Project description:Esophageal cancer is the seventh most common cancer, with an estimated 572,000 new cases, and the sixth most common cause of cancer-related deaths in 2018 with 509,000 annual worldwide deaths. Advanced esophageal squamous cell carcinoma (ESCC) is one of devastating tumors with a 5-year survival rate of less than 5% in patients with metastatic disease. Treatment options for patients with advanced ESCC are limited. Current guidelines recommend chemotherapy containing a platinum and a fluoropyrimidine agent as a first-line treatment. Recently, immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have demonstrated antitumor activity and clinical efficacy in patients with advanced ESCC that is refractory or intolerant to first-line chemotherapy. ICIs are game-changers that not only transformed oncological strategy but also have a wide range of clinical potential in combination with conventional cytotoxic chemotherapy and radiotherapy. There is still an urgent, unmet need for reliable treatment options to conquer this intractable disease.
Project description:BackgroundPrimary adenosquamous carcinoma (ASC) of the lung is a rare and aggressive disease and limited information is available on the efficacy of immune checkpoint inhibitors (ICIs) for this disease. Here, we evaluated the expression status of programmed death-1 ligand 1 (PD-L1) and efficacy of ICIs in patients with pulmonary ASC.MethodsThe efficacy and toxicity of ICIs were examined in 38 patients with previously treated lung ASC from November 2017 to October 2021 in Zhejiang Cancer Hospital (Hangzhou, China). Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model applied for univariate and multivariate analyses.ResultsA total of 38 patients with ASC were included in this retrospective study. ICI treatment induced an objective response rate (ORR) of 23.7% and a disease control rate (DCR) of 86.8%. The median progression-free survival (PFS) and median overall survival (OS) were 5.47 and 24.10 months, respectively. Seventeen patients were successfully evaluated for PD-L1 expression status, with 11 (64.7%) identified as PD-L1-positive. ORR and DCR for PD-L1-positive patients were 36.4% (4/11) and 100% (11/11) and the corresponding values for PD-L1-negative patients were 0 (0/6) and 50% (3/6), respectively. The median PFS of PD-L1-positive and PD-L1-negative patient groups was 5.00 and 1.90 months (P=0.166) while the median OS was 11.30 months and not reached, respectively (P=0.966). The incidence rate of immune-related adverse events (irAEs) was 52.6%, with 13.2% grade 3-4 irAEs. The most common irAEs were malaise and pneumonitis. One patient died of pneumonitis during the study.ConclusionsICIs show considerable potential as a treatment option for lung ASC. PFS and OS rates are similar for PD-L1-positive and PD-L1-negative patients. Further large-scale studies are required to establish the relationship between PD-L1 expression and response to ICIs in ASC.
Project description:BackgroundThe advent of immune checkpoint inhibitors (ICIs) therapy has resulted in significant survival benefits in patients with non-small-cell lung cancer (NSCLC) without increasing toxicity. However, the utilisