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To verify the treatment effect of the combination of transpulmonary chemoembolization (TPCE) and microwave ablation (MWA), targeting the treatment of recurrent or advanced non-small cell lung cancer (NSCLC). A total of 53 patients were studied and grouped according to the diameter of the largest pulmonary nodule, defined as index tumor size (ITS). Patients with an ITS > 3 cm (n = 20) were treated with TPCE and MWA. Patients with an ITS ≤ 3 cm were treated either with a combination therapy (n = 24) or MWA alone (n = 9). The treatment response, including complications and survival outcome, was then analyzed. After TPCE, there was an average ITS reduction of 0.91 cm, and 25% of patients in ITS > 3 cm were downgraded to ITS ≤ 3 cm. After TPCE, there were 12 patients (27%) with PR status and 32 (73%) with SD status. No PD patient in our case series was noted before MWA.The complication rate of MWA was significantly higher in ITS ≤ 3 cm than in ITS > 3 cm (p = 0.013). The median survival time (MST) was 26.7 months, and the time to progression was 13.2 months. The patients in the ITS ≤ 3 cm had longer MST than the others (31.6 vs. 15.8 months, p = 0.003). The significant prognostic factor was ITS > 3 cm (HR: 1.18, p = 0.02). A combination of TPCE and MWA might be feasible to control non-operable, recurrent, or advanced NSCLC., (© 2024. The Author(s).)

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 and Objectives: Lung cancer is one of the prevailing malignancies worldwide. Surgical interventions hold an important position in the treatment framework for lung cancer. Pleural metastasis is often assumed to be a surgical contraindication, but not all instances of pleural metastasis can be accurately identified before surgery. The question of how to address pleural metastasis detected intraoperatively is still undecided., Methods: This retrospective study included 187 lung cancer patients who underwent surgery from 2005 to 2017 in whom pleural metastasis was discovered incidentally during the operation. Data on demographic, surgical, pathological, postoperative treatment, and survival information were collected for further analysis., Results: For patients with intraoperatively detected pleural metastasis, two independent protective prognostic factors were receiving primary tumor resection (compared to only receiving pleural nodule biopsy, HR = 0.079, p = 0.022) and receiving postoperative adjuvant chemotherapy (HR = 0.081, p < 0.001). Simultaneously, performing systematic lymph node dissection during primary tumor resection was found to be detrimental to long-term prognosis (HR = 2.375, p = 0.044). However, the resection of pleural metastatic lesions did not significantly impact patient prognosis., Conclusion: Our study supports the implementation of major tumor resection in patients with pleural metastasis detected intraoperatively but not lymph node dissection or the resection of pleural metastatic lesions. Postoperative chemotherapy is also necessary., (© 2024. The Author(s).)

This study aimed to explore the impact of PM 2.5 exposure on survival, post-operative outcomes, and tumor recurrence in resectable non-small cell lung cancer (NSCLC) patients. The study cohort comprised 587 patients at Chiang Mai University Hospital between January 1, 2010, and December 31, 2017. Patients were categorized based on their residents' average PM 2.5 concentration into two groups: exposed (PM 2.5 ≥ 25 µg/m3 annual mean) and unexposed (PM 2.5 < 25 µg/m3 annual mean). The exposed group had 278 patients, while the unexposed group had 309 patients. Baseline differences in gender and surgical approach were observed between the groups. Multivariable regression analysis revealed that patients in the exposed group had a higher risk of death (HR 1.44, 95% CI, 1.08-1.89, p = 0.012). However, no significant associations were found between PM 2.5 and post-operative pulmonary complications (RR 1.12, 95% CI, 0.60-2.11, p = 0.718), in-hospital mortality (RR 1.98, 95% CI, 0.40-9.77, p = 0.401), and tumor recurrence (HR 1.12, 95% CI, 0.82-1.51, p = 0.483). In conclusion, a PM 2.5 concentration ≥ 25 µg/m3 annual mean was associated with decreased overall survival and a potential increase in in-hospital mortality among resectable NSCLC patients. Larger studies with extended follow-up periods are required to validate these findings., (© 2024. The Author(s).)

Background: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting., Methods: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation., Results: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups., Conclusions: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms., (© 2024. The Author(s).)

Purpose: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor ( EGFR )-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy., Patients and Methods: Patients with EGFR -mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C trough ; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC D1-D15 ). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point., Results: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively., Conclusion: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Background: There is controversy regarding the optimal treatment for stage IIIA-N2 non-small cell lung cancer (NSCLC). We aimed to address this crucial issue through a frequentist network meta-analysis., Methods: We conducted a literature database search for randomized controlled trials comparing the following treatment modalities before March 1st, 2023: surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and various combinations of these treatments. Summary data on overall survival (OS) and treatment-related deaths (trDeath) were analyzed using frequentist methods., Results: Twenty-two randomized controlled trials (RCTs) with 3269 participants were included, covering 17 treatment regimens. In terms of overall survival, surgery followed by adjuvant targeted therapy (S-T), neoadjuvant targeted therapy followed by surgery and adjuvant targeted therapy (T-S-T), and neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy (C-S-C) were relatively more advantageous than other treatment regimens. Overall, S-T is the most likely treatment option to prolong OS, with a 59.8% likelihood, while immunotherapy plus chemotherapy followed by surgery and adjuvant chemotherapy (IC-S-C) demonstrates good safety., Conclusion: S-T and T-S-T treatments have the greatest potential to be the optimal overall survival treatments for stage IIIA-N2 NSCLC patients with positive driver genes, demonstrating significant clinical application prospects. While for patients with negative driver genes, C-S-C treatments benefit the most. The protocol was registered in the Prospective Register of Systematic Reviews, PROSPERO (CRD42022372711)., (© 2024. The Author(s).)

Recently, several studies have reported that the survival benefit of wedge resection might not be inferior to that of lobectomy in early-stage NSCLC patients, but there is no unified definition of the details or cutoff value. Patients with early-stage NSCLC with a tumour size ≤ 2.0 cm were chosen from the SEER database. The influence of confounding factors was minimized by 1:1 propensity score matching (PSM). Kaplan‒Meier curves and Cox proportional hazards models were used to evaluate the overall survival (OS) and lung cancer-specific survival (LCSS) of patients undergoing lobectomy and wedge resection. A total of 3891 patients with early-stage NSCLC with tumour size ≤ 2.0 cm were enrolled, of whom 2839 underwent lobectomy and 1052 underwent wedge resection. Both before and after PSM, lobectomy significantly improved OS and LCSS compared with wedge resection in the unstratified study population. In the tumour size ≤ 1 cm group, lobectomy had better OS and LCSS than wedge resection (P < 0.05) before PSM; after PSM, there was no significant difference in OS (P = 0.16) and LCSS (P = 0.17). In Grade I patients, before PSM, lobectomy was superior to wedge resection in LCSS (P = 0.038), while there was no significant difference in OS (P = 0.16); after PSM, there were no significant differences in either OS (P = 0.78) or LCSS (P = 0.11). For early-stage NSCLC patients with a tumour size ≤ 1 cm or with a tumour size ≤ 2 cm and with Grade I, there was no significant difference in survival between wedge resection and lobectomy., (© 2024. The Author(s).)

Objective The current standard treatment for locally advanced, unresectable stage III non-small-cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CCRT) and durvalumab administration. Although reports have indicated that the prognosis of squamous cell carcinoma is poorer than that of adenocarcinoma, real-world data are currently inadequate. Methods The present study analyzed patients with stage III NSCLC who received CCRT at the study center between April 2018 and February 2022. These patients were retrospectively classified into adenocarcinoma and squamous cell carcinoma groups for an analysis of the progression-free survival (PFS), overall survival (OS), and patient background factors, including the age, performance status, smoking history, and pre-CCRT laboratory data. Results A total of 109 patients were included for the analysis; 25 were excluded, and 44 and 40 patients were classified into the adenocarcinoma and squamous cell carcinoma groups, respectively. The median PFS was significantly longer in the adenocarcinoma group than in the squamous cell carcinoma group [27.9 (95% confidence interval (CI): 15.2-not achieved) vs. 9.63 (95% CI: 5.88-13.9) months; p<0.01]. Similarly, the median OS was significantly longer in the adenocarcinoma group than in the squamous cell carcinoma group [not achieved (95% CI: 48.1-not achieved) vs. 23.8 (95% CI; 14.6-not achieved) months; p<0.01]. In the multivariate Cox proportional hazard analysis, the histological type was the only prognostic factor for the PFS (p<0.05) and OS (p<0.05). Conclusion The median PFS and OS were poorer in patients with squamous cell carcinoma than in those with stage III NSCLC treated with CCRT and durvalumab. The histological type was an independent factor affecting the PFS and OS.

