The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non–small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection.

BackgroundPD-1/PD-L1 inhibitors have significantly improved the outcomes of those patients with various malignancies. However, the incidence of adverse events also increased. This meta-analysis aims to systematically evaluate the risk of cardiovascular toxicity in patients treated with PD-1/PD-L1 inhibitors.Materials and methodsWe searched PubMed, Embase, the Cochrane Library databases for all randomized controlled trials (RCTs) comparing all-grade and grade 3-5 cardiovascular toxicity of single-agent PD-1/PD-L1 inhibitors to placebo/chemotherapy, PD-1/PD-L1 inhibitors combined with chemotherapy to chemotherapy, or PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors to single-agent immune checkpoint inhibitors (ICIs) and pooled our data in a meta-analysis stratified by tumor types and PD-1 or PD-L1 inhibitors. The Mantel-Haenszel method calculated the odds ratio (OR) and its corresponding 95% confidence intervals (CIs).ResultsA total of 50 trials were included in the analysis. Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR=2.11, 95%CI 1.02-4.36, P=0.04). Compared with chemotherapy, patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a significant higher risk of all-grade (OR=1.53, 95%CI 1.18-1.99, P=0.001) and grade 3-5 cardiotoxicity (OR=1.63, 95%CI 1.11-2.39, P=0.01) cardiotoxicity, especially patients with non-small cell lung cancer (NSCLC) [all-grade cardiotoxicity (OR=1.97, 95%CI 1.14-3.41, P=0.02) and grade 3-5 cardiotoxicity (OR=2.15, 95%CI 1.08-4.27, P=0.03)]. Subgroup analysis showed that PD-1 inhibitors combined with chemotherapy were associated with a higher risk of grade 3-5 cardiotoxicity (OR=2.08, 95%CI 1.18-3.66, P=0.01). Compared with placebo or chemotherapy, single-agent PD-1/PD-L1 inhibitors did not increase the risk of all-grade of myocarditis, arrhythmia and hypertension. However, PD-1/PD-L1 inhibitors combined with chemotherapy increased the risk of all-grade arrhythmia (OR=1.63, 95%CI 1.07-2.46, P=0.02) [PD-L1 inhibitor-containing treatment (OR=1.75, 95%CI 1.09-2.80, P=0.02)], and the risk of all-grade hypertension (OR=1.34, 95%CI 1.02-1.77, P=0.04) and grade 3-5 hypertension (OR=1.54, 95%CI 1.10-2.15, P=0.01).ConclusionsOur results suggest that single-agent PD-1/PD-L1 inhibitors increase the risk of all-grade cardiotoxicity, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of all-grade and grade 3-5 cardiotoxicity, especially in those patients treated with PD-1 inhibitor-containing treatment and those with NSCLC. In addition, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of arrhythmia and hypertension. Therefore, this evidence should be considered when assessing the benefits and risks of PD-1/PD-L1 inhibitors in treating malignancies.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022303115.

BackgroundMolecular targeted therapy combined with immunotherapy significantly improves the prognosis of patients with advanced liver cancer. Additionally, hepatic arterial infusion chemotherapy (HAIC) can improve the prognosis of patients with advanced liver cancer. This real-world study aimed to evaluate the clinical efficacy and safety of HAIC combined with molecular targeted therapy and immunotherapy in the treatment of primary unresectable hepatocellular carcinoma (uHCC).MethodsA total of 135 patients with uHCC were enrolled in this study. Progression-free survival (PFS) was the primary endpoint. The efficacy of the combination therapy was assessed based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. Overall survival (OS), adverse events (AEs) and surgical conversion rate were the secondary endpoints. Univariate and multivariate Cox regression analyses were performed to examine independent prognostic factors. For sensitivity analysis, inverse probability weighting (IPW) was used to balance the influence of the tested confounding factors between groups to verify the robustness of conversion surgery for survival benefits. The E-values were estimated to assess robustness to unmeasured confounders.ResultsThe median number of therapies was three. Approximately 60% of the patients had portal vein tumour thrombosis (PVTT). The most common targeted drugs were lenvatinib and bevacizumab, whereas the most common immunotherapy drug was sintilimab. The overall objective response rate (ORR) was 54.1%, and the disease control rate (DCR) was 94.6%. A total of 97 (72%) patients experienced AEs of grades 3–4. Fatigue, pain and fever were the most common symptoms of grade 3-4 AEs. The median PFS was 28 months and 7 months in the successful and unsuccessful conversion groups, respectively. The median OS was 30 months and 15 months in the successful and unsuccessful conversion groups, respectively. Successful conversion surgery, sex, hapatic vein invasion, BCLC stage, baseline tumour size, AFP levels and maximum therapeutic response were independent prognostic factors for PFS. Successful conversion surgery, number of interventions, hapatic vein invasion and total bilirubin levels were independent prognostic factors for OS. After IPTW, no standardised differences exceeding 0.1 were found. IPW-adjusted Kaplan–Meier curves showed that successful conversion surgery was an independent prognostic factor for both PFS and OS. The E-values of successful conversion surgery were 7.57 and 6.53 for OS and PFS, respectively, which indicated a relatively robust impact of successful conversion surgery on the prognosis of patients.ConclusionPatients with primary uHCC undergoing HAIC combined with immunotherapy and molecular targeted therapy have a higher tumour regression rate and the side effects are manageable. Patients undergoing surgery after combination therapy have survival benefits.

Circulating tumor DNA (ctDNA) has potential as a promising biomarker for molecular residual disease (MRD) detection in lung cancer. As the next‐generation sequencing standardized panel for ctDNA detection emerges, its clinical utility needs to be validated. We prospectively recruited 184 resectable lung cancer patients from four medical centers. Serial postoperative ctDNAs were analyzed by a standardized panel. A total of 427 postoperative plasma samples from 177 eligible patients were enrolled. ctDNA positivity after surgery was an independent predictor for disease recurrence and preceded radiological recurrence by a median of 6.6 months (range, 0.7–27.0 months). ctDNA‐positive or ‐negative patients with tumors of any stage had similar disease‐free survival (DFS). Patients who received targeted therapy had significantly improved DFS than those not receiving adjuvant therapy or receiving chemotherapy, regardless of baseline/preadjuvant ctDNA status. According to whether the ctDNA variants were detected in its matched tissue, they were classified into tissue derived and non‐tissue derived. Patients with detectable postoperative ctDNA with tissue‐derived mutations had comparable DFS with those with non‐tissue‐derived mutations. Collectively, we demonstrated that postoperative ctDNA has the potential to stratify prognosis and optimize tumor stage in resectable lung cancer. ctDNA variants not identified in tissue samples should be considered in MRD test.