Background: The aim of this network meta‐analysis (NMA) was to evaluate the efficacy and safety of PD‐1/PD‐L1 inhibitors, alone or in combination with chemotherapy, as first‐line treatment for wild‐type advanced non‐small cell lung cancer.Methods: We systematically searched databases, Clinical Trial.gov and included randomized clinical trials focusing on advanced NSCLC using PD‐1/PD‐L1 inhibitors as first‐line treatment. Hazard ratio for overall survival and progression‐free survival, odds ratio for any‐cause high‐adverse events (grade 3 or higher) were documented according to Bayesian NMA. Subgroup analysis was performed according to PD‐L1 level and histology.Results: Thirteen trials including 9154 patients were included. In the PD‐L1 nonselective cohort, chemotherapy in combination with pembrolizumab and atezolizumab, respectively, were significantly better than any other treatment strategies in both OS benefit (HR = 0.63; HR = 0.85) and PFS benefit (HR = 0.52; HR = 0.63). In subgroup analysis, pembrolizumab appeared to provide the best OS benefit (HR = 0.67) as well as the best PFS benefit (HR = 0.67) in the PD‐L1 ≥ 50% cohort. In contrast, pembrolizumab combined with chemotherapy exhibited the best OS benefit in the PD‐L1 < 50% cohort. Furthermore, OS benefit from pembrolizumab plus chemotherapy was more obvious in nonsquamous patients (HR = 0.56). Additionally, pembrolizumab plus chemotherapy was associated with fewer adverse events than other chemotherapy combination strategies.Conclusions: In the first‐line treatment, chemotherapy plus pembrolizumab or atezolizumab could enhance efficacy compared with chemotherapy alone or other PD‐1/L1‐based treatment strategies, especially in the nonsquamous population. Furthermore, pembrolizumab plus chemotherapy guarantees reliable security simultaneously, which may be the optimal treatment strategy for patients with major advanced NSCLC.

Immunotherapy brought long-term benefits for partial patients with lung squamous cell carcinoma (LUSC). The predictor of anti-PD-L1 therapy was controversial and limited in LUSC. We aimed to explore novel biomarker for LUSC immunotherapy and the potential mechanism. Five hundred and twenty-five Chinese patients (Geneplus cohort) with LUSC underwent targeted sequencing and were involved to explore the genomic profiling. TP53 and LRP1B were the most frequently recurrent genes and correlated to higher tumor mutational burden (TMB). We observed that LUSC patients with TP53 and LRP1B co-wild (co-wild type) were associated with better survival of anti-PD-L1 therapy compared with TP53 mutant or LRP1B mutant (mutant type) in POPAR/OAK cohort. Copy-number variation (CNV) and whole genome doubling (WGD) data from TCGA LUSC cohort were obtained to assess the CNV events. There were fewer CNV alterations and lower chromosome instability in patients with TP53/LRP1B co-wild compared with those with TP53/LRP1B mutant. RNA expression data from the TCGA LUSC cohort were collected to explore the differences in RNA expression and tumor immune microenvironment (TIME) between mutant and co-wild groups. The TP53/LRP1B co-wild type had a significantly increased proportion of multiple tumor-infiltrating lymphocytes (TILs), including activated CD8 T cell, activated dendritic cell (DC), and effector memory CD8 T cell. Immune-related gene sets including checkpoint, chemokine, immunostimulatory, MHC and receptors were enriched in the co-wild type. In conclusion, TP53/LRP1B co-wild LUSC conferred an elevated response rate in anti-PD-L1 therapy and improved survival, which was associated with a chromosome-stable phenotype and an activated immune microenvironment.

Context: Cardiac troponins have become the gold standard for diagnosing acute myocardial infarction (AMI) in the general population; however, their diagnostic accuracy for hemodialysis (HD) patients presenting with chest pain or dyspnea is uncertain. Objective: To examine the diagnostic accuracy of high-sensitivity cardiac troponin T (hs-cTnT) assay for AMI in HD patients. Design: In this prospective study, we enrolled 670 consecutive stable HD patients presenting with chest pain or dyspnea on routine predialysis therapy in the nephrology department. Receiver operating characteristic (ROC) curves were used to examine the diagnostic accuracy of hs-cTnT levels at enrollment in HD patients presenting with chest pain or dyspnea, and the dynamic change in these levels after 3 hours. Results: Acute myocardial infarction was the adjudicated final diagnosis in 12% of HD patients. Among patients with a final diagnosis other than AMI, 97% had a plasma hs-cTnT concentration above the 99th percentile. At the time of enrollment, the area under the ROC curve of hs-cTnT levels for diagnosis of AMI was 0.68 (95% confidence interval [CI], 0.62–0.74; P < .001) with a cutoff value of 107.7 ng/L; the relative change after 3 hours was 0.90 (95% CI, 0.82–0.96, P < .001) with a cutoff value of 24%, and the absolute change was 0.88 (95% CI, 0.82–0.94, P < .001) with a cutoff value of 32.6 ng/L. The prognostic value for 40-day mortality varied with the magnitude of elevation in hs-cTnT levels. Conclusions: Tracking the dynamic change in hs-cTnT levels during the short term significantly increased this measure's diagnostic accuracy for AMI in HD patients.