Background: The association of body mass index (BMI) with survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with first-line chemotherapy, immunotherapy, or chemoimmunotherapy is controversial. We aimed to investigate these associations, including associations in male and female patients specifically, in a multicenter cohort study., Methods: We retrospectively analyzed data from seven cohorts comprising 7021 advanced non-small cell lung cancer patients who received chemotherapy (three cohorts), immunotherapy (two cohorts), and chemoimmunotherapy (two cohorts) from five data sources, including a de-identified nationwide (US-based) NSCLC clinico-genomic database and two randomized, double-blind, phase 3 clinical trials. BMI was categorized as underweight, normal weight, overweight, or obese. Underweight patients were excluded because of their small proportion. The primary endpoints were the associations between BMI and progression-free survival (PFS) and overall survival (OS) stratified by treatment type and sex, which were assessed using Kaplan-Meier methods and adjusted Cox modeling. Meta-analyses were performed to combine the adjusted hazard ratios., Results: In the pooled analysis, obesity was significantly associated with improved OS in patients receiving chemotherapy (hazard ratios [HR] = 0.84, 95% confidence interval (CI) 0.76-0.93), but there was no association with PFS (HR = 0.91, 95% CI 0.82-1.02). The association of BMI with OS for patients receiving chemotherapy differed by sex, with an inverse association in men (HR = 0.74, 95% CI 0.64-0.84), but no association observed in women (HR = 0.96, 95% CI 0.81-1.13, P interaction = 0.018). No impact of BMI on OS or PFS was detected in patients receiving immunotherapy or chemoimmunotherapy. Obese patients had the lowest level of tumor mutational burden, similar level of programmed death-ligand 1 expression and ESTIMATE scores., Conclusions: Obesity may be associated with an increased overall survival among male patients treated with chemotherapy, whereas not associated with the outcomes in patients treated with immunotherapy or chemoimmunotherapy., (© 2024. The Author(s).)

Accurate assessment of N staging in patients with non-small cell lung cancer (NSCLC) is critical for the development of effective treatment plans, the optimization of therapeutic strategies, and the enhancement of patient survival rates. This study proposes a hybrid model based on 3D convolutional neural networks (CNNs) and transformers for predicting the N-staging and survival rates of NSCLC patients within the NSCLC radiogenomics and Nsclc-radiomics datasets. The model achieved accuracies of 0.805, 0.828, and 0.819 for the training, validation, and testing sets, respectively. By leveraging the strengths of CNNs in local feature extraction and the superior performance of transformers in global information modeling, the model significantly enhances predictive accuracy and efficacy. A comparative analysis with traditional CNN and transformer architectures demonstrates that the CNN-transformer hybrid model outperforms N-staging predictions. Furthermore, this study extracts the one-year survival rate as a feature and employs the Lasso-Cox model for survival predictions at various time intervals (1, 3, 5, and 7 years), with all survival prediction p -values being less than 0.05, illustrating the time-dependent nature of survival analysis. The application of time-dependent ROC curves further validates the model's accuracy and reliability for survival predictions. Overall, this research provides innovative methodologies and new insights for the early diagnosis and prognostic evaluation of NSCLC.

Introduction: Several trials of perioperative immunotherapy for resectable non-small cell lung cancer (NSCLC) reported positive results. They were designed to adjuvant, neoadjuvant and sandwich (neoadjuvant plus adjuvant) immunotherapy with immune checkpoint inhibitors and chemotherapy (CT). The differences between neoadjuvant and sandwich modalities were unclear., Method: We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, WHO ICTRP and major international conferences., Results: We analyzed 8 studies involving 3429 patients, including 6 neoadjuvant plus adjuvant (Neo-Adj) and 2 neoadjuvant (Neo) trials. Neo-Adj had better event-free survival (EFS) (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.45-0.71) than CT. There existed no difference between Neo-Adj and Neo in EFS (HR = 0.87, 95% CI: 0.53-1.46) and overall survival (OS) (HR = 1.04, 95% CI: 0.38-2.57). Neo might have lower incidence of treatment-related adverse events (TRAEs) (relative risk [RR] = 0.96, 95% CI: 0.87-1.12) than Neo-Adj. Subgroup analysis of PD-L1 ≥ 50% suggested that EFS of Neo-Adj (HR = 0.46, 95% CI: 0.27-0.76) and Neo (HR = 0.24, 95% CI: 0.06-0.89) was better than CT, and Neo-Adj potentially caused shorter EFS than Neo (HR = 1.92, 95% CI: 0.46-7.84)., Conclusions: Our results suggest that Neo-Adj and Neo have similar EFS for patients with PD-L1 < 1% or 1-49%. However, patients with PD-L1 ≥ 50% may obtain more EFS benefit from Neo than Neo-Adj. Neo might present a more favorable assessment than Neo-Adj when evaluating OS. Moreover, adding adjuvant immunotherapy may increase toxicity., (© 2024. The Author(s).)

Plasma epidermal growth factor receptor mutation (EGFRm) circulating tumor DNA (ctDNA) dynamics exhibit promise in predicting outcomes in patients with EGFRm-advanced non-small cell lung cancer (NSCLC). However, there remains limited trial-level data on integrating ctDNA monitoring into clinical practice. We performed a prospective, multicenter trial to investigate the relationship between EGFRm ctDNA dynamic changes and clinical outcomes in NSCLC patients with EGFRm. Ninety-eight treatment-naive EGFRm-advanced NSCLC patients were recruited and administered icotinib until disease progression. Plasma samples were collected at baseline and four weeks after icotinib administration. ctDNA was analyzed using a droplet-digital polymerase chain reaction. At baseline, 71.4% of patients had detectable EGFRm ctDNA. Among them, 45.9% of patients' ctDNA became undetectable within four weeks of treatment. These patients demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) than those with detectable ctDNA after treatment (P = 0.004 and < 0.001, respectively) and were comparable to those with undetectable ctDNA at both baseline and four weeks. ctDNA detectable at four weeks emerged as a poor independent risk factor for PFS and OS. Patients whose ctDNA became undetectable after treatment had outcomes similar to those with initially undetectable ctDNA, underscoring the predictive value of ctDNA dynamics in treatment efficacy.Registry and the Registration No. of the study/trial: ChiCTR-DDD-17013131. Date of registration: 2017-10-27., (© 2024. The Author(s).)

The insulin-like growth factor 1 receptor (IGF1R) has been associated with growth and metastasis in various cancers. However, its role in postoperative recurrence and prognosis in lung cancer lacks clear consensus. Therefore, this study aimed to investigate the potential relationship between IGF1R and postoperative recurrence as well as long-term survival in a large cohort. Additionally, we assessed the relationship between IGF1R and programmed death ligand 1 (PD-L1) expression. Our study encompassed 782 patients with non-small cell lung cancer (NSCLC). Immunostaining of surgical specimens was performed to evaluate IGF1R and PD-L1 expression. Among the patients, 279 (35.8%) showed positive IGF1R expression, with significantly worse relapse-free survival (RFS) and overall survival (OS). Notably, no significant differences in RFS and OS were observed between IGF1R-positive and -negative groups in stages 2 and 3. However, in the early stages (0-1), the positive group displayed significantly worse RFS and OS. In addition, PD-L1 expression was detected in 100 (12.8%) patients, with a significant predominance in the IGF1R-positive. IGF1R may serve as a prognostic indicator and a guide for perioperative treatment strategies in early-stage lung cancer. In conclusion, our findings underscore an association between IGF1R expression and poor survival and PD-L1 expression in NSCLC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nagamine 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: T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported., Methods: We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants., Results: Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood., Conclusion: Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Liu, Wang, Tang, Luo, Du, Christiani and Wei.)

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433-0.973) and 0.682 (95% CI: 0.464-0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511-1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14-3.4) and PFS 2.13 (95% CI: 1.28-3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation., (© 2024. The Author(s).)

