Comparing the cost-effectiveness of sintilimab + pemetrexed plus platinum and pemetrexed plus platinum alone as a first-line therapy for Chinese patients with nonsquamous non-small cell lung cancer.

Background: Pemetrexed plus platinum alone is the conventional first-line therapy for locally advanced metastatic nonsquamous non-small cell lung cancer (NSCLC) without targetable genetic aberrations. The ORIENT-11 trial revealed that sintilimab + pemetrexed plus platinum could yield more survival benefits for patients with nonsquamous NSCLC. The present study aimed to assess the cost-effectiveness of sintilimab + pemetrexed plus platinum vs. that of pemetrexed plus platinum alone as the first-line therapy for patients with nonsquamous NSCLC to inform clinically rational drug use and provide a basis for medical decision-making. Methods: A partitioned survival model was created to evaluate the cost-effectiveness of two groups from the perspective of the healthcare system in China. The clinical data for adverse event probabilities and extrapolating long-term survival originally collected in a phase III clinical trial (ORIENT-11) were retrieved. Local public databases and literature were used to acquire data on utility and cost. The heemod package in R software was used to calculate the life years (LYs), quality-adjusted LYs (QALYs), and total costs in each group to generate the incremental cost-effectiveness ratio (ICER) in the base case and to conduct deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA). Results: Our base case analysis (BCA) revealed that sintilimab combined with pemetrexed plus platinum provided an increase of 0.86 in QALYs with an increasing cost of United State dollar (USD) $4,317.84 relative to pemetrexed plus platinum in Chinese patients with nonsquamous NSCLC who were negative for targetable genetic variations, which induced an ICER of USD $5,020.74/QALY. The ICER value was lower than the set threshold value. The results exhibited strong robustness in the sensitivity analysis. In DSA, the parameter for the overall survival (OS) curve in chemotherapy and the cost of best supportive care were the main factors that impacted the result of the ICER. The PSA indicated that sintilimab and chemotherapy combination therapy was cost-effective. Conclusions: This study suggests that the combination of sintilimab + pemetrexed plus platinum is cost-effective as a first-line therapy in Chinese patients with nonsquamous NSCLC who are negative for targetable genetic variations from the perspective of the healthcare system.

Metabolomics Combined with Network Pharmacology-Based Strategy to Reveal the Underlying Mechanism of Zhenhuang Submicron Emulsion in Treating Oropharyngeal Mucositis Complications of Radiation Therapy for Head and Neck Cancer.

Introduction: Head and neck tumors account for more than 6% of all cancers. The primary treatment for tumors of the head and neck is radiation therapy, which can induce oropharyngeal mucositis as a side effect. At present, there is no widely available therapeutic for the treatment of oropharyngeal mucositis in clinical practice. Based on the traditional prescription Liushen Wan, the pathogenesis and pathology, we developed a new Chinese medicine prescription and made Zhenhuang submicron emulsion (ZHSE) spray, which has an efficacious therapeutic effect for oropharyngeal mucositis. However, its mechanism is unclear. Methods: This research explored the mechanism behind the modulatory effects of ZHSE by a strategy of metabolomics and network pharmacology. Multivariate data analyses, including unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA), were performed. Potential biomarkers were identified depending on the mass-charge ratio of the selected compound. Statistical and pathway enrichment analysis was performed in the KEGG pathway database. Network pharmacology combining metabolomic analyses was conducted to illustrate the key targets and pathways. Results: Critical metabolic pathways were investigated, 56f biomarkers were enriched and key metabolites such as linoleic acid, 9,10-epoxyoctadecenoic acid, acetoacetic acid and citric acid were identified. A complex network of "compound-target-potential metabolite" interactions was drawn to illuminate the regulation of chemical constituents on key metabolites. These findings manifest that ZHSE regulates endogenous metabolite disorders during the treatment of oropharyngeal mucositis by various constituents, interacting with multiple targets associated with inflammation and pain. Conclusion: In this work, we determined several critical biomarkers and metabolic pathways and identified the possible regulatory mechanism by which ZHSE functions in the treatment of oropharyngeal mucositis. This study provides a new perspective on integrating metabolomics and network pharmacology for exploring improved therapy for head and neck tumors based on the traditional classic prescription of LSW.

Cost-effectiveness of pembrolizumab versus docetaxel as second-line treatment of non-small cell lung cancer in China.