Background: The biomarkers of immune checkpoint inhibitors in the treatment of non‐small cell lung cancer (NSCLC) patients have limited predictive performance. In this study we aimed to investigate the feasibility of molecular tumor burden index (mTBI) in circulating tumor DNA (ctDNA) as a predictor for immunotherapy in patients with NSCLC.Methods: From February 2017 to November 2020, pretreatment and on‐treatment (3~6 weeks after first cycle of immunotherapy) dynamic plasma ctDNA samples from NSCLC patients receiving immune monotherapy or combination therapy were analyzed by targeted capture sequencing of 1021 genes. PyClone was used to infer the mTBI. The impact of pretreatment mTBI on survival outcomes was verified in the POPLAR/OAK trials.Results: We found that patients without detectable baseline ctDNA had better survival outcomes (median overall survival [OS]: not reached vs. 12.8 months; hazard ratio [HR], 0.15; p = 0.035]). RB1 and SMARCA4 mutations were remarkably associated with worse survival outcomes. Furthermore, lower pretreatment mTBI was associated with superior OS (median: not reached vs. 8.1 months; HR, 0.22; p = 0.024) and PFS (median: 32.9 vs. 5.4 months; HR, 0.35; p = 0.045), but not objective response, which was validated in the POPLAR/OAK cohort, suggesting that baseline mTBI was a prognostic factor for NSCLC immunotherapy. Early dynamic changes of mTBI (ΔmTBI) significantly distinguished responsive patients, and patients with mTBI decrease to more than 68% at the final tumor evaluation had longer OS (median: 38.2 vs. 4.0 months; HR, 0.18; p = 0.017) and PFS (median: not reached vs. 2.3 months; HR, 0.24; p = 0.030).Conclusion: ΔmTBI had a good sensitivity to identify potential beneficial patients based on the best effect CT scans, demonstrating that mTBI dynamics were predictive of benefit from immune checkpoint blockade.

Background: Sarcopenia has recently emerged as a new condition with increasing importance in lung cancer patients. The aim of this study was to investigate the influence of sarcopenia on tolerance and efficacy of afatinib.Methods: We retrospectively evaluated 35 patients with epidermal growth factor receptor (EGFR) mutant advanced non‐small cell lung cancer (NSCLC) treated with first‐line afatinib. Skeletal muscle area (SMA) was measured at the third lumbar vertebra using routine conducted computed tomography (CT) images for evaluation of disease burden. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height²) ≤38.5 cm²/m² for women and ≤52.4 cm²/m² for men based on previous criteria. Fisher's exact tests, Kaplan–Meier method, and logistic regression modeling were used.Results: The median age at diagnosis was 65 years (range,39–84 years). A total of 24 (68.6%) patients were diagnosed with sarcopenia. The most frequent adverse events (AEs) related to afatinib were diarrhea (94.3%) followed by rash (77.1%) and paronychia (60%). Overall, 19 (54.3%) patients had dose reduction. Sarcopenic patients had a significantly higher rate of grade ≥ 2 diarrhea (75.0 vs. 27.3%, p = 0.011) and toxicity‐related dose reduction (75.0 vs. 9.1%, p = 0.001). Multivariate analysis also showed that sarcopenia (odds ratio [OR] 51.7, 95% confidence interval [CI]: 2.4–1081.3, p = 0.01) was an independent risk factor for dose reduction of afatinib. The median progression‐free survival (PFS) for afatinib was 12.0 months (95% CI: 10.6–13.4). Both dose reduction and sarcopenia did not affect therapeutic efficacy.Conclusions: Toxicity‐related dose reduction is common with initiation of afatinib 40 mg/day. Sarcopenic patients might begin treatment with a low dose of afatinib according to tolerance.