Purpose: First-line tislelizumab plus chemotherapy significantly improved progression-free survival (PFS) versus chemotherapy alone in advanced squamous non-small-cell lung cancer (sq-NSCLC) at the interim analysis of the phase III RATIONALE-307 trial. We present the final analysis of this trial., Patients and Methods: Patients with treatment-naive, stage IIIB/IV, sq-NSCLC were randomized (1 : 1: 1) to 21-day cycles of i.v.: tislelizumab plus paclitaxel and carboplatin (arm A); tislelizumab plus nab-paclitaxel and carboplatin (arm B); or paclitaxel and carboplatin (arm C). The primary endpoint was independent review committee-assessed PFS; overall survival was a secondary endpoint., Results: In total, 360 patients were randomized; 355 received treatment. At the final analysis (median study follow-up: 16.7 months), tislelizumab plus chemotherapy had a manageable safety profile, consistent with that at the interim analysis. Improvement in PFS was maintained for arms A and B versus C {hazard ratio (HR) 0.45 [95% confidence interval (CI) 0.33-0.62] and 0.43 (95% CI 0.31-0.60), respectively}. Overall survival HRs for arms A and B versus C were 0.68 (95% CI 0.46-1.01) and 0.75 (95% CI 0.50-1.12), respectively., Conclusions: The RATIONALE-307 final analysis demonstrated superior clinical benefit with addition of tislelizumab to chemotherapy, and a manageable safety profile, as first-line treatment of advanced sq-NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The purpose of this study was to report an updated, final analysis with longer follow-up for the open-label phase III RATIONALE-304 study of first-line tislelizumab plus chemotherapy versus chemotherapy alone for advanced nonsquamous non-small-cell lung cancer (nsq-NSCLC)., Materials and Methods: Patients with histologically confirmed stage IIIB/IV nsq-NSCLC were randomized (2 : 1) to 4-6 cycles of tislelizumab plus platinum-based chemotherapy and pemetrexed every 3 weeks, followed by maintenance tislelizumab and pemetrexed, or platinum-based chemotherapy and pemetrexed alone every 3 weeks followed by maintenance pemetrexed. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS IRC ). Overall survival (OS), safety, and tolerability were secondary endpoints., Results: Overall, 334 patients were randomized (tislelizumab plus chemotherapy: n = 223; chemotherapy: n = 111). At final analysis (median follow-up 16.1 months), safety/tolerability profiles in both arms were consistent with the interim analysis. Tislelizumab plus chemotherapy continued to demonstrate prolongation of PFS IRC versus chemotherapy alone {stratified hazard ratio (HR) 0.63 [95% confidence interval (CI) 0.47-0.86]; median PFS IRC 9.8 months (95% CI 8.9-11.7 months) versus 7.6 months (95% CI 5.6-8.0 months), respectively}. OS stratified HR for tislelizumab plus chemotherapy versus chemotherapy was 0.90 (95% CI 0.63-1.28), with median OS of 21.4 months (95% CI 17.7 months-not estimable) versus 21.3 months (95% CI 15.6 months-not estimable), respectively. At a subsequent ad hoc analysis (median follow-up 19.3 months), OS HR between arms was 0.85 (95% CI 0.63-1.14); when adjusted for crossover using the two-stage method, the OS HR was 0.68 (95% CI 0.48-0.96)., Conclusions: After longer follow-up, first-line tislelizumab plus chemotherapy continued to demonstrate a manageable safety profile and a favorable PFS benefit over chemotherapy alone in patients with advanced/metastatic nsq-NSCLC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Randomized controlled trials (RCTs) have unequivocally established the therapeutic advantages of combining immune checkpoint inhibitors (ICIs) with chemotherapy in the treatment of early-stage non-small cell lung cancer (NSCLC). Presently, numerous perioperative immunotherapy regimens centered around the integration of ICIs and chemotherapy have undergone clinical trials. Nonetheless, due to the absence of direct comparative RCTs among these treatment regimens, this study aims to employ Bayesian network meta-analysis to ascertain the optimal combination of ICIs and chemotherapy., Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, Web of Science databases, and major international conference publications up to April 10, 2024. This comprehensive search yielded a total of 1434 studies. Following a rigorous screening process that involved evaluating the studies for relevance, methodological quality, and alignment with our research objectives, 8 studies were carefully selected for inclusion in the final analysis. Based on these curated search results, a systematic review and network meta-analysis were conducted., Results: 8 RCTs were included, encompassing 7 treatments and involving 3699 operable NSCLC patients at stages I-III. Compared to chemotherapy alone, perioperative immunotherapy demonstrated higher efficacy. The combination of toripalimab and chemotherapy showed the most significant improvement in event-free survival (EFS) (HR= 0.40; 95% CI, 0.28-0.58). The regimen that most notably enhanced overall survival (OS) was Nivolumab combined with chemotherapy (HR = 0.62; 95% CI, 0.36-1.07). In terms of pathological complete response (pCR), the combination of Toripalimab and chemotherapy exhibited the highest benefit (OR = 32.89; 95% CI, 7.88-137.32). Regarding the improvement in R0 resection, Pembrolizumab plus chemotherapy performed most prominently(OR=2.15; 95% CI, 1.30-3.56). In terms of the incidence of grade 3 or higher adverse events, durvalumab combined with chemotherapy had the lowest incidence (OR = 1.05; 95% CI, 0.79-1.38), while the incidence for other regimens was higher than chemotherapy alone., Conclusion: The efficacy of perioperative immunotherapy plus chemotherapy in patients with early NSCLC is significantly improved compared to chemotherapy alone. Although there is a certain risk of adverse events, the safety is within a controllable range. After a comprehensive evaluation of five endpoints in this study, it is believed that the combination of Toripalimab or Nivolumab with chemotherapy may be the optimal immunotherapy regimen for the treatment of stage Ib-IIIb NSCLC. These findings will help guide the design of clinical treatment plans and ICIs selection., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42024536799., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Wang, Yue, Chen, Zhu, Cui, Zhang, Jin and Xiao.)

Objectives: Several studies rely on archived tissue blocks to assess the PD-L1 scores; however, a detailed analysis of potential variations of scores between fresh and archived tissue blocks still lacks. In addition, the prognostic implications of PD-L1 in lung cancers have not yet been completely understood. Here, we aimed to investigate the temporal variation in PD-L1 scores from clinical samples and the clinical implications of PD-L1 in non-small cell lung cancer (NSCLC)., Methods: NSCLC cases from January 2005 to June 2023 were considered for this study, and PD-L1 scores in archived and fresh tissue blocks were analyzed. Association of PD-L1 with various driver mutations was explored, and implications of PD-L1 in progression-free survival (PFS) and overall survival (OS) were analyzed., Results: Our study revealed a significant disparity in PD-L1 scores between archived and fresh tissue blocks, and a temporal variation in scores within 6 months of tissue acquisition. Advanced-stage primary tumors, metastatic lymph nodes, and visceral pleural invasion revealed higher PD-L1 expression as presented by tumor proportion score (TPS). Notably, in fully resected stage I/II NSCLC cases, OS was better in the high PD-L1 (≥ 50% TPS) cohort with driver mutations compared to cases without driver mutations (hazard ratio-0.5129, 95% confidence interval 0.2058-1.084, p = 0.0779). In contrast, high PD-L1 was associated with worse OS compared to no PD-L1 (< 1% TPS) (hazard ratio-2.431, 95% confidence interval 1.144-6.656, p = 0.0242) in the cohort without driver mutations. Furthermore, the presence of a KRAS mutation favored the outcome of anti-PD-L1/PD1 immunotherapy in advanced NSCLC., Conclusion: PD-L1 detection from tissue blocks was found to vary temporally, urging for a prioritized consideration for patients with marginal scores when archived blocks are employed for its detection. Prognostic roles of PD-L1 were associated with driver mutations, and KRAS mutations favored the outcome of anti-PD-L1/PD1 therapy in advanced NSCLC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The objective was to develop and evaluate the portability of a text mining algorithm for prospectively capturing disease progression in electronic health record (EHR) data of patients with metastatic non-small cell lung cancer (mNSCLC) treated with immunochemotherapy., Methods: This study used EHR data from patients with mNSCLC receiving immunochemotherapy (between October 1, 2018, and December 31, 2022) in four Dutch hospitals. A text mining algorithm for capturing disease progression was developed in hospitals 1 and 2 and then transferred to hospitals 3 and 4 to evaluate portability. Performance metrics were calculated by comparing its outcomes with manual chart review. In addition, data were simulated to come available over time to assess performance in real-time applications. Median progression-free survival (PFS) was calculated using the Kaplan-Meier method to compare text mining with manual chart review., Results: During development and portability, the text mining algorithm performed well in capturing disease progression, with all performance scores >90%. When real-time performance was simulated, the performance scores in all four hospitals exceeded 90% from week 15 after the start of follow-up. Although the exact progression dates varied in 46 patients of 157 patients with progressive disease, the number of patients labeled with progression too early (n = 24) and too late (n = 22) was well balanced with discrepancies ranging from -116 to 384 days. Nevertheless, the PFS curves constructed with text mining and manual chart review were highly similar for each hospital., Conclusion: In this study, an accurate text mining algorithm for capturing disease progression in the EHR data of patients with mNSCLC was developed. The algorithm was portable across different hospitals, and the performance over time was good, making this an interesting approach for prospective follow-up of multicenter cohorts.

Introduction: Neoadjuvant immunotherapy plus chemotherapy has ushered in a new era for surgical treatment for patients with NSCLC. This study aimed to examine the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy in NSCLC., Methods: Eligible studies were identified from PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and conference meeting abstracts. The endpoints included major pathological response (MPR), complete pathological response (pCR), surgical resection rate, R0 resection, treatment-related adverse events (TRAEs), severe adverse events (SAEs), surgical complications, treatment discontinuation, surgical delay, and treatment-related death. Stata 18 software was used for statistical analysis, and p < 0.05 was considered statistically significant. Twenty-two studies including a total of 1108 patients were eligible for this study., Results: Among the patients who received neoadjuvant immunotherapy plus chemotherapy, the pooled MPR rate was 51% (95% CI [0.44-0.58]), and pCR rate was 34% (95% CI [0.28-0.40]). The pooled surgical resection rate was 85% (95% CI [0.81-0.89]), and the pooled R0 rate was 94% (95% CI [0.91-0.96]). The pooled rate of pathological tumor downstaging was 84% (95% CI [0.79-0.88]), and the pooled rate of pathological nodal downstaging was 38% (95% CI [0.23-0.57]). During the treatment of neoadjuvant immunotherapy plus chemotherapy with or without surgery, the pooled rate of TRAEs (any grade) was 84% (95% CI [0.73-0.91]), and the pooled rate of SAEs was 29% (95% CI [0.21-0.38]). Surgical complications pooled rate was 25% (95% CI [0.14-0.41]). The pooled rate of treatment discontinuation (11%, 95% CI [0.09-0.13]), surgical delay (3%, 95% CI [0.02-0.05]), and treatment-related death (2%, 95% CI [0.02-0.03]) were conducted., Conclusion: Neoadjuvant immunotherapy plus chemotherapy provides a high pathological response, surgical resection rate, R0 resection rate, and pathological downstage rate and has a low risk of increasing the incidence of SAEs, surgical complications, treatment discontinuation, surgical delay, and treatment-related death. The validation of prospective and large sample studies is needed to confirm this conclusion., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Objectives: The clinical trial showed that sublobar resection was not inferior to lobectomy in terms of disease-free survival in patients with peripherally located non-small-cell lung cancer ≤2 cm. However, it is not clear whether sublobar resection is indicated for all types of c-stage IA lung cancer. The purpose of this study was to clarify whether sublobar resection is indicated for c-stage IA hypermetabolic lung cancer., Methods: Patients with c-stage IA lung cancer who underwent F-18 fluorodeoxyglucose positron emission tomography/computed tomography and lobectomy or sublobar resection were assessed. Of these, patients who had a maximum standardized uptake value ≥3.0 on positron emission tomography/computed tomography were evaluated. We compared survival rates after lobectomy versus sublobar resection. Propensity score matching was performed to balance patient characteristics between groups., Results: Between April 2004 and March 2023, 723 patients underwent lobectomy or sublobar resection and had a maximum standardized uptake value ≥3.0 on positron emission tomography/computed tomography. Lobectomy and sublobar resection were performed in 532 (73.6%) and 191 (26.4%) patients, respectively. Both the 5-year overall and disease-free survival rates were worse after sublobar resection compared with lobectomy (62.3% vs 79.9% and 53.9% vs 70.3%, respectively). After propensity score matching, the 5-year overall and disease-free survival rates remained worse after sublobar resection compared with lobectomy (60.7% vs 75.2% and 51.6% vs 67.7%, respectively)., Conclusions: Patients with c-stage IA hypermetabolic lung cancer with standardized uptake value ≥3.0 on positron emission tomography/computed tomography had a worse prognosis after sublobar resection than after lobectomy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC., Methods: In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome., Results: In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts., Discussion: Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: As more treatments emerge for advanced, stage IV non-small-cell lung cancer (NSCLC), oncologists have difficulty predicting functional resiliency versus functional decline throughout cancer treatment. Our study evaluates functional resilience among patients with advanced NSCLC., Methods: Functional status was evaluated through 12 months of follow-up based on disability score using the modified EQ-5D-5L (mEQ-5D-5L) survey. Participants were classified into 4 groups: functional maintenance, decline, resilient, or variable. Characteristics of 207 participants with newly diagnosed NSCLC included demographics, comorbidities, baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS), mEQ-5D-5L scores, psychological symptoms, and lung cancer-specific symptoms. Treatment toxicity and grade were recorded. Resilience was defined as improvement from baseline disability scores. A 1-point increase in functional status score represents a 0.5 standard deviation change on the mEQ-5D-5L. Differences between the 4 groups were determined through Fisher's exact test or ANOVA. Kaplan-Meier curves describe overall survival (baseline through 18 months) stratified by baseline mEQ-5D-5L scores., Results: Among participants, 42.0 % maintained functional status, 37.7 % experienced functional decline, 10.6 % were resilient, and 9.7 % had variable functional status. Participants with the best baseline function (score of 0) had the longest overall survival and participants with the worst baseline function (score of 5 + ) had the shortest overall survival. Among the healthiest patients, early score increases indicated shorter overall survival. Baseline ECOG PS was not associated with overall survival (p = 0.47)., Conclusion: Baseline functional status may help better predict functional resiliency and overall survival than ECOG PS among patients receiving treatment for advanced NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Wong reported conflicts of interest outside of the submitted work (royalties from UpToDate, immediate family member is an employee of Genentech with stock ownership). No other authors have conflicts to report., (Copyright © 2024. Published by Elsevier B.V.)