BACKGROUND: Pharmacoeconomic information for pembrolizumab as a second-line lung cancer treatment is insufficient in China, so we aimed to assess its cost-effectiveness versus docetaxel as a second-line treatment for patients with non-small cell lung cancer (NSCLC) in China. METHODS: A partitioned survival model was developed to assess the cost-effectiveness of pembrolizumab versus docetaxel in the treatment of NSCLC patients. A phase III clinical trial (KEYNOTE-010) was used as the clinical data. Long-term survival data were extrapolated based on the clinical study data. Lifetime cost and utility were calculated with a discount set at 3%. One-way deterministic sensitivity analyses and probabilistic sensitivity analysis were used to test the robustness of incremental cost-effectiveness ratios (ICER). RESULTS: In the base-case scenario, the ICERs were $107,846/quality-adjusted life year (QALY) and $448,414/QALY for pembrolizumab (2 and 10 mg/kg) groups, respectively. Both ICER values were 3-fold higher than the threshold of China's per-capita GDP in 2019 ($30,055.01). One-way deterministic sensitivity analyses showed that the price of pembrolizumab is the main factor affecting the result of ICER. Median ICERs were $108,658/QALY ($107,005/QALY-$110,089/QALY) for the pembrolizumab 2 mg/kg group and $451,590/QALY ($443,685/QALY-$457,496/QALY) for the pembrolizumab 10 mg/kg group using the current price in China. For patients receiving regimens with 2 mg/kg pembrolizumab, the probabilities will be exceeding 95% when the price of pembrolizumab decreases by 25% in a high-income region (willing to pay setting as $71,406/QALY). CONCLUSIONS: The results suggest that for it to become a second-line treatment of NSCLC in China, a reduction in the cost of pembrolizumab is needed.

Efficacy and safety of first-line treatments with immune checkpoint inhibitors plus chemotherapy for non-squamous non-small cell lung cancer: a meta-analysis and indirect comparison.

BACKGROUND: Recently, several clinical studies have evaluated the first-line use of immune checkpoint inhibitors (ICIs) combined with platinum-doublet chemotherapy in patients with non-squamous non-small cell lung cancer (NSCLC), however, the differences in safety and efficacy between the various types of ICIs still require investigation. In this study, we evaluated the efficacy and safety of the first-line use of ICIs combined with platinum-doublet chemotherapy in patients with non-squamous NSCLC by meta-analysis and indirect comparison. METHODS: Literature searches were performed using PubMed, the Cochrane Library, Embase, China Knowledge Resource Integrated Database, and Wanfang Data to identify all relevant randomized clinical trials for non-squamous NSCLC after 2010. Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) were pooled for meta-analysis and indirect comparison. Subgroup analyses were conducted to examine the factors associated with PFS. RESULTS: The meta-analysis showed that the additional use of ICIs could significantly improve PFS and OS. The indirect comparison showed no significant difference in pembrolizumab + chemotherapy and atezolizumab + chemotherapy in the reducing of disease progression, while a significant difference in restricted mean survival time (RMST) was found between pembrolizumab + chemotherapy compared with atezolizumab + chemotherapy. A significant increase in grade ≥3 AEs was observed with the additional use of atezolizumab combined with chemotherapy. Subgroups including PD-1 status [high (>50%), intermediate (1-49%), and negative (<1%) expression], sex (male and female), smoking status (current or former smoker, and never smoked), liver metastases (with and without), age (>65 and ≤65) and Eastern Cooperative Oncology Group (ECOG) score (ECOG=0 and ECOG=1) were all associated with better PFS. CONCLUSIONS: This meta-analysis confirmed the treatment effects of ICIs combined with chemotherapy for non-squamous NSCLC. The pembrolizumab combination group had a greater RMST benefit compared with the atezolizumab combination group. Furthermore, our study also demonstrated a PFS advantage for non-squamous NSCLC using ICIs combined with chemotherapy irrespective of programmed death-ligand 1 (PD-L1) expression level, smoking status, liver metastasis status, sex, age and ECOG score. Due to the significant increase in AEs (> grade 3), more attention should be paid to the additional use of atezolizumab.

A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier.

Of late, lorlatinib has played an increasingly pivotal role in the treatment of brain metastasis from non-small cell lung cancer. However, its pharmacokinetics in the brain and the mechanism of entry are still controversial. The purpose of this study was to explore the mechanisms of brain penetration by lorlatinib and identify potential biomarkers for the prediction of lorlatinib concentration in the brain. Detection of lorlatinib in lorlatinib-administered mice and control mice was performed using liquid chromatography and mass spectrometry. Metabolomics and transcriptomics were combined to investigate the pathway and relationships between metabolites and genes. Multilayer perceptron was applied to construct an artificial neural network model for prediction of the distribution of lorlatinib in the brain. Nine biomarkers related to lorlatinib concentration in the brain were identified. A metabolite-reaction-enzyme-gene interaction network was built to reveal the mechanism of lorlatinib. A multilayer perceptron model based on the identified biomarkers provides a prediction accuracy rate of greater than 85%. The identified biomarkers and the neural network constructed with these metabolites will be valuable for predicting the concentration of drugs in the brain. The model provides a lorlatinib to treat tumor brain metastases in the clinic.