Cancer Net Japan and JAMT. Hidetoshi Hayashi has received grants or contracts from IQVIA Services, Syneos Health, EPS Corporation, Nippon Kayaku, Takeda, MSD, Amgen, Taiho, Bristol Myers Squibb, Janssen, CMIC, Pfizer, Labcorp Drug Development, Kobayashi, Eisai, EP-CRSU, Shionogi, Otsuka, GlaxoSmithKline, Sanofi, Chugai, Nippon Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, Bayer Yakuhin, Parexel, Kissei, EPS Corporation, Daiichi Sankyo, Ono, PPD-SNBL, SymBio, Mebix, AstraZeneca, Mochida, Japan Clinical Research Operations, Eli Lilly, Novartis, Otsuka, and SRL; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Ono, Daiichi Sankyo, AstraZeneca, Eli Lilly, Chugai Pharmaceutical, MSD, Pfizer, Nippon Boehringer Ingelheim, Merck, 3H Clinical Trial, Novartis, Bristol Myers Squibb, Amgen, Sysmex Corporation, Takeda, and Guardant Health. Satoru Miura has received payment or honoraria for lectures from Chugai, Taiho, Ono, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Boehringer Ingelheim, and Takeda. Hiroshi Kagamu has received payment or honoraria for lectures from Chugai, Ono, AstraZeneca, and Bristol Myers Squibb. Ichiro Yoshino has received grants or contracts from AstraZeneca, Chugai, Daiichi Sankyo, and Taiho; consulting fees from AstraZeneca, Chugai, Covidien, and Johnson & Johnson; and payment or honoraria for lectures from AstraZeneca, Chugai, Daiichi Sankyo, Eli Lilly, Covidien, Johnson & Johnson, Taiho, Amgen, MSD, CSL Behring, KM Biologics, Intuitive Surgical, Shionogi, Tsumura, and Takeda. Toshihiro Misumi has received honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai, AstraZeneca, and Miyarisan. Atsuto Mouri has received payment or honoraria for lectures from Chugai. Noriko Yanagitani has received consulting fee from Chugai and payment or honoraria for lectures from AstraZeneca, Eli Lilly, Pfizer, Chugai, Takeda, Bayer Yakuhin, Ono, and Bristol Myers Squibb. Hiroshi Nokihara has received payment or honoraria for lectures from MSD, Ono, AstraZeneca, and Chugai. Masahiro Seike has received payment or honoraria for lectures from Chugai, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Nippon Kayaku, Merck Biopharma, MSD, Taiho, Ono, Nippon Boehringer Ingelheim, Novartis, Kyowa-Kirin, and Daiichi-Sankyo. Masahide Mori has received research funding from Chugai, Ono, MSD, and Delta-fly; and payment or honoraria for lectures from AstraZeneca, Boehringer Ingelheim, MSD, Eli Lilly, Novartis, Chugai, Taiho, Kyowa-Kirin, Ono, Otsuka, Nihon-Kayaku, Pfizer, Daiichi Sankyo, Takeda, and Shionogi. Tetsuya Mitsudomi has received grants or contracts from MSD, Ono, AstraZeneca, and Chugai; payment or honoraria for speaker’s bureau from MSD, Ono, Bristol Myers Squibb, AstraZeneca, and Chugai; has participated in Advisory Boards for MSD, Ono, Bristol Myers Squibb, AstraZeneca, and Chugai; and has been a President at IASLC. The remaining authors have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Real-world, large-scale studies on the association between immune-related adverse events (irAE) and immune checkpoint inhibitor therapy effectiveness are limited. We evaluated overall survival (OS) and progression-free survival based on the occurrence and grade of irAEs., Patients and Methods: We used data from Japanese patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) who received atezolizumab and were enrolled in J-TAIL, a multicenter, prospective, single-arm observational study., Results: Among the 1,002 patients, 190 (19.0%) developed irAEs. The most common irAEs were skin disorders (3.8%) of any grade and interstitial lung disease (1.5%) of grade ≥3. Patients who developed irAEs within 4 or 6 weeks of treatment initiation had higher baseline C-reactive protein levels than those without irAEs. OS was longer in patients with irAEs [HR, 0.66; 95% confidence interval (CI), 0.54-0.82], particularly in those with low-grade irAEs (HR, 0.45; 95% CI, 0.33-0.62), than in patients without irAEs. The HR (95% CI) for OS in patients with low-grade and high-grade skin or endocrine disorder-related irAEs was 0.42 (0.28-0.64) and 0.37 (0.15-0.88), respectively. The HR (95% CI) for OS in patients with low-grade and high-grade irAEs other than skin or endocrine disorders was 0.44 (0.30-0.65) and 1.27 (0.96-1.69), respectively., Conclusions: In patients with unresectable advanced or recurrent NSCLC treated with atezolizumab in real-world settings, irAEs are associated with a clinical benefit except in those with high-grade irAEs other than skin and endocrine disorders., Significance: Immune checkpoint inhibitors are useful for treating NSCLC but can cause life-threatening irAEs. This study had a large sample size and stratified the analysis by irAE type and grade. The results suggest that improved management of irAEs may improve the therapeutic effect of atezolizumab., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor., Methods: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing., Findings: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group., Interpretation: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival., Funding: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests YoS has received grants from Chugai Pharmaceutical; and personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical, and Kyowa Kirin, all outside of the submitted work. ShN has received grants from AstraZeneca, Chugai Pharmaceutical, and MSD; consulting fees from Asahi Kasei Pharma; and personal fees from AstraZeneca, Bayer, Chugai Pharmaceutical, Asahi Kasei Pharma, Kyowa Hakko Bio, and MSD, all outside of the submitted work. SS has received grants from AnHeart Therapeutics, AstraZeneca, Chugai Pharmaceutical, MSD, Daiichi Sankyo, Bristol Myers Squibb, Nippon Boehringer Ingelheim, Ono Pharmaceutical, AbbVie, Amgen, Taiho Pharmaceutical, Takeda, Accerise, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, Towa Pharmaceutical, Sysmex, and Eisai, all outside of the submitted work. HidehH has received research fundings from MSD, AbbVie, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Janssen, Chugai Pharmaceutical, and Roche; personal fees from AstraZeneca, MSD, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Roche, Amgen, and Abbvie; and personal fees from AstraZeneca, Chugai Pharmaceutical, Roche, Ono Pharmaceutical, Bristol Myers Squibb, and AbbVie (served on the advisory board), all outside of the submitted work. YaY has received personal fees from Taiho Pharmaceutical and Takeda, all outside of the submitted work. HidetH has received grants from IQVIA Services Japan, Eisai, Syneos Health Clinical, EP-CRSU, EPS, Shionogi, Nippon Kayaku, Otsuka Pharmaceutical, Takeda, GSK, MSD, Sanofi, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, Bristol Myers Squibb, SRL Medisearch, Janssen Pharmaceutical, PRA Health Sciences, CMIC, Astellas Pharma, Pfizer R&D Japan, Ascent Development Services, Labcorp Development Japan, Eisai, Kobayashi Pharmaceutical, Bayer, and Pfizer Japan; royalties or licenses from Sysmex; personal fees from Ono Pharmaceutical, Merck, Daiichi Sankyo, 3H Clinical Trial, AstraZeneca, Novartis Pharma, Chugai Pharmaceutical, Bristol Myers Squibb, Eli Lilly Japan, Amgen, MSD, Sysmex, Pfizer Japan, Takeda, Nippon Boehringer Ingelheim; and personal fees for serving on an advisory board from Daiichi Sankyo, Nippon Boehringer Ingelheim, AstraZeneca, Amgen, Chugai Pharmaceutical, Novocure, Eli Lilly Japan, Gilead Science, and Blueprint Medicine, all outside of the submitted work. KA has received lecture fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, Bristol Myers Squibb, and Takeda, all outside of the submitted work. SN has received grants from GSK, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Teijin, Kyowa Kirin, Shionogi, Boehringer Ingelheim, Daiichi Sankyo, Kyorin, and Nippon Kayaku; personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, MSD, Ono Pharmaceutical, Eisai, Kyorin, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Novartis, Amgen, Merck, Nippon Kayaku, and Kyowa Kirin; and personal fees for serving on advisory boards from AstraZeneca and Daiichi Sankyo, all outside of the submitted work. RM has received personal fees from Daiichi Sankyo, Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Eli Lilly Japan, MSD, Amgen, and Merck; and personal fees for serving on an advisory board from Daiichi Sankyo, all outside of the submitted work. MY has received grants from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Taiho Pharmaceutical, and Takeda; and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, MSD, Nippon Kayaku, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical, all outside of the submitted work. TY has received grants from MSD, Chugai Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim Japan, Takeda, Delta-Fly Pharma, Janssen, AbbVie, Daiichi Sankyo, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Pfizer Japan, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Nippon Kayaku, MSD, Novartis, and Merck, all outside of the submitted work. KY has received grants from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Pfizer, Taiho Pharmaceutical, and Takeda; and personal fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, Kyowa Kirin, Lilly, Merck Serono, Novartis, Ono Pharmaceutical, Otsuka, Taiho Pharmaceutical, and Takeda, all outside of the submitted work. TakayK has received grants from AstraZeneca, Amgen, MSD, Janssen, Takeda, and Daiichi Sankyo; and personal fees from AstraZeneca, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, Pfizer, and Nippon Kayaku, all outside of the submitted work. HO has received grants from Bristol Myers Squibb, MSD, and Taiho Pharmaceutical, all outside of the submitted work. TakasK has received personal fees from MSD, AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol Myers Squibb, all outside of the submitted work. KK has received personal fees from AstraZeneca, MSD, Chugai Pharmaceutical, Eli Lilly Japan, and Taiho Pharmaceutical; payment for expert testimony from Eli Lilly Japan; and personal fees for serving on advisory boards from Eli Lilly Japan and AstraZeneca, all outside of the submitted work. YF has received personal fees from AstraZeneca, Amgen, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; payment for expert testimony from Chiome Bioscience, Otsuka Pharmaceutical, and Ono Pharmaceutical; and personal fees for serving on advisory boards from AstraZeneca, Daiichi Sankyo, Micron, and Ono Pharmaceutical, all outside of the submitted work. SM has received grants from AstraZeneca, Takeda, Chugai Pharmaceutical, Sanofi, MSD, Daiichi Sankyo, Ono Pharmaceutical, and Janssen; and personal fees from AstraZeneca, Chugai Pharmaceutical, Takeda, Eli Lilly, MSD, Pfizer, Novartis, and Taiho Pharmaceutical, all outside of the submitted work. SK has received personal fees from Boehringer Ingelheim Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, MSD, Ono Pharmaceutical, and Guardant Health Japan, all outside of the submitted work. HA reports grants from Amgen and Chugai Pharmaceutical; personal fees from Amgen, AstraZeneca, Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; personal fees for serving on advisory boards from Amgen, MSD, Janssen, and Sandoz; and a role on the WCLC Patient Advocacy Committee, all outside of the submitted work. HK has received grants from Eli Lilly; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Novartis, Eli Lilly Japan, Ono Pharmaceutical, and Takeda, all outside of the submitted work. ToshiK has received grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Kyowa Hakko Kirin, Merck, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, Labcorp Development Japan, IQVIA Services Japan, Gilead Sciences, Pfizer, and Bayer; consulting fees from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer Japan, Daiichi Sankyo, Bayer, and AbbVie; and personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck, Nippon Kayaku, Novartis, Daiichi Sankyo, Takeda, Bayer, Sawai, Amgen, and Eisai, all outside of the submitted work. HF has received grants from the National Cancer Center Research and Development Fund; and lecture fees from Kyowa Kirin, Chugai Pharmaceutical, and CMIC, all outside of the submitted work. YO reports grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, LOXO, Kirin, Sumitomo, Pfizer, Taiho Pharmaceutical, Novartis, Takeda, Kissei, Daiichi Sankyo, and Janssen; personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, and Daiichi Sankyo; payment for expert testimony from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics, and PharmaMar; personal fees for serving on an advisory board from Haihe Biopharma; and roles in the Japanese Society of Medical Oncology, Japan Lung Cancer Society, and Japan Clinical Oncology Group, all outside of the submitted work. IO has received grants from the National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development during the conduct of the study; grants from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, Pfizer, and AbbVie; consulting fees from AstraZeneca, Bristol Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, and Pfizer, all outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Lung cancer is the leading cause of the global cancer incidence and mortality. It is important to obtain an accurate diagnosis of lymph-node metastasis before surgery to select the therapeutic strategy for non-small cell lung cancer (NSCLC) patients. Carbonic anhydrase 9 (CA9) is considered a marker of hypoxia and it has reported that CA9 is associated with tumor invasion and metastasis. In this study, the correlation between the CA9 expression for lymph-node metastases in NSCLC and [18F]FDG PET/CT results was investigated in order to clarify the efficacy of [18F]FDG PET/CT for detecting lymph-node metastases of NSCLC patients., Methods: Among the 564 patients who underwent surgical treatment for NSCLC between 2010 and 2016 at our hospital, a total of 338 patients who underwent preoperative [18F]FDG PET/CT were included in this study. CA9 expression was evaluated by immunochemistry. A lymph node with maximum standardized uptake value (SUVmax) ≥2.5 on [18F]FDG PET/CT was preoperatively defined as a metastatic lymph node., Result: CA9 positivity was detected in 122 patients; the other 216 patients were CA9-negative. The CA9-positive NSCLC cases significantly associated with pleural invasion (p = 0.0063), pT-factor (p = 0.0080), pN-factor (p = 0.036) and pStage (p = 0.043). CA9-positive patients presented significantly poorer survival rate for OS than that of the CA9-negative patients (p = 0.0024). In the multivariable analysis, histological SCC and CA9 positivity were independent poor-prognosis factors for OS. For the total patient population, the sensitivity and specificity of [18F]FDG PET/CT for lymph-node metastases were 54% and 89%, respectively. In contrast, the sensitivity and specificity were particularly low in the CA9-positive SCC cases (36% and 69%, respectively)., Conclusion: [18F]FDG PET/CT might not be useful for diagnosing lymph-node metastases of CA9-positive SCC cases of NSCLC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Suzuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Mobocertinib is a novel, synthetic, orally administered tyrosine kinase inhibitor that inhibits many activated forms of epidermal growth factor receptor (EGFR), including those containing exon 20 insertion (ex20ins) mutations. This study aimed to assess the efficacy of mobocertinib in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR ex20ins mutations., Methods: This was a phase 2, open-label study. Patients with NSCLC harboring EGFR ex20ins mutations who had not had previous systemic treatment received mobocertinib 160 mg once daily. The primary endpoint was the confirmed objective response rate. A planned interim analysis was completed for the first 14 patients with a centrally confirmed EGFR ex20ins mutation, with enrollment stopped if the number of patients with an objective response was five or fewer., Results: In total, 33 patients were enrolled into the study (63.6% women; median age: 66 years). At the interim analysis, the objective response rate evaluated by a central independent review committee was 28.6% (4/14, 90% confidence interval: 10.4-54.0); therefore, enrollment was stopped for futility. In the full analysis set, the objective response rate was 18.2% (6/33, 95% confidence interval: 7.0-35.5); of the six responders, one patient (3.0%) had a complete response and five patients (15.2%) had partial responses. The most common treatment-related adverse events were diarrhea, paronychia, stomatitis, and nausea., Conclusion: Although study enrollment was terminated early owing to futility, our results showed modest activity of mobocertinib in Japanese patients with NSCLC with EGFR ex20ins mutations with no additional safety concerns., (© 2024. Takeda Pharmaceutical Company Limited.)