Background: Capmatinib is a selective MET inhibitor with demonstrated efficacy in a phase II study of non-small cell lung cancer (NSCLC) patients harboring METex14 mutations. However, the real-world outcomes of capmatinib are largely unknown. From June 2019, the French Early Access Program (EAP) provided capmatinib to METex14 NSCLC patients who were ineligible for or for whom first-line standard therapies had failed., Methods: IFCT-2104 CAPMATU was a multicenter study that included all METex14 NSCLC patients who received capmatinib as part of the EAP until August 2021. The primary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR)., Results: A total of 146 patients were included. The median age was 74.9 years, 56.6 % were never-smokers, and 32.4 % had brain metastases. The median TTF, median PFS and median OS from capmatinib initiation were 5.1 months (95 % CI 4.2-6.0), 4.8 months (95 % CI 4.0-6.0) and 10.4 months (95 % CI 8.3-13.2), respectively. Evaluation of the best response to capmatinib was available for 134 patients and resulted in an ORR of 55.3 % (95 % CI 46.8 %-63.6 %). The median PFS was 7.7 months for treatment-naïve patients and 6.0 and 4.1 months for patients who had received one or 2 + prior lines of treatment, respectively. For patients with brain metastases, the median PFS was 3.0 months. Capmatinib had a known and manageable safety profile, with grade 3 to 4 adverse events, mostly peripheral edema (8.2 %), occurring in 17.8 % of patients., Conclusion: In this large real-world study of METex14 NSCLC patients, the efficacy of capmatinib was confirmed, with a manageable safety profile, even in patients with brain metastases and in those who received several lines of treatment. This study reinforces the key role of capmatinib for these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Ferreira: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, BMS. A. Swalduz: Financial Interests, Personal, Other, honoraria: AstraZeneca, Janssen, Roche, Amgen, BMS; Financial Interests, Personal, Advisory Role: AstraZeneca, Janssen, Roche, Amgen, BMS, Pfizer, Lilly. P. du Rusquec: Financial Interests, Personal, Other, Travel, Accommodations: Roche, Pfizer, Sandoz, Daiichi Sankyo, Merck, Novartis, Lilly, Amgen, Eisai, BMS, Takeda, AstraZeneca, Janssen, Sanofi. Advisory Role: Sanofi, Takeda. A.C. Toffart: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, BMS, Roche, Amgen, Takeda, Jannsen. J. Raimbourg: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS. V. Gounant: Financial Interests, Personal, Advisory Role: BMS, AstraZeneca, Takeda; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sanofi, Pfizer. S. Couraud: Financial Interests, Personal, Other, honoraria: Amgen, AstraZeneca, BMS, MSD, Roche, Sanofi, Fabentech, Boehringer Ingelheim, Takeda; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, BMS, MSD, Roche, Sanofi, Chugai, Novartis, Pfizer, Sysmex, Cellgene, Takeda, Janssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, Roche, Takeda. M. Wislez: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, Amgen, BMS, Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, MSD, Amgen, BMS, Roche; Financial Interests, Institutional, Funding, research funding: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, MSD, Amgen, BMS, Roche. C. Descarpentries reports personal fees and nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Novartis Pharma SAS, nonfinancial support from Roche SAS, nonfinancial support from Boehringer Ingelheim france, nonfinancial support from Pfizer, outside the submitted work; G. Herbreteau reports personal fees and nonfinancial support from Pierre Fabre Oncology. V. Westeel: Financial Interests, Personal, Other, Honoraria: AstraZeneca, BMS, Amgen, Roche; Financial Interests, Personal, Advisory Role: MSD, Takeda; Financial Interests, Personal, Speaker’s Bureau: BMS, AstraZeneca, Roche, MSD, Pfizer, Amgen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS, AstraZeneca, Sanofi. A. B. Cortot: Financial Interests, Personal, Other, Consulting fees: Roche Novartis; Financial Interests, Personal, Other, Honoraria: Novartis Pfizer Takeda Roche; Financial Interests, Personal, Advisory Board: Roche Novartis Pfizer Takeda. All other authors have declared no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The goal was to explore clinical factors and build a predictive model for the disease-free and overall survival of patients with non-small cell lung cancer (NSCLC) receiving neoadjuvant chemotherapy combined with immune checkpoint inhibitors., Methods: Inclusion criteria for patients in this multicentre study were as follows: (i) Patients who were diagnosed with stages I-III NSCLC after a bronchoscopy biopsy or puncture; (ii) patients who were examined with computed tomography/positron emission tomography-computed tomography before treatment and surgery; (iii) patients who received neoadjuvant chemotherapy combined with immune checkpoint inhibitors for 2 to 6 cycles preoperatively; (iv) patients whose peripheral blood indicators and tumour markers were assessed before treatment and preoperatively; (v) patients who underwent radical lung cancer surgery after neoadjuvant therapy. Cases were divided into high- and low-risk groups according to 78 clinical indicators based on a 10-fold Least Absolute Shrinkage and Selection Operator selection. We used Cox proportional hazards models to predict disease-free and overall survival. Then, we used time-dependent area under the curve and decision curve analyses to examine the accuracy of the results., Results: Data were collected continuously, and 212 and 85 cases were randomly assigned to training and testing sets, respectively. The area under the curve for the prediction of disease-free survival (training: 1 year, 0.83; 2 years, 0.81; 3 years, 0.83 versus testing: 1 year, 0.65; 2 years, 0.66; 3 years, 0.70), overall survival (training: 1 year, 0.86; 2 years, 0.85; 3 years, 0.86 versus testing: 1 year, 0.66; 2 years, 0.57; 3 years, 0.70) were determined. The coefficient factors including pathological response; preoperative tumour maximum diameter; preoperative lymph shorter diameter; preoperative tumour and lymph maximum standardized uptake value; change in tumour standardized uptake value preoperatively; and blood-related risk factors were favourably associated with prognosis (P < 0.001)., Conclusions: Our prediction model, which integrated data from preoperative positron emission tomography-CT, preoperative blood parameters and pathological response, was able to make highly accurate predictions for disease-free and overall survival in patients with NSCLC receiving neoadjuvant immunity with chemical therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations., Methods: In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m 2 on day 1 and either plinabulin (30 mg/m 2 ) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed., Findings: Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group., Interpretation: Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population., Funding: BeyondSpring Pharmaceuticals., Competing Interests: Declaration of interests TF received research funding from BeyondSpring Pharmaceuticals to conduct this trial and is a speaker for Sanofi and Sobi. CH received research funding from BeyondSpring Pharmaceuticals to conduct this trial. GHK is President of Kentucky Society of Oncology and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from BMS, Genentech, AstraZeneca, Regeneron, Guardant, EMD Serono, and Novartis; consulting fees from BMS, Genentech, AstraZeneca, Regeneron, and Guardant; and payment for participation on a data safety monitoring board or advisory board from BMS, Genentech, AstraZeneca, and Regeneron. LB has received research support from Beyondspring and consulting fees from Sanofi, Gilead, Pfizer, Boehringer Ingelheim, Neuvogen, Bayer, BioAtla, Daichi, Summit, Anheart, Merck, Abbvie, Regeneron, Janssen, Genentech, Novocure, InterVenn, Elevation Oncology, Turning Point, and Novartis; and has participated on data safety monitoring board or advisory boards for ORIC Pharmaceuticals. JZ, ZJ, BH, FY, ZL, YSu, and JS have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from MSD, BeiGene, Roche, and AstraZeneca. 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: Patients with early-stage lung cancer and interstitial lung disease have a poorer prognosis than those without interstitial lung disease. This study aimed to compare the long-term outcomes of lobar and sublobar resections in these patients., Methods: We retrospectively analyzed 138 consecutive patients with clinical stage I non-small cell lung cancer and interstitial lung disease who underwent surgical treatment at two institutions between January 2010 and December 2020. Propensity score matching analysis was performed to adjust for baseline characteristics., Results: Thirty-six patients underwent sublobar resection and 102 underwent lobar resection. The median follow-up was 45.7 months. In all patients, 5-year overall survival (OS) rates were 33.2% and 73.2%, and 5-year recurrence-free survival (RFS) rates were 24.2% and 60.1% in the sublobar and lobar resection groups, respectively (p < 0.01, <0.01). Death due to lung cancer and locoregional recurrence were significantly more frequent in the sublobar resection group than in the lobar resection group (p = 0.034, <0.01, respectively). On propensity score matching analysis, the 5-year OS rates of the 19 matched pairs were 46.3% and 73.2%, and the RFS rates were 31.6% and 67.6% in the sublobar and lobar resection groups, respectively (p = 0.036, <0.01). The Cox proportional hazards model demonstrated a significant association between lobar resection and improved survival (p = 0.047)., Conclusion: The patients in the lobar resection group had better survival rates than those in the sublobar resection group. In terms of long-term prognosis, deliberately limited surgery may not be necessary for patients who tolerate lobectomy., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Pralsetinib, a selective RET targeted tyrosine kinase inhibitor (TKI), has been approved for treating locally advanced or metastatic RET fusion-positive NSCLC in adults who have previously received platinum-based chemotherapy in China., Methods: In this retrospective analysis conducted at Hunan Cancer Hospital in China, we examined 36 patients with advanced NSCLC with RET fusion, who were treated with pralsetinib between January 2021 and December 2023. The study focused on assessing the efficacy (Progression-free survival (PFS) and overall survival (OS)) and safety profile of pralsetinib in these patients. Statistical analyses were conducted using SPSS version 20.0, with a significance level set at p < 0.05., Results: The results revealed that pralsetinib exhibited significant activity in this patient cohort. Kaplan-Meier survival analysis indicated a median PFS of 10.7 months and a median OS of 21.2 months. The overall response rate(ORR) and disease control rate (DCR) was 55.6 % and 72.2 %, respectively. Pralsetinib was generally well tolerated, with most adverse events being mild to moderate (grades 1-2). The most common serious adverse events (≥grade 3) observed were lymphopenia (13.9 %), hypertension (11.1 %), leukopenia (8.3 %), neutropenia (8.3 %), and creatine kinase elevation (8.3 %)., Conclusion: Pralsetinib demonstrated promising activity in patients with advanced NSCLC harboring RET fusion with a favorable safety profile., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: MET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC., Materials and Methods: NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences. Immune cell fractions were estimated from bulk RNA sequencing (quanTIseq). Real-world survival data (mOS) was calculated from insurance claims. Statistical analyses employed Chi-square, Fisher's exact, or Mann-Whitney U and log-rank tests and were corrected for hypothesis testing where applicable., Results: A total of 711 METex14+ cases were detected. Of 575 cases of defined histology, 77 (13.6 %) were squamous (Sq), 474 (82.3 %) were nSq (non-squamous), and 24 (4.1 %) were adenosquamous. Mutations in POT1 and BRCA2 were enriched, and amplifications in MDM2, HMGA2, CDK4, and MET were common in METex14+ tumors. TMB-high and TP53 mutated tumors were reduced in METex14+ independent of histology. KEAP1 (2.1 vs 14.7 %) and STK11 mutations (0.8 vs 17.1 %) were reduced only in METex14+ nSq (vs METex14+ Sq, q < 0.05). While the prevalence of PD-L1 high tumors was enriched in METex14+ independent of histology, T-cell inflamed tumors were enriched only in nSq METex14+. B-cells and CD8+ T-cells (1.07-1.43-fold) were enriched in nSq METex14+, and dendritic cells (0.32 fold) were reduced only in METex14+ Sq. METex14+ tumors had a modest improvement in mOS compared to METex14- tumors (mOS = 22.9 m vs 18.6 m, HR = 0.914, p = 0.04). Moreover, METex14+ tumors who received immunotherapy (IO) had a modest improvement in survival (mOS = 27.5 m vs 21.8 m; HR = 0.803, p = 0.03) compared to those who did not receive IO. METex14+ nSq tumors were associated with improved mOS compared to METex14+ Sq tumors (mOS = 27.7 vs 8.9 m, HR = 0.493, p < 0.0001)., Conclusion: METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennifer Marks holds R&D authorship with Janssen Scientific Affairs. Nishant Gandhi, Joanne Xiu, Phillip Walker, and Matthew J. Oberley are employed by Caris Life Sciences. So Yeon Kim receives institutional grant funding from Boehringer Ingelheim, Astra Zeneca, Genentech, BMS, Loxo-Lilly, Genmab, and Dynamicure. Additionally, she has consulted for Amgen.Balazs Halmos receives institutional grant funding from Boehringer Ingelheim, Astra Zeneca, Merck, BMS, Advaxis, Amgen, AbbVie, Daiichi, Pfizer, GSK, Beigene, Janssen, Black Diamond Therapeutics, Forward Pharma, Numab, and Arrivent. He also serves on the Data Safety Monitoring Board/Advisory board for BMS, TPT, Apollomics, eFECTOR, and City of Hope. Melina E. Marmarelis reports research funding from Eli Lilly (Inst), AstraZeneca (Inst), Merck (Inst), Genentech (Inst), and holds a consulting role with Astra Zeneca, Novocure, Boehringer Ingelheim, Janssen, Takeda, Blueprint Pharmaceuticals, Bayer, Bristol Myers Squibb, Ikena, Regeneron. She also receives honorarium from Thermo Fisher and holds stock in Merck and Johnson & Johnson. Lyudmila Bazhenova reports a professional medical writing service funded by Mirati Therapeutics Inc, along with consulting roles with Pfizer, Genentech, Janssen, Novocure, Daiichi Sankyo, Anheart, BMS, Sanofi, Gilead, Teligene, Boehringer Ingelheim, Neuvogen, Bayer, BioAtla, Summit Therapeutics, Merck, Abbvie, Regeneron, Intervenn, Elevation Oncology, and Mirati. Additionally, she has institutional consulting with Takeda and Astra Zeneca, serves on the Data Safety Monitoring for ORIC Pharmaceuticals and Neuvogen, and holds stock in Epic Sciences. Stephen V. Liu holds a consulting role with AstraZeneca, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Novartis, Regeneron, Sanofi, and Takeda. He also receives research institutional grant funding from Alkermes, Bristol-Myers Squibb, Elevation Oncology, Genentech, Gilead, Merck, Merus, Nuvalent, Pfizer, RAPT, and Turning Point Therapeutics, and serves on the Data Safety Monitoring Board for Candel Therapeutics. The remaining authors have no relevant financial disclosures to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: High and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients., Methods: This is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2., Results: Distribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48-8.04 mg/day) vs. 9.15 mg/day (IQR:8.33-9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69-1.003)., Conclusion: This large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Ruben Malmberg has received payment for lectures from BMS. Roelof van Leeuwen has received grants from BMS and Pfizer, consulting fees from BMS, MDS, Pfizer, Pierre Fabre, AstraZeneca, and Roche, and payment for presentations and attending meetings from AstraZeneca. Hans Smit is a member on the advisory board of BMS and MSD and is a member representative of the Dutch scientific committee for pulmonary disease (no payments involved). Juliëtte Zwaveling has received a grant from AstraZeneca. All other 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.)

PURPOSEThe impact of the intratumoral microbiome on immune checkpoint inhibitor (ICI) efficacy in patients with non-small-cell lung cancer (NSCLC) is unknown. Preclinically, intratumoral Escherichia is associated with a proinflammatory tumor microenvironment and decreased metastases. We sought to determine whether intratumoral Escherichia is associated with outcome to ICI in patients with NSCLC.PATIENTS AND METHODSWe examined the intratumoral microbiome in 958 patients with advanced NSCLC treated with ICI by querying unmapped next-generation sequencing reads against a bacterial genome database. Putative environmental contaminants were filtered using no-template controls (n = 2,378). The impact of intratumoral Escherichia detection on overall survival (OS) was assessed using univariable and multivariable analyses. The findings were further validated in an external independent cohort of 772 patients. Escherichia fluorescence in situ hybridization (FISH) and transcriptomic profiling were performed.RESULTSIn the discovery cohort, read mapping to intratumoral Escherichia was associated with significantly longer OS (16 v 11 months; hazard ratio, 0.73 [95% CI, 0.59 to 0.92]; P = .0065) in patients treated with single-agent ICI, but not combination chemoimmunotherapy. The association with OS in the single-agent ICI cohort remained statistically significant in multivariable analysis adjusting for prognostic features including PD-L1 expression ( P = .023). Analysis of an external validation cohort confirmed the association with improved OS in univariable and multivariable analyses of patients treated with single-agent ICI, and not in patients treated with chemoimmunotherapy. Escherichia localization within tumor cells was supported by coregistration of FISH staining and serial hematoxylin and eosin sections. Transcriptomic analysis correlated Escherichia-positive samples with expression signatures of immune cell infiltration.CONCLUSIONRead mapping to potential intratumoral Escherichia was associated with survival to single-agent ICI in two independent cohorts of patients with NSCLC.

Purpose: Despite the generally favourable prognoses observed in patients with ALK-positive non-small cell lung cancer (NSCLC), there remains significant variability in clinical outcomes. The objective of this study is to enhance patient stratification by examining both the specific sites of gene fusion and the presence of co-occurring mutations., Methods: We collected retrospective clinical and pathological data on ALK-positive patients with locally advanced or metastatic disease. ALK fusion variants and concomitant mutations were identified through next-generation sequencing technology. We then assessed treatment efficacy via tumor response and survival metrics., Results: This study included a total of 59 patients, with 49 harboring echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions and 10 presenting with rare fusions. The median follow-up period was 33 months. Clinical outcomes between non-EML4-ALK and EML4-ALK patients were comparable. Among the EML4-ALK cohort, patients with longer variants (v1, v2, v8) demonstrated superior progression-free survival (PFS) (median PFS: 34 months vs. 11 months; hazard ratio [HR]: 2.28; P = 0.05) compared to those with shorter variants (v3, v5). Furthermore, patients treated with second-generation ALK inhibitors (ALKi) displayed a progression-free survival advantage (median PFS: not reached [NR] vs. 9 months; HR: 5.37; P = 0.013). Baseline TP53 co-mutation were linked with a substantially shorter OS (median OS,37 months vs. NR; HR 2.74; P = 0.047)., Conclusions: In ALK+ NSCLC, longer EML4-ALK variants correlate with improved prognosis and enhanced response to second-generation ALKi, while TP53 co-mutations indicate a negative prognosis., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Existing survival prediction models rely only on baseline or tumor kinetics data and lack machine learning integration. We introduce a novel kinetics-machine learning (kML) model that integrates baseline markers, tumor kinetics, and four on-treatment simple blood markers (albumin, C-reactive protein, lactate dehydrogenase, and neutrophils). Developed for immune-checkpoint inhibition (ICI) in non-small cell lung cancer on three phase II trials (533 patients), kML was validated on the two arms of a phase III trial (ICI and chemotherapy, 377 and 354 patients). It outperformed the current state-of-the-art for individual predictions with a test set C-index of 0.790, 12-months survival accuracy of 78.7% and hazard ratio of 25.2 (95% CI: 10.4-61.3, P < 0.0001) to identify long-term survivors. Critically, kML predicted the success of the phase III trial using only 25 weeks of on-study data (predicted HR = 0.814 (0.64-0.994) vs. final study HR = 0.778 (0.65-0.931)). Modeling on-treatment blood markers combined with predictive machine learning constitutes a valuable approach to support personalized medicine and drug development. The code is publicly available at https://gitlab.inria.fr/benzekry/nlml&#95;onco., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Optimal treatment for stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT)., Materials and Methods: In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to 2 years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1)., Results: Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), nine (26%), and four (12%) had a tumor proportion score of < 1%, 1%-50%, and ≥ 50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a 5-year DFS rate of 29%. The OS rate was 86% at 2 years and 76% at 5 years. Patients with tumor recurrence within 6 months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified., Conclusion: Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