The nature of microRNA (miRNA) dysfunction in carcinogenesis remains controversial because of the complex connection between miRNA structural diversity and biological processes. Here, we found that oncofetal IGF2BP3 regulates the selective production of a subset of 3'-isoforms (3'-isomiRs), including miR-21-5p and Let-7 family, which induces significant changes in their cellular seed occupancy and structural components, establishing a cancer-specific gene expression profile. The D-score, reflecting dominant production of a representative miR-21-5p+C (a 3'-isomiR), discriminated between clinical early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks, and was associated with molecular features of cell cycle progression, epithelial-mesenchymal transition pressure, and immune evasion. We found that IGF2BP3 controls the production of miR-21-5p+C by directing the nuclear Drosha complex to select the cleavage site. IGF2BP3 was also involved in the production of 3'-isomiRs of miR-425-5p and miR-454-3p. IGF2BP3-regulated these three miRNAs are suggested to be associated with the regulation of p53, TGF-β, and TNF pathways in LUAD. Knockdown of IGF2BP3 also induced a selective upregulation of Let-7 3'-isomiRs, leading to increased cellular Let-7 seed occupancy and broad repression of its target genes encoding cell cycle regulators. The D-score is an index that reflects this cellular situation. Our results suggest that the aberrant regulation of miRNA structural diversity is a critical component for controlling cellular networks, thus supporting the establishment of a malignant gene expression profile in early stage LUAD., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Several patients treated with osimertinib experience progressive disease. The aim was to clarify the mechanisms underlying resistance to osimertinib., Methods: ELUCIDATOR: A multi-centre, prospective, observational study involved chemotherapy-naive patients with advanced non-small cell lung cancer receiving osimertinib. Mutations in cancer-associated genes, detected via ultrasensitive next-generation sequencing of circulating tumour deoxyribonucleic acid samples, were collected at baseline and after progressive disease detection. These paired plasma samples were compared., Results: Of 188 patients enrolled (May 2019-January 2021), 178 (119 females [67 %]) median age 74 years, were included. Patients, n = 95 (53 %) had epidermal growth factor receptor exon 19 deletion mutations. Among 115 patients with progressive disease, circulating tumour deoxyribonucleic acid levels of 85 patients were analysed. MET amplification (n = 4), TP53 mutations (n = 4), PIK3CA mutations (n = 3), BRINP3 mutation (n = 2), BRAF mutation (n = 2), APC mutation (n = 1), RET mutation (n = 1) and epidermal growth factor receptor (EGFR) resistance mutation, and C797S (n = 1) were detected. Patients with baseline TP53 mutations, with MET or EGFR amplification had shorter progression-free (PFS) and overall survival. Patients with PIK3CA mutations tended to shorter PFS., Conclusion: MET amplification and PIK3CA mutation mechanisms underly resistance to osimertinib in patients. Patients with coexisting mutations or amplifications at baseline had shorter PFS and overall survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background/aim: For patients treated with osimertinib as first-line therapy, there have been no studies comparing both progression-free survival (PFS) and overall survival (OS) according to performance status (PS). Furthermore, no studies have examined differences in baseline genetic abnormalities between patients with poor and good PS. Therefore, we aimed to investigate differences in baseline genetic abnormalities and treatment effects between patients with poor and good PS who received osimertinib as the primary treatment., Patients and Methods: This is a secondary analysis of the ELUCIDATOR study, which is a multi-center prospective observational study in Japan that assessed mechanisms underlying resistance to osimertinib as first-line treatment for advanced non-small cell lung cancer with epidermal growth factor receptor mutations., Results: There were 153 and 25 patients in the good and poor PS groups, respectively. Multivariate analysis revealed no significant between-group differences in PFS (hazards ratio [HR]: 0.98, 95% confidence interval [CI]: 0.52-1.72, p = 0.946). Multivariate analysis of OS revealed that poor PS was a poor prognostic factor (HR: 2.67, 95% CI: 1.43-4.73, p = 0.003). Regarding baseline genetic abnormalities, there was a significant increase in APC-positive cases (20.0% vs. 2.2%, p = 0.009) and a trend toward more CTNNB1-positive cases in the poor PS group than in the good PS group (14.3% vs. 2.9%, p = 0.062)., Conclusion: There was no between-group difference in PFS, although OS was significantly inferior in the poor PS group. Additionally, there was a significant increase in APC-positive cases and a trend toward more CTNNB1-positive cases in the poor PS group., (© 2024. The Author(s).)