Purpose: The treatment of the advanced non-small cell lung cancer (NSCLC) with KRAS mutation has been closely paid more attention. The aim of this study is to investigate the efficacy of different first-line regimens in advanced KRAS-mutated non-small cell lung cancer., Methods: In our retrospective study, we collected patients with advanced NSCLC with KRAS mutation in Zhejiang Cancer Hospital between January 2015 and May 2023. We analyzed the benefit of different first-line therapy according to theraputic methods and the differential effect of the same treatment method among KRAS-mutated subtypes. We divided the patients into group A (A1, chemotherapy alone; A2, immunotherapy alone) and group B (B1, chemotherapy plus immunotherapy; B2, chemotherapy combined with antiangiogenic therapy; B3, chemotherapy combined with immunotherapy plus antiangiogenic therapy). The Kaplan-Meier survival curve was used to reflect the PFS and OS of different methods. The objective response rate (ORR) and the disease control rate (DCR) were used to evaluated the response., Results: We enrolled 227 patients including eighty-two with KRAS G12C mutation. The ORR and DCR of first-line treatment in the overall population were 32.2% and 80.6% respectively. The median PFS was 6.7 months and the median OS was 17.4 months for the overall population. The PFS of the Group B was significantly better than that of the Group A (7.7 months vs 5.4 months, P = 0.003), while no significant difference in OS was observed (19.4 months vs 15.0 months, P = 0.077). In the Group B, chemotherapy combined immunotherapy with antiangiogenic therapy showed better PFS than chemotherapy plus immunotherapy (14.1 months vs 7.7 months, P = 0.049), and OS also showed that tendency of difference (31.9 months vs 19.3 months, P = 0.158). There was no statistically significant difference between KRAS G12C and non-G12C mutation according to first-line treatment methods, whereas patients with TP53 co-mutation showed a better survival benefit (OS, 23.7 vs 12.5 months, P = 0.023)., Conclusion: In the first-line treatment, combination regimen has advantages over single regimen. Among them, chemotherapy combined with immunotherapy plus antiangiogenic therapy can achieve significant efficacy benefits., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Purpose: Adding immune checkpoint blockade (ICB) to concurrent chemoradiotherapy (cCRT) has improved overall survival (OS) for inoperable locally advanced non-small cell lung cancer. Trials of cCRT-ICB are heterogeneous for factors such as tumor stage and histology, programmed cell death ligand-1 (PDL-1) status, and cCRT-ICB schedules. We therefore aimed to determine the ICB contribution to survival across studies and identify factors associated with survival gain., Methods and Materials: Data were collated from cCRT-ICB clinical studies published 2018 to 2022 that treated 2196 patients with non-small cell lung cancer (99% stage 3). Associations between 2-year OS and ICB, CRT, patient and tumor factors were investigated using metaregression. A published model of survival after radiation therapy (RT) or CRT was extended to include ICB effects. The model was fitted simultaneously to the cCRT-ICB data and data previously compiled for RT/CRT treatments alone. The net ICB contribution (OS gain) and its associations with factors were described by fitted values of ICB terms added to the model. Statistical significance was determined by likelihood-ratio testing., Results: The gain in 2-year OS from ICB was 9.9% overall (95% CI, 7.6%, 12.2%; P = .018). Both OS gain and 2-year OS itself rose with increasing planned ICB duration (P = .008, .002, respectively) and with tumor PDL-1 ≥ 1% (P = .034, .023). Fitted OS gains were also greater for patients with stage 3B/C disease (P = .021). OS gain was not associated with tumor histology, patient performance status, radiation therapy dose, ICB drug type (anti-PDL-1 vs anti-programmed cell death-1), or whether ICB began concurrently with or after cCRT., Conclusions: Fitted gains in 2-year OS due to ICB were higher in cohorts with greater fractions of stage 3B/C patients and patients with tumor PDL-1 ≥ 1%. OS gain was also significantly higher in a single cohort with a planned ICB duration of 2 years rather than 1, but was not associated with whether ICB treatment began during versus after CRT., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited., Patients and Methods: Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation., Results: In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ -50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment., Conclusions: Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Objective: This study aimed to analyze the prognosis of patients with non-small cell lung cancer (NSCLC) after receiving immunotherapy and construct a prediction model to evaluate the overall survival rate of patients., Methods: This study was a retrospective study that collected data from 493 NSCLC patients who received immunotherapy for the first time. Survival data were analyzed using Cox regression models and the Kaplan-Meier method. The average age of patients was 56 years, and the data collection process included regular outpatient follow-up and observation of overall survival (OS) in the last 36 months., Results: Multivariate analysis identified significant risk factors such as smoking history, age, T stage, and M stage on survival and disease progression. The model's performance indicators (C-index and AUC) and calibration curve verified the model's accuracy and predictive ability. In the training set, the AUCs of 3-year and 5-year survival were 0.761 and 0.763, respectively, and in the validation set, they were 0.739 and 0.761., Conclusion: This study developed a prediction model for evaluating the survival of NSCLC patients after immunotherapy that integrates multiple influencing factors. This predictive model can be used as a tool to assess individual risks in NSCLC patients after immunotherapy, helping clinicians to develop more precise treatment and follow-up plans, potentially improving patient outcomes.

Purpose: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe., Methods: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis., Results: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38)., Conclusion: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe., (© 2024. The Author(s).)

Background and Purpose: Stereotactic ablative body radiotherapy (SABR) is increasingly used for early-stage lung cancer, however the impact of dose to the heart and cardiac substructures remains largely unknown. The study investigated doses received by cardiac substructures in SABR patients and impact on survival., Materials and Methods: SSBROC is an Australian multi-centre phase II prospective study of SABR for stage I non-small cell lung cancer. Patients were treated between 2013 and 2019 across 9 centres. In this secondary analysis of the dataset, a previously published and locally developed open-source hybrid deep learning cardiac substructure automatic segmentation tool was deployed on the planning CTs of 117 trial patients. Physical doses to 18 cardiac structures and EQD2 converted doses (α/β = 3) were calculated. Endpoints evaluated include pericardial effusion and overall survival. Associations between cardiac doses and survival were analysed with the Kaplan-Meier method and Cox proportional hazards models., Results: Cardiac structures that received the highest physical mean doses were superior vena cava (22.5 Gy) and sinoatrial node (18.3 Gy). The highest physical maximum dose was received by the heart (51.7 Gy) and right atrium (45.3 Gy). Three patients developed grade 2, and one grade 3 pericardial effusion. The cohort receiving higher than median mean heart dose (MHD) had poorer survival compared to those who received below median MHD (p = 0.00004). On multivariable Cox analysis, male gender and maximum dose to ascending aorta were significant for worse survival., Conclusions: Patients treated with lung SABR may receive high doses to cardiac substructures. Dichotomising the patients according to median mean heart dose showed a clear difference in survival. On multivariable analyses gender and dose to ascending aorta were significant for survival, however cardiac substructure dosimetry and outcomes should be further explored in larger studies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Co-occurring mutations in KEAP1 and STK11/KRAS have emerged as determinants of survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. However, these mutational contexts identify a fraction of nonresponders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models., Experimental Design: The Cancer Genome Atlas was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of patients with advanced NSCLC treated with immunotherapy and profiled by RNA sequencing (SU2C n = 153; OAK/POPLAR n = 439). The NSCLC TRACERx421 multiregion sequencing study (tumor regions, n = 947) was used to investigate evolutionary trajectories., Results: KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of patients with NSCLC treated with immunotherapy (SU2C PFS P = 0.042, OS P = 0.008; OAK/POPLAR PFS P = 0.0014, OS P < 0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors., Conclusions: We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in patients with NSCLC treated with immunotherapy., (©2024 American Association for Cancer Research.)

Introduction: Minimally invasive lung resection has been associated with improved outcomes; however, institutional characteristics associated with utilization are unclear. We hypothesized that the presence of surgical robots at institutions would be associated with increased utilization of minimally invasive techniques ., Methods: Patients with cT1/2N0M0 non-small cell lung cancer who underwent lung lobectomy between 2010 and 2020 in the National Cancer Database were identified. Patients were categorized by operative approach as minimally invasive surgery (MIS) versus open. Institutions were categorized as "high utilizers" of MIS technique if their proportion of MIS lobectomies was >50%. Multivariate logistic regressions were used to determine factors associated with proportion of procedures performed minimally invasively. Further multivariate models were used to evaluate the association of proportion of MIS procedures with 90-d mortality, hospital length of stay, and hospital readmission., Results: In multivariate analysis, passage of time by year (odds ratio [OR] 1.26; confidence interval [CI] 1.22-1.30) and presence of a robot at the facility (OR 3.48; CI 2.84-4.24) were associated with high MIS-utilizing facilities. High utilizers of MIS were associated with lower 90-d mortality (OR 0.89; CI 0.83-0.97) and hospital length of stay (coeff -0.88; CI -1.03 to -0.72). Hospital readmission was similar between high and low MIS-utilizing facilities (compared to low MIS-utilizing facilities: OR 1.06; CI 0.95-1.09)., Conclusions: Passage of time and the presence of surgical robots were independently associated with increased utilization of MIS lobectomy. In addition to being associated with improved patient-level outcomes, robotic surgery is correlated with a higher proportion of procedures being performed minimally invasively., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: This exploratory integrated analysis of the randomized Phase III IMpower130 and IMpower132 trials evaluated the efficacy and safety of atezolizumab plus platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC) who were aged ≥75 years or had renal dysfunction., Materials and Methods: Chemotherapy-naïve patients with stage IV non-squamous NSCLC received atezolizumab-containing therapy or platinum-doublet chemotherapy in IMpower130 and IMpower132. This integrated analysis assessed efficacy (including overall survival [OS], progression-free survival [PFS], and objective response rates) and safety in the integrated population and in patients ≥75 years old. Subgroup analyses by baseline creatinine clearance (<45, 45 to <60, and ≥60 mL/min) were conducted for each study population., Results: This integrated analysis included 1224 patients: 737 in the atezolizumab-containing group and 487 in the chemotherapy group. At data cutoff, the hazard ratio (HR) for PFS was 0.62 (95% CI: 0.54-0.71) in the integrated population and 0.59 (95% CI: 0.40-0.88) in the ≥75-years subgroup. The HR for OS was 0.81 (95% CI: 0.68-0.95) in the integrated population and 0.65 (95% CI: 0.39-1.07) in the ≥75-years subgroup. PFS and OS benefits with the atezolizumab combination vs chemotherapy were maintained across subgroups with varying renal function in IMpower130, and PFS benefits were maintained across subgroups in IMpower132., Conclusions: The results of this post hoc integrated analysis of IMpower130 and IMpower132 show that the efficacy and safety of atezolizumab plus platinum-doublet chemotherapy is maintained in patients ≥75 years old and in patients with renal dysfunction., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Makoto Nishio declares honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo, Eli Lilly, Janssen, Merck, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda. Satoshi Watanabe declares grants from Boehringer Ingelheim and Nippon Kayaku and lecture fees from AstraZeneca, Bristol Myers Squibb, Celltrion, Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, Merck, Novartis, Nippon Kayaku, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical. Hibiki Udagawa declares grants from Boehringer Ingelheim and Takeda. Naoko Aragane declares grants from Boehringer Ingelheim, Chugai Pharmaceutical Co, Ltd, Eli Lilly, Ono Pharmaceutical, and Taiho Pharmaceutical; and honoraria from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical Co, Ltd, Guardant Health, Ono Pharmaceutical, and Taiho Pharmaceutical. Yuki Nakagawa and Yuki Kobayashi declare employment by and stock ownership in Chugai Pharmaceutical Co, Ltd. Haruhiro Saito declares grants from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical Co, Ltd, and Ono Pharmaceutical; and honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co, Ltd, Ono Pharmaceutical, and Pfizer. All authors declare support from Chugai Pharmaceutical Co, Ltd for third-party editorial assistance from professional medical writers., (Copyright © 2024. Published by Elsevier B.V.)

Background: The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population., Methods: In this systematic review and meta-analysis, we used single-arm, pairwise, and network meta-analytical approaches. We searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and relevant international conference proceedings from database inception to Jan 31, 2024, without language restrictions, to identify eligible clinical trials that assessed ICI-based treatments for individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs. Studies considered eligible were published and unpublished phase 1, 2, or 3 clinical trials enrolling participants with histologically or cytologically confirmed advanced EGFR-mutated NSCLC who had progressed after at least one EGFR-TKI treatment, and that evaluated ICI-based treatment strategies on at least one of the clinical outcomes of interest. The primary outcome analysed was progression-free survival. The protocol is registered with PROSPERO, CRD42021292626., Findings: 17 single-arm trials and 15 randomised controlled trials, involving 2886 participants and seven ICI-based treatment strategies (ICI monotherapy, ICI plus chemotherapy [ICI-chemo], ICI plus antiangiogenesis [ICI-antiangio], ICI plus antiangiogenesis plus chemotherapy [ICI-antiangio-chemo], dual ICIs [ICI-ICI], dual ICIs plus chemotherapy [ICI-ICI-chemo], and ICI plus EGFR-TKI [ICI-TKI]), were included. Three of these strategies-ICI monotherapy, ICI-antiangio-chemo, and ICI-chemo-had sufficient data across the included studies to perform a pairwise meta-analysis. The pairwise meta-analysis showed that, compared with chemotherapy, ICI monotherapy led to shorter progression-free survival (hazard ratio [HR] 1·73 [95% CI 1·30-2·29], I 2 =0%), whereas ICI-antiangio-chemo (HR 0·54 [0·44-0·67], I 2 =0%) and ICI-chemo (HR 0·77 [0·67-0·88], I 2 =0%) prolonged progression-free survival. The network meta-analysis showed that ICI-antiangio-chemo yielded the best progression-free survival results, with substantial benefits over ICI-chemo (HR 0·71 [95% credible interval 0·59-0·85]), ICI monotherapy (HR 0·30 [0·22-0·41]), and non-ICI treatment strategies including antiangio-chemo (HR 0·76 [0·58-1·00]) and chemotherapy alone (HR 0·54 [0·45-0·64]). ICI-antiangio-chemo was associated with higher risks of both any-grade and grade 3 or worse adverse events over ICI-chemo and chemotherapy in the network meta-analysis., Interpretation: For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non-small cell lung cancer. However, population-based studies evaluating this impact on survival by race and socioeconomic factors are lacking., Methods: We used the Surveillance, Epidemiology, and End Results Program-Medicare database to identify patients with metastatic non-small cell lung cancer diagnosed between 2015 and 2019. The primary study outcomes were the receipt of an immune checkpoint inhibitor and overall survival. χ2 tests and logistic regression were used to identify demographic factors associated with receipt of immune checkpoint inhibitors. The Kaplan-Meier method was used to calculate 2-year overall survival rates, and log-rank tests were used to compare survival by race and ethnicity., Results: Of 17 134 patients, approximately 39% received an immune checkpoint inhibitor. Those diagnosed with cancer recently (in 2019); who are relatively younger (aged younger than 85 years); non-Hispanic White, non-Hispanic Asian, or Hispanic; living in high socioeconomic status or metropolitan areas; not Medicaid eligible; and with adenocarcinoma histology were more likely to receive immune checkpoint inhibitors. The 2-year overall survival rate from diagnosis was 21% for the overall population. The 2-year overall survival rate from immune checkpoint inhibitor initiation was 30%, among those who received at least 1 cycle and 11% among those who did not receive immune checkpoint inhibitors. The 2-year overall survival rates were higher among non-Hispanic White (22%) and non-Hispanic Asian (23%) patients compared with non-Hispanic Black (15%) and Hispanic (17%) patients. There was no statistically significant racial differences in survival for those who received immune checkpoint inhibitors., Conclusion: Immune checkpoint inhibitor utilization rates and the resulting outcomes were inferior for certain vulnerable groups, mandating the need for strategies to improve access to care., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Previous studies investigating whether metastatic lymph node count is a relevant prognostic factor in pathological N1 non-small cell lung cancer (NSCLC), showed conflicting results. Hypothesizing that outcome may also be related to histological features, we determined the prognostic impact of single versus multiple metastatic lymph nodes in different histological subtypes for patients with stage II-N1 NSCLC., Methods: We performed a retrospective cohort study using data from the Netherlands Cancer Registry, including patients treated with a surgical resection for stage II-N1 NSCLC (TNM 7th edition) in 2010-2016. Overall survival (OS) was assessed for patients with single (pN1a) and multiple (pN1b) metastatic nodes. Using multivariable analysis, we compared OS between pN1a and pN1b in different histological subtypes., Results: After complete resection of histologically proven stage II-N1 NSCLC, 1309 patients were analyzed, comprising 871 patients with pN1a and 438 with pN1b. The median number of pathologically examined nodes (N1 + N2) was 9 (interquartile range 6-13). Five-year OS was 53% for pN1a versus 51% for pN1b. In multivariable analysis, OS was significantly different between pN1a and pN1b (HR 1.19, 95% CI 1.01-1.40). When stratifying for histology, the prognostic impact of pN1a/b was only observed in adenocarcinoma patients (HR 1.44, 95% CI 1.15-1.81)., Conclusion: Among patients with stage II-N1 adenocarcinoma, the presence of multiple metastatic nodes had a significant impact on survival, which was not observed for other histological subtypes. If further refinement as to lymph node count will be considered for incorporation into a new staging system, evaluation of the role of histology is recommended.

Lung cancer is a widely recognized cancer with a very low survival rate, as it is mostly diagnosed at advanced stages. The most prevalent type of lung cancer is non-small cell lung cancer (NSCLC). LncRNAs are widely involved in cancer progression and migration. Therefore, we intended to estimate the circulatory expression levels of LINC01559 and LINC01410 in NSCLC and their roles in tumor prognosis evaluation as less invasive potential markers. The relative expression levels of the plasma cell-free lncRNAs LINC01559 and LINC01410 in seventy patients with NSCLC and seventy healthy subjects as controls were measured by real-time PCR. Enzyme-linked immunosorbent assays were utilized to measure carcinoembryonic antigen (CEA) concentrations. The LINC01559 and LINC01410 expression levels were significantly increased in NSCLC patients versus controls. Both lncRNAs showed good performance in the ROC curve analysis with high sensitivity and specificity for distinguishing patients from controls. LINC01559 had the highest AUC in the ROC curve analysis (0.96, 95 CI% CI: 0.93-0.99) for distinguishing patients from controls, while LINC01410 had the highest AUC (0.77, 95 CI% CI: 0.65-0.89) for differentiating metastatic tumors from nonmetastatic tumors. High expression levels of LINC01410 and LINC01559 were associated with low overall survival (log rank = 47.04 and 28.18, respectively, P < 0.001) and low progression-free survival (log rank = 40.68 and 28.77, respectively (P < 0.001)) and with the presence of metastasis. We suggest that LINC01559 and LINC01410 can be used as valuable, high-performing biomarkers in NSCLC diagnosis and prognosis prediction., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)