Background/objectives: Although tumor recurrence after surgical resection in pancreatic cancer (PC) is generally considered incurable, it is well-accepted that clinical presentations and outcomes vary according to the recurrent sites (e.g., liver vs. lung recurrence), suggesting a possible biological inhomogeneity of PC recurrence. Understanding the behavior of biological factors, specifically tumor markers (TMs), at different recurrence sites may contribute to individualized treatment strategies. Therefore, this study aimed to compare the dynamics of pre-recurrence TMs at liver and lung recurrence sites., Methods: Patients with isolated postoperative liver or lung recurrence as their first recurrence were enrolled. Starting from the recurrence date confirmed by imaging examinations, the values of TMs (carbohydrate antigen 19-9: CA19-9; carcinoembryonic antigen: CEA) were retrospectively evaluated 6 and 3 months before recurrence and at the time of recurrence., Results: Patients with liver recurrence displayed a significant increase in CA19-9 and CEA levels from as early as 6 months before recurrence. Contrastingly, patients with lung recurrence demonstrated a significant elevation of CA19-9 levels starting from 3 months before recurrence, with no increase in CEA levels, even at the time of recurrence. The relative change in CA19-9 and CEA levels during each period were significantly lower in patients with lung recurrence., Conclusions: Both TMs exhibited organ-specific variations in patients with postoperative PC recurrence. This disparity may reflect the biological heterogeneity of PC between recurrence patterns, thereby highlighting the importance of conducting postoperative follow-up with consideration of this fact., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population., Methods: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete)., Findings: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea., Interpretation: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated., Funding: Merck (CrossRef Funder ID: 10.13039/100009945)., Competing Interests: Declaration of interests Y-LW reports receiving institute grants from AstraZeneca, Bristol Myers Squibb, and Pfizer; consulting fees from AstraZeneca, Boehringer Ingelheim, Merck, and Roche; and speaker fees from AstraZeneca, Eli Lilly, Hengrui, Pfizer, Roche, and Sanofi. VG reports receiving personal fees for advisory board membership from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, and Olema Oncology; speaker fees from Amgen, AstraZeneca, Eli Lilly, Exact Sciences, Gilead, GSK, and Novartis; fees for expert testimony for Eli Lilly; and travel support from Gilead, AstraZeneca, and PharmaMar. PJV reports receiving personal fees for advisory board membership from Amgen, AstraZeneca, BeiGene, Ipsen, MSD, Novartis, Pfizer, and Roche. MWi reports receiving personal advisory board fees, consulting fees, speaker fees, and institute grants from AstraZeneca. CKL reports receiving research grants from AstraZeneca and Boehringer Ingelheim; honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Janssen, MSD, Novartis, Pfizer, Roche, and Zuellig Pharma; travel support from AstraZeneca, Boehringer Ingelheim, Merck, MSD, Novartis, Pfizer, and Roche; and personal fees for advisory board membership from AstraZeneca, Janssen, MSD, Novartis, Pfizer, and Roche. JM reports receiving advisory board fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, Novartis, Merck, Daiichi Sankyo, and MSD, and research funding to his institution from Roche, AstraZeneca, and Pierre Fabre. LMT reports receiving advisory board fees from AstraZeneca, Janssen, Merck, Novartis, Pfizer, and Roche; personal honoraria fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, and Roche; and travel support from AstraZeneca, Merck, Novartis, Pfizer, and Roche. HH reports receiving honoraria fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Eli Lilly, Boehringer Ingelheim, Sysmex Corporation, 3H Medi Solution, Chugai Pharmaceutical, Pfizer, Novartis, Merck Biopharma Co, Tokyo, Japan, an affiliate of Merck, Amgen, Daiichi Sankyo/UCB Japan, Takeda, and MSD; research funding from IQVIA, Syneos Health Clinical, EPS Corporation, Nippon Kayaku, Takeda, MSD, Amgen, Taiho Pharmaceutical, Bristol Myers Squibb, Janssen, CMIC, Pfizer R&D, LabCorp, Kobayashi Pharmaceutical, Pfizer, Eisai, EP-CRSU, Shionogi & Co, Otsuka Pharmaceutical, GSK, Sanofi, Chugai Pharmaceutical, Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, and Bayer; and financial support for the present manuscript from Guardant Health. PLC reports receiving advisory board fees from AstraZeneca, Merck, and Pfizer, and honoraria fees from AstraZeneca. JR reports receiving personal honoraria from Bristol Myers Squibb, speaker fees (to their institution) from Merck, and advisory board fees (to their institution) from Merck. GF reports receiving personal fees for speaker engagements with AstraZeneca, Bristol Myers Squibb, and MSD, and travel support from Roche. TK reports receiving honoraria from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; receiving research funding for their institution from AbbVie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis, Pfizer, Regeneron, Takeda, and TurningPoint; receiving advisory board fees from AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck, MSD, Novartis, and Pfizer; and their spouse as an employee of Eli Lilly. EN reports receiving research funding from Roche, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Bristol Myers Squibb; consulting fees from Roche, Bristol Myers Squibb, MSD, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Daiichi Sankyo, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Pierre Fabre, Qiagen, and Bayer; personal honoraria for lectures from Roche, Bristol Myers Squibb, MSD, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Qiagen, Mirati, and Bayer; travel support from Takeda, MSD, AstraZeneca, and Roche; and fees for participation in data safety meetings from Apollomics. HSH reports receiving research grants for their institution from AstraZeneca, Merck, Janssen, Novartis, and Boehringer Ingelheim; honoraria and fees for lectures and advisory board meetings from AstraZeneca, MSD, Novartis, Pfizer, Roche, and Janssen; and travel support from AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Roche. EFS reports receiving advisory or consultancy fees to their institution from Eli Lilly, AstraZeneca, MSD, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, and Daiichi Sankyo; personal speaker fees from Boehringer Ingelheim; and advisory board fees from Merck and Daiichi Sankyo. MWe reports holding a consulting or advisory role for Bristol Myers Squibb, Novartis, Eli Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, and ImCheck therapeutics; honoraria fees from Eli Lilly, Boehringer Ingelheim, SYNLAB, Janssen, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, GWT, Amgen, and Novartis; travel support from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics, and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck; and research funding to his institution from Roche. DT reports receiving consulting fees for their institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DKSH, GSK, Merck, Novartis, Roche, Pfizer, and Takeda; research funding from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer; and speaker fees for their institution from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda. MM reports receiving research funding from Boehringer Ingelheim and Eli Lilly; personal honoraria fees from Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; and other clinical trial support from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Kissei, Taiho, and Novartis. AO’B, SA, BMP, CS, DJ, RS, BE-L, and NK report being employees of Merck. KB reports being an employee of Merck at the time of the study and manuscript preparation. KG reports being an employee of EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck. XL reports receiving consulting fees from EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, AstraZeneca, Spectrum Pharmaceuticals, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen Oncology, Daiichi Sankyo, Blueprint Medicines, Sensei Biotherapeutics, AbbVie, Arrivent, and Regeneron; travel support from Spectrum Pharmaceuticals and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and research funding to their institution from Eli Lilly, Boehringer Ingelheim, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Regeneron. TMK reports receiving grants for their institution from AstraZeneca; consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda, and Yuhan; honoraria for lectures from AstraZeneca, IMBDx, Janssen, Takeda, and Yuhan; advisory board fees from AstraZeneca, Janssen, Regeneron, and Takeda; and clinical trial funding to their institution from AbbVie, Amgen, AstraZeneca/Medimmune, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, Dizal, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Roche/Genentech, Hanmi, Genmab, Janssen, Novartis, RAPT Therapeutics, Regeneron, Sanofi, Takeda, and Yuhan. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Predicting the prognosis of lung cancer is crucial for providing optimal medical care. However, a method to accurately predict the overall prognosis in patients with stage IV lung cancer, even with the use of machine learning, has not been established. Moreover, the inter-institutional generalizability of such algorithms remains unexplored. This study aimed to establish machine learning-based algorithms with inter-institutional generalizability to predict prognosis., Materials and Methods: This multicenter, retrospective, hospital-based cohort study included consecutive patients with stage IV lung cancer who were randomly categorized into the training and independent test cohorts with a 2:1 ratio, respectively. The primary metric to assess algorithm performance was the area under the receiver operating characteristic curve in the independent test cohort. To assess the inter-institutional generalizability of the algorithms, we investigated their ability to predict patient outcomes in the remaining facility after being trained using data from 15 other facilities., Results: Overall, 6,751 patients (median age, 70 years) were enrolled, and 1,515 (22 %) showed mutated epidermal growth factor receptor expression. The median overall survival was 16.6 (95 % confidence interval, 15.9-17.5) months. Algorithm performance metrics in the test cohort showed that the areas under the curves were 0.90 (95 % confidence interval, 0.88-0.91), 0.85 (0.84-0.87), 0.83 (0.81-0.85), and 0.85 (0.82-0.87) at 180, 360, 720, and 1,080 predicted survival days, respectively. The performance test of 16 algorithms for investigating inter-institutional generalizability showed median areas under the curves of 0.87 (range, 0.84-0.92), 0.84 (0.78-0.88), 0.84 (0.76-0.89), and 0.84 (0.75-0.90) at 180, 360, 720, and 1,080 days, respectively., Conclusion: This study developed machine learning algorithms that could accurately predict the prognosis in patients with stage IV lung cancer with high inter-institutional generalizability. This can enhance the accuracy of prognosis prediction and support informed and shared decision-making in clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daichi Fujimoto reported receiving grants and personal fees from AstraZeneca KK and Boehringer Ingelheim Japan Inc. and personal fees from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD KK, Eli Lilly Japan K.K., Kyowa Kirin, Daiichi Sankyo, and Novartis Pharma KK outside the submitted work. Hidetoshi Hayashi reported receiving grants from PAREXEL International Corp., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K., Ono Pharmaceutical Co., Ltd., SYNEOS HEALTH CLINICAL K.K., Covance Japan Inc., Sanofi K.K., Novartis Pharma K.K., Bristol Myers Squibb Company, Janssen Pharmaceutical K.K., Eisai Co., Ltd., Japan Clinical Research Operations, AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Sysmex Corporation, Takeda Pharmaceutical Co., Ltd., IQVIA Services JAPAN K.K., GlaxoSmithKline K.K., EPS Corporation, Medical Research Support, PRA Health Science, Inc., Eisai., Inc., Nippon Boehringer Ingelheim Co., Ltd., and PPD-SNBL K.K. and personal fees from AstraZeneca K.K., Bristol Myers Squibb Company, Amgen, Inc., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., and Pfizer Japan Inc outside the submitted work. Yukihiro Toi reported receiving personal fees from Bristol-Myers Squibb Company, Ono Pharmaceutical Co., Ltd., MSD K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Pfizer, Inc., and Kyowa Kirin Co., Ltd., outside the submitted work. Toshihide Yokoyama reported receiving personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc, Bristol-Myers Squibb Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., MSD, Novartis, and Merck Biopharma Co., Ltd. outside the submitted work. Terufumi Kato reported receiving grants from Abbvie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai, Daiichi-Sankyo, Eli Lilly, Haihe, Merck KGaA, MSD, Novartis, Pfizer, Regeneron, Takeda, and TurningPoint and personal fees from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda outside the submitted work, and his wife is an employee of Eli Lilly. Teppei Yamaguchi reported receiving personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, MSD, Bristol-Meyers Squibb, and Novartis outside the submitted work. Kaoru Tanaka reported receiving personal fees from AstraZeneca, Merck Biopharma, Eisai, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Chugai Pharmaceutical, Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical, and Novartis Pharma outside the submitted work. Satoru Miura reported receiving personal fees from AstraZeneca KK, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., Boehringer Ingelheim Japan Inc, Eli Lilly Japan K.K., Novartis Pharma K.K., Pfizer, Kyowa Hakko Kirin, Daiichi Sankyo, Abbive, Nippon Kayaku, AMGEN, Merck, and Takeda Pharmaceutical Co., Ltd. outside the submitted work. Motohiro Tamiya reported receiving personal fees from Pfizer, Chugai Pharmaceutical, Ono Pharmaceutical, MSD, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, and Amgen outside the submitted work. Motoko Tachihara reported receiving grants and personal fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., and Eli Lilly Japan Co., Ltd., and personal fees from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., MSD K.K., Novartis pharmaceuticals K.K., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo, Pfizer Japan, Inc., and Janssen Pharmaceutical K.K. Takehito Shukuya reported receiving grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Novartis, and MSD and personal fees from Taiho Pharma, Daiichi-Sankyo, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Kayaku, Pfizer, Takeda Pharmaceutical Co., Ltd., and Eli Lilly outside the submitted work. Yuko Tsuchiya-Kawano reported receiving personal fees from Bristol-Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Kyowa Hakko Kirin, MSD, and Ono Pharmaceutical outside the submitted work. Yuki Sato reported receiving personal fees from AstraZeneca, MSD, Novartis, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Nippon Kayaku, Bristol Myers Squibb, Eli Lilly, Takeda Pharmaceutical Co., Ltd., Kyowa Kirin, and Boehringer Ingelheim outside the submitted work. Satoshi Ikeda reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Takeda Pharmaceutical Co., Ltd., Daiichi-Sankyo, and Pfizer outside the submitted work. Shinya Sakata reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. Takeshi Masuda reported receiving personal fees from MSD K.K., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Co., Ltd., and Kyowa Kirin outside the submitted work. Isamu Okamoto reported receiving personal fees from Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca Plc., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., and Novartis Pharma K.K. outside the submitted work. Nobuyuki Yamamoto reported receiving grants from AstraZeneca K.K., MSD K.K., Amgen Astellas BioPharma, Eisai Co., Ltd., Sanofi K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Janssen Pharmaceutical K.K., Amgen K.K., Taiho Pharmaceutical Co., Ltd., Toppan USA, Inc., Nippon Boehringer Ingelheim Co., Ltd., and Daiichi Sankyo Co., Ltd. and personal fees from MSD K.K., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., and Merck Biopharma Co., Ltd., outside the submitted work. The remaining authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The tumor suppressor p53 prevents cancer development by regulating dozens of target genes with diverse biological functions. Although numerous p53 target genes have been identified to date, the dynamics and function of the regulatory network centered on p53 have not yet been fully elucidated. We herein identified inhibitor of DNA-binding/differentiation-3 (ID3) as a direct p53 target gene. p53 bound the distal promoter of ID3 and positively regulated its transcription. ID3 expression was significantly decreased in clinical lung cancer tissues, and was closely associated with overall survival outcomes in these patients. Functionally, ID3 deficiency promoted the metastatic ability of lung cancer cells through its effects on the transcriptional regulation of CDH1. Furthermore, the ectopic expression of ID3 in p53-knockdown cells restored E-cadherin expression. Collectively, the present results demonstrate that ID3 plays a tumor-suppressive role as a downstream effector of p53 and impedes lung cancer cell metastasis by regulating E-cadherin expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: For advanced non-small cell lung cancer (NSCLC), combination therapies including a PD-1 inhibitor plus chemotherapy or a PD-1 inhibitor, CTLA-4 inhibitor, and chemotherapy are standard first-line options. However, data directly comparing these regimens are lacking. This study compared the efficacy of pembrolizumab plus chemotherapy (CP) against nivolumab plus ipilimumab and chemotherapy (CNI) in a real-world setting., Methods: In this multicenter retrospective study, we compared the efficacy and safety of CP and CNI as first-line therapies in 182 patients with stage IIIB-IV NSCLC. Primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the response rate (RR) and safety profiles. Kaplan-Meier survival curves and Cox proportional hazards models were utilized for data analysis, adjusting for confounding factors such as age, gender, and PD-L1 expression., Results: In this study, 160 patients received CP, while 22 received CNI. The CP group was associated with significantly better PFS than the CNI group (median 11.7 vs. 6.6 months, HR 0.56, p = 0.03). This PFS advantage persisted after propensity score matching to adjust for imbalances. No significant OS differences were observed. Grade 3-4 adverse events occurred comparably, but immune-related adverse events were numerically more frequent in the CNI group., Conclusions: In real-world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown., Methods: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid., Results: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8 + tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration., Conclusions: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Background: Immune checkpoint inhibitors have recently become the standard of care in the first-line treatment of extensive-stage small cell lung cancer. Although immune-related adverse events have been reported to influence prognosis in non-small cell lung cancer patients, few studies have investigated the prognostic value of immune-related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune-related adverse events after first-line treatment with immune checkpoint inhibitor-based chemotherapy for extensive-stage small cell lung cancer., Methods: We enrolled 90 patients with extensive-stage small cell lung cancer who received immune checkpoint inhibitor-based chemotherapy as first-line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune-related adverse events., Results: There were 23 patients with and 67 without immune-related adverse events. Seventeen patients had grade 1-2 immune-related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune-related adverse event was a skin rash. The median survival time was 22 months in patients with immune-related adverse events and 9.3 months in patients without immune-related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19-0.83, p = 0.013)., Conclusions: The results of this study show that immune-related adverse events are associated with improved survival outcomes in patients with extensive-stage small cell lung cancer., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, exactly when to initiate durvalumab therapy after chemoradiation completion remains unknown. We evaluated the efficacy and safety of durvalumab, administered immediately after CCRT completion, for patients with unresectable stage III NSCLC., Patients and Methods: This study was a prospective, single-arm, open-label phase II clinical trial. Patients without disease progression after definitive CCRT (two cycles of platinum-based doublet chemotherapy with 60 Gy/30 Fr radiotherapy) received durvalumab (every 2 weeks for up to 12 months) from the next day (up to 5 days) after the final radiation dose. The primary endpoint was the 1-year progression-free survival (PFS) from registration before the start of CCRT., Results: From January 2020 to August 2020, 47 of 50 enrolled patients were evaluable for treatment efficacy and safety. The 1-year PFS from registration was 75.0% [60% confidence interval (CI), 69.0-80.0 and 95% CI, 59.4-85.3]. The objective response rate throughout the study treatment and median PFS from registration were 78.7% and 14.2 months (95% CI, 13.4 to not reached), respectively. Grade 3/4 pneumonitis and febrile neutropenia were each 4.3%., Conclusions: Our study met the primary endpoint. The incidence of pneumonitis was similar to that of a Japanese subset in the PACIFIC study. Our data support the efficacy and safety of durvalumab administered immediately after the completion of CCRT for patients with unresectable stage III NSCLC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: I report honoraria from Ono Pharmaceutical, Merck Biopharma, Daiichi Sankyo, 3H Clinical Trial, AstraZeneca, Novartis Pharma, Chugai Pharmaceutical, Bristol Myers Squibb, Eli Lilly Japan, Amgen, MSD, Sysmex Corp, Pfizer Japan, Takeda Pharmaceutical, Janssen Pharmaceutical, Nippon Boehringer Ingelheim, and Guardant Health Japan. I also report research funding from IQVIA Services Japan, Eisai, Syneos Health Clinical, EP-CRSU, EPS, Shionogi & Co, Nippon Kayaku, Otsuka Pharmaceutical, Takeda Pharmaceutical, GlaxoSmithKline, MSD, Sanofi, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, Bristol Myers Squibb, SRL Medisearch, Janssen Pharmaceutical, PRA Health Sciences, CMIC, Astellas Pharma, Pfizer R&D Japan, Ascent Development Services, Labcorp Development Japan, and Eisai.

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this., Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC., Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020., Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population., Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group., Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

A 61-year-old woman, who had a history of total thyroidectomy for follicular variant of papillary thyroid carcinoma (PTC), visited our hospital for assessment of an enlarging nodule which appeared in the lung with multiple metastatic lesions of PTC which had been stable for 17 years. Wedge resection of the lung was performed. Miliary nodules were confirmed to be metastatic PTCs based on their morphological as well as immunohistochemical findings. As for the main nodule, its morphological features suggested a diagnosis of metastatic PTC, while its immunohistochemical findings were identical with primary lung adenocarcinoma. Further genetic analysis provided no definitive information for the diagnosis of the main nodule. The present case shows the need of comprehensive analyses for differentiation between primary lung adenocarcinoma and metastatic PTCs., (© 2023 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Immune checkpoint inhibitors have been reported to have excellent therapeutic effects on various malignant tumors. However, immune-related adverse events can occur, targeting various organs., Case Presentation: A 49-year-old male with lung carcinoma was started on carboplatin + pemetrexed + nivolumab (every 3 weeks) + ipilimumab (every 6 weeks), and nivolumab/ipilimumab was administered in the 3rd course. Subsequently, fever and fatigue developed, and grade 3 liver damage was also noted, so he was admitted to Kindai University Hospital. A bone marrow aspirate examination was performed on the third day of illness, and a definitive diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made. It was determined that immediate therapeutic intervention was necessary, and pulse therapy with methylprednisolone was started on the third day of illness. After 3 days of pulse treatment, a rapid recovery of platelet values, a decrease in ferritin levels, and a decrease in lactate dehydrogenase were observed. Subjective symptoms such as fever and fatigue also quickly improved., Conclusion: Early diagnosis and treatment for HLH resulted in a positive response. The number of HLH cases may increase in the future due to the expansion of immune checkpoint inhibitor indications., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background/aim: The association between resected non-small cell lung cancer (NSCLC) and long-term outcomes of muscle mass depletion and muscle weakness has also not been well documented. This study evaluated whether muscle mass depletion assessed by bioelectrical impedance analysis (BIA) and low muscle strength assessed by the peak expiratory flow rate as a percentage of predicted value (%PEFR) were associated with surgical outcomes in patients with resected NSCLC., Patients and Methods: This retrospective study included 219 patients with resected NSCLC between 2016 and 2021. The cutoff value for muscle mass depletion was according to guidelines, for low muscle strength, we defined by receiver operating characteristics analysis for recurrence-free survival (RFS). Survival analysis was performed, and postoperative outcomes were compared., Results: A total of 76 patients (34.7%) had muscle mass depletion, and 114 patients (52.1%) had low muscle strength. Muscle mass depletion and low muscle strength were independent poor prognostic factors for overall survival [hazard ratio (HR)=2.631, p=0.003; HR=1.983, p=0.044] and RFS (HR=3.120, p<0.001; HR=1.857, p=0.028) in multivariate analysis. Postoperative complication was associated with low muscle strength (p=0.009). Postoperative recurrence was associated with muscle mass depletion (p=0.03)., Conclusion: Preoperative muscle mass depletion assessed by BIA and low muscle strength determined by %PEFR are worse prognostic factors after surgical resection for NSCLC. Our results may provide some important information for preoperative management., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Pancreatic cancer with distant metastasis typically results in a poor prognosis, but patients with only pulmonary metastasis are reported to have a relatively good prognosis. In this study, we investigated the clinicopathological data and prognosis of 15 patients who underwent surgery for lung metastasis of pancreatic cancer at our hospital between April 2010 and December 2021. The median disease-free interval after pancreatic cancer treatment was 24.5 (9.6-71.8) months. Ten of the 15 patients underwent successful radical resection, while the remaining 5 had pleural dissemination and underwent non-radical resection. The median follow-up duration was 13.5 months, with the median survival time for radical resection and non-radical resection cases being 49.5 months and 31.2 months, respectively. This indicates significantly worse prognosis for non-radical resection cases( p=0.010). Furthermore, the median CA19-9 levels before lung resection were 22 U/ml for radical resection and 2,181 U/ml for non-radical resection cases, significantly higher in the latter (p=0.049). Immunostaining of resected specimens revealed that MMP-2 was positive in 11 of 15 cases, particularly in 4 of 5 cases with pleural dissemination. CA19-9 levels before lung resection may be a predictive factor for pleural dissemination, and MMP-2 may play a role in the mechanism of pleural dissemination.

Purpose: This report reviews our experience with right lower sleeve lobectomy and describes our technique and approach to perioperative patient management., Methods: We retrospectively reviewed 11 patients who underwent right lower sleeve lobectomy for lung cancer. Surgical techniques and perioperative management were also investigated., Results: Bronchoplasty was performed using 4-0 absorbable monofilament sutures. The deepest portion was anastomosed using continuous sutures; interrupted sutures were used for the more superficial portions. The truncus intermedius and right middle lobe bronchus should be anastomosed in a natural position. Anastomosis patency was confirmed using intraoperative bronchoscopy. Separation of the right upper and middle lobes and pericardiotomy at the inferior edge of the superior pulmonary vein are useful for mobilizing the right middle lobe. Death during hospitalization and treatment-related death did not occur. One patient developed pneumonia, and another developed a bronchopleural fistula., Conclusion: We reported our technique of right lower sleeve lobectomy and our approach to perioperative patient management. Sharing knowledge is essential to completing this rare surgery.

Background: In survivors of head and neck cancer (HNC), second primary lung cancer (SPLC) often develop as a result of a common risk factor, that is, smoking. A multicenter experience was reviewed to evaluate how the history of a diagnosis of HNC affects the outcomes of patients undergoing pulmonary resection for SPLC., Methods: A multicenter retrospective analysis of patients hospitalized between January 2012 and December 2018 was performed. From a cohort of 4521 patients undergoing therapeutic pulmonary resection for primary non-small cell lung cancer, 100 patients with a previous history of HNC (HNC group) were identified. These patients were compared with a control group consisting of 200 patients without an HNC history from the same cohort pair-matched with operating facility, age, sex, and pathologic stage of lung cancer., Results: At the time of surgery for SPLC, the HNC group showed malnutrition with a lower prognostic nutritional index compared with the control group (P < .001). The HNC group was determined to have postoperative complications more frequently (P = .02). The 5-year overall survival rates in the HNC and control groups were 59.0% and 83.2%, respectively (P < .001). Statistically, HNC history, lower prognostic nutritional index, squamous cell lung cancer, and TNM stage were identified to be independently associated with poor survival., Conclusions: Patients with SPLC after primary HNC often present with malnutrition and are predisposed to postoperative complications and poor survival after pulmonary resection., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor ( EGFR )-mutated non-small-cell lung cancer (NSCLC)., Methods: This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR- mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data., Results: Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations., Conclusion: After tumor progression with EGFR TKI therapy and PBC in patients with EGFR -mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR- mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

Introduction: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling., Methods: ALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status., Results: ALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples., Conclusions: Patients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Programmed cell death-ligand 1 (PD-L1) on tumor cells can be degraded to soluble form (sPD-L1) and enter circulation, however, the clinical significances of sPD-L1 in peripheral blood remains to be elucidated in non-small-cell lung cancer (NSCLC). We monitored plasma sPD-L1 levels during perioperative periods and evaluated PD-L1-positive cells in tumor tissues in patients with operable NSCLC. Then the correlation between preoperative plasma sPD-L1 levels and relapse-free survival (RFS) was analyzed retrospectively. In patients who underwent radical surgery (n = 61), plasma sPD-L1 levels (median; 63.5 pg/mL) significantly increased 1 month after surgery (72.2 pg/mL, P < 0.001). The combined score of PD-L1-positive cells including tumor cells and tumor-associated macrophages (TAMs) was significantly associated with preoperative plasma sPD-L1 levels. In patients with high levels of preoperative plasma sPD-L1, the probability of 5-year RFS was significantly poor for patients with low PD-L1 expression intensity of tumor cells (tcPD-L1) compared with those with high tcPD-L1 (33.3% vs. 87.5%, respectively, P = 0.016; 95% CI, 0.013-0.964). In former group, PD-L1-positive TAMs were markedly infiltrating compared with those from latter group (246.4 vs. 76.6 counts/mm 2 , respectively, P = 0.003). In NSCLC, plasma sPD-L1 can reflect the accumulation of PD-L1-posotive TAMs, not just PD-L1-positive tumor cells. In patients with high levels of preoperative plasma sPD-L1, the prognoses after surgery depends on which PD-L1-positive cells, tumor cells or TAMs, are the primary source of the sPD-L1. Thus, measuring both plasma sPD-L1 levels and PD-L1 expression status of tumor cells and TAMs is of benefit for assessment of postoperative prognosis in operable NSCLC., (© 2023. The Author(s).)

A woman in her 70s presented with gallbladder carcinoma with liver metastases and peritoneal dissemination. After standard chemotherapy failed, a liver biopsy was performed. A FoundationOne CDx analysis showed that the tumor mutational burden (TMB) was high (34 mutations/megabase). Treatment with pembrolizumab, which is an immune checkpoint inhibitor (ICI), resulted in a partial response, and there were no significant immune-related adverse events. According to recently published reports, the frequency of TMB-high biliary tract cancer (BTC) is 3.4-4%, which makes it extremely rare. In conclusion, ICIs may be effective in patients with TMB-high BTC.

Importance: Administration of durvalumab after concurrent chemoradiotherapy is the standard treatment of unresectable, locally advanced non-small cell lung cancer (NSCLC); however, 20% to 30% of patients do not receive durvalumab because of adverse events (AEs) during concurrent chemoradiotherapy. In addition, radiotherapy and immunotherapy have a synergistic effect., Objective: To investigate the efficacy and safety of durvalumab immunotherapy plus concurrent radiotherapy followed by maintenance with durvalumab therapy for treatment of locally advanced NSCLC without chemotherapy., Design, Setting, and Participants: The multicenter, single-arm DOLPHIN (Phase II Study of Durvalumab [MEDI4736] Plus Concurrent Radiation Therapy in Advanced Localized NSCLC Patients) nonrandomized controlled trial was performed by 12 institutions in Japan from September 13, 2019, to May 31, 2022. Participants in the primary registration phase included 74 patients with programmed cell death ligand 1 (PD-L1)-positive, unresectable, locally advanced NSCLC. The current analyses were conducted from June 1, 2022, to October 31, 2022., Interventions: Patients received radiotherapy (60 Gy) in combination with concurrent and maintenance durvalumab immunotherapy, 10 mg/kg every 2 weeks, for up to 1 year., Main Outcomes and Measures: The primary end point of the rate of 12-month progression-free survival (PFS), as assessed by an independent central review, was estimated using the Kaplan-Meier method and evaluated with 90% CIs calculated using the Greenwood formula. The key secondary end points were PFS, objective response rate, treatment completion rate, and AEs., Results: Data from 35 patients (median [range] age, 72 [44-83] years; 31 [88.6%] men) were included in the full analysis set of the evaluable population. The 12-month PFS rate was 72.1% (90% CI, 59.1%-85.1%), and the median PFS was 25.6 months (95% CI, 13.1 months to not estimable) at a median follow-up of 22.8 months (range, 4.3-31.8 months). Scheduled radiation therapy was completed in 97.1% of patients. The confirmed objective response rate was 90.9% (95% CI, 75.7%-98.1%), and the treatment completion rate was 57.6% (95% CI, 39.2%-74.5%). Among 34 patients evaluated in the safety analysis set, AEs of grade 3 or 4 occurred in 18 patients (52.9%), and of grade 5 in 2 patients (5.9%). Pneumonitis or radiation pneumonitis of any grade occurred in 23 patients (67.6%), and of grades 3 or 4 in 4 patients (11.8%)., Conclusions and Relevance: Findings from this phase 2 nonrandomized controlled trial indicate that durvalumab immunotherapy combined with curative radiotherapy for patients with PD-L1-positive, unresectable, locally advanced NSCLC is a promising treatment with tolerable AEs and is appropriate as a study treatment for phase 3 clinical trials., Trial Registration: Japan Registry of Clinical Trials ID: jRCT2080224763.

Purpose: Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2-mutant ( HER2 m; defined as single-nucleotide variants and exon 20 insertions) metastatic non-small-cell lung cancer (mNSCLC)., Methods: DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2 m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review., Results: One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ≥ 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively., Conclusion: T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.

Background: In CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up., Methods: Adults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients., Results: At 62.1 months' minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%-75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed., Conclusions: At 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC., (© 2023. The Author(s).)

Introduction: Docetaxel is an established standard therapy after osimertinib and platinum-based doublet chemotherapy (Pt-doublet) for locally advanced or metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor gene (EGFR) mutation. To facilitate future therapeutic developments in these patients after treatment with osimertinib and Pt-doublet, we estimated the outcomes of currently used post-treatment therapies., Methods: Data of patients with NSCLC who received at least one medication after osimertinib and Pt-doublet between April 2008 and August 2021 were extracted from the Medical Data Vision claims database. The duration of treatment (DoT) (first treatment after osimertinib and Pt-doublet) and overall survival (OS) were estimated. The index date was the first day on which the medication was prescribed., Results: In total, 731 patients (mean age 64 years) were screened. The most frequent post-treatments were docetaxel-based chemotherapy (30.2%), immune checkpoint inhibitor (ICI) alone or in combination (17.2%), first-/second-generation EGFR-tyrosine kinase inhibitors (16.7%), osimertinib (16.3%), and Pt-doublet (5.2%). The median DoT and OS (95% confidence interval) of all post-treatments were 3.5 (3.27, 3.77) and 10.3 (9.3, 12.1) months, respectively, reflecting the median DoT (3.8 months) and OS (10.0 months) of docetaxel-based chemotherapy. Among all post-treatment regimens, ICIs resulted numerically the shortest [2.77 (2.33, 3.00) months] and osimertinib the longest [4.40 (3.47, 5.67) months] median DoT. The median OS was shortest in patients post-treated with ICIs [7.07 (5.40, 9.90) months] and longest in patients rechallenged with Pt-doublet (12.27 months), followed by patients post-treated with osimertinib (11.70 months). In a subset analysis of patients who received first-line osimertinib and second-line Pt-doublet as well as Pt-doublet immediately after osimertinib, those post-treated with ICIs had the shortest median DoT., Conclusion: Given the limited real-world efficacy on EGFR-mutant NSCLC resistant to osimertinib and platinum-based chemotherapy, the development of more highly potent post-treatment therapies is warranted., (© 2023. The Author(s).)

Introduction: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE)., Methods: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers., Results: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8 + tumor-infiltrating lymphocyte density and the high CD73 + cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8 + tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity., Conclusions: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery., Patients and Methods: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors., Results: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001)., Conclusion: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation., (© 2023. The Author(s).)

Background: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial., Methods: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment., Results: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected., Conclusion: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment., Clinical Trial Registration: jRCTs051180009., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the prognostic impact of restrictive ventilatory impairment in patients who undergo pulmonary resection of metachronous second primary lung cancer., Methods: The clinical characteristics and surgical outcomes of 70 patients with metachronous second primary lung cancer were analyzed., Results: The surgical procedures consisted of wedge resection in 40 patients, segmentectomy in 17, lobectomy in 12, and completion pneumonectomy in one. Patients who underwent ipsilateral pulmonary resection developed more perioperative complications (p = 0.0339). Three-year and 5-year overall survival rates were 78.2% and 69.2%, respectively. In univariate analysis, sex, restrictive ventilatory impairment, and histology of second primary lung cancer were significantly poor prognostic factors (all p <0.05). Multivariate analysis identified restrictive ventilatory impairment to be an independent predictor of a poor prognosis (p = 0.0193). In the 22 patients who died, the cause of death was lung cancer in 11 and other diseases, including pneumonia and respiratory failure, in 11. Death from another disease was significantly more common in patients with restrictive ventilatory impairment (p = 0.0216)., Conclusion: Restrictive ventilatory impairment was an independent predictor of a poor prognosis in patients with a second primary lung cancer. Restrictive ventilatory impairment as a result of repeated thoracic surgery may increase the likelihood of death from another disease.

The 18 F-labeled fibroblast activation protein inhibitor (FAPI) [ 18 F]FAPI-74 has the benefit of a higher synthetic yield and better image resolution than 68 Ga-labeled FAPI. We preliminarily evaluated the diagnostic performance of [ 18 F]FAPI-74 PET in patients with various histopathologically confirmed cancers or suspected malignancies. Methods: We enrolled 31 patients (17 men and 14 women) with lung cancer ( n = 7), breast cancer ( n = 5), gastric cancer ( n = 5), pancreatic cancer ( n = 3), other cancers ( n = 5), and benign tumors ( n = 6). Twenty-seven of the 31 patients were treatment-naïve or preoperative, whereas recurrence was suspected in the remaining 4 patients. Histopathologic confirmation was obtained for the primary lesions of 29 of the 31 patients. In the remaining 2 patients, the final diagnosis was based on the clinical course. [ 18 F]FAPI-74 PET scanning was performed 60 min after the intravenous injection of [ 18 F]FAPI-74 (240 ± 31 MBq). The [ 18 F]FAPI-74 PET images were compared between the primary or local recurrent lesions of malignant tumors ( n = 21) and nonmalignant lesions ( n = 8: type-B1 thymomas, granuloma, solitary fibrous tumor, and postoperative or posttherapeutic changes). The uptake and number of detected lesions on [ 18 F]FAPI-74 PET were also compared with those on [ 18 F]FDG PET for available patients ( n = 19). Results: [ 18 F]FAPI-74 PET showed higher uptake in primary lesions of various cancers than in nonmalignant lesions (median SUV max , 9.39 [range, 1.83-25.28] vs. 3.49 [range, 2.21-15.58]; P = 0.053), but some of the nonmalignant lesions showed high uptake. [ 18 F]FAPI-74 PET also showed significantly higher uptake than [ 18 F]FDG PET (median SUV max , 9.44 [range, 2.50-25.28] vs. 5.45 [range, 1.22-15.06] in primary lesions [ P = 0.010], 8.86 [range, 3.51-23.33] vs. 3.84 [range, 1.01-9.75] in lymph node metastases [ P = 0.002], and 6.39 [range, 0.55-12.78] vs. 1.88 [range, 0.73-8.35] in other metastases [ P = 0.046], respectively). In 6 patients, [ 18 F]FAPI-74 PET detected more metastatic lesions than [ 18 F]FDG PET. Conclusion: [ 18 F]FAPI-74 PET showed higher uptake and detection rates in primary and metastatic lesions than did [ 18 F]FDG PET. [ 18 F]FAPI-74 PET is a promising novel diagnostic modality for various tumors, especially for precise staging before treatment, including characterization of tumor lesions before surgery. Moreover, 18 F-labeled FAPI ligand might serve a higher demand in clinical care in the future., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Vanishing tumor of the lung, also known as phantom tumor, is uncommonly observed in congestive heart failure. We report a case of a vanishing tumor that rapidly disappeared and reappeared in just a few minutes due to repositioning in a patient after open-heart surgery.

Limited treatment options exist for EGFR -mutated NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy. HER3 is highly expressed in EGFR -mutated NSCLC, and its expression is associated with poor prognosis in some patients. Patritumab deruxtecan (HER3-DXd) is an investigational, potential first-in-class, HER3-directed antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. In an ongoing phase I study, HER3-DXd demonstrated promising antitumor activity and a tolerable safety profile in patients with EGFR -mutated NSCLC, with or without identified EGFR TKI resistance mechanisms, providing proof of concept of HER3-DXd. HERTHENA-Lung01 is a global, registrational, phase II trial further evaluating HER3-DXd in previously treated advanced EGFR -mutated NSCLC. Clinical Trial Registration : NCT04619004 (ClinicalTrials.gov); 2020-000730-17 (EudraCT).

Background: It is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC., Methods: Elderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more., Results: We enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11)., Conclusion: Although several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC., Trial Registration: Unique ID issued by UMIN: UMIN000007819 (Date of registration: Apr 25, 2012) https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000009128. Trial ID issued by jRCT: jRCTs061180089 (Date of registration: Mar 22, 2019, for a shift toward a "specified clinical trial" based on Clinical Trials Act in Japan) https://jrct.niph.go.jp/en-latest-detail/jRCTs061180089., Competing Interests: HY1 received honoraria from Taiho Pharmaceutical outside the work. JS1 received honoraria from Johnson and Johnson and Intuitive outside the work. HN received grants from Taiho Pharmaceutical outside the work. KH received honoraria from Pfizer, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Takeda Pharmaceutical, MSD, BMS, Ono Pharmaceutical, Taiho Pharmaceutical and Boehringer-Ingelheim outside the work, and grants from MSD, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, BMS and Abbvie outside the work. HY2 received consulting fees from Delta-Fly Pharma and honoraria for lectures from AstraZeneca, Boehringer-Ingelheim, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, MSD, Novartis, BMS, Pfizer, Daiichi-Sankyo, Kyowa Kirin, Takeda Pharmaceutical, Nippon Kayaku and Otsuka Pharmaceutical outside the work. SM received honoraria for lectures from Taiho Pharmaceutical outside the work. HD received grants from Taiho Pharmaceutical outside the work. ST received grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, PFDeNA, MSD, AstraZeneca and a non-profit organization West Japan Oncology Group (WJOG) (supported by AstraZeneca for the operating expense of the clinical trial) outside the work. All other authors declared no conflicts of interest regarding this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background/aim: Atypical bronchoplasty is essential for complete tumor removal and preservation of peripheral lung tissue. This study compared surgical outcomes after atypical or typical bronchoplasty in patients who underwent pulmonary sleeve resection with bronchoplasty., Patients and Methods: Typical bronchoplasty was defined as that after one-lobe sleeve resection; atypical bronchoplasty was defined as that after sleeve bilobectomy or sleeve removal of one lobe plus segments. Double-barreled bronchoplasty was also included in the atypical group. Surgical outcomes were retrospectively investigated according to type of bronchoplasty., Results: Fifty-one patients underwent typical bronchoplasty and 20 atypical bronchoplasty. Recurrence was seen in 17 out of 51 (33%) patients after typical bronchoplasty and 10 out of 20 patients (50%) after atypical bronchoplasty. The recurrence-free survival rate was significantly poorer in the atypical bronchoplasty group (p=0.038). However, patients in the atypical bronchoplasty group were able to receive anticancer treatment for tumor recurrence, and there was no significant difference in overall survival rates between the groups., Conclusion: Preservation of pulmonary function by atypical bronchoplasty might contribute to tolerability of anticancer treatment for tumor recurrence. Pulmonary resection with atypical bronchoplasty is reliably beneficial for overall survival., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: In centrally located non-small cell lung cancer (CLNSCLC) surgery, large tumors and extension to neighboring structures prevent the attainment of adequate surgical fields and make operations more difficult, and some patients have extremely poor outcomes. This study aimed to identify novel postoperative prognostic factors in patients with advanced CLNSCLC., Patients and Methods: CLNSCLC was defined as a tumor requiring pneumonectomy or sleeve lobectomy for complete removal. We retrospectively investigated the clinical courses of 35 patients with cT3-4 CLNSCLC., Results: This study included 21 patients with cT3 and 14 with cT4 lung cancer. Nine patients underwent pneumonectomy and 26 underwent sleeve lobectomy. Univariate analysis revealed that a high neutrophil-to-lymphocyte ratio (NLR, p=0.005) and carcinoembryonic antigen (CEA) positivity (p=0.028) were significant poor prognostic factors. Only high NLR (p=0.020) was a significant independent predictor in multivariate analysis. Nine of 16 patients with high NLR (56%) experienced disease recurrence, whereas 6 of 19 patients without high NLR (32%) had recurrent disease., Conclusion: High NLR and CEA positivity were significant poor prognostic factors in patients with cT3-4 CLNSCLC, and only high NLR was an independent predictor. Our findings may be helpful in selecting optimal treatments for advanced CLNSCLC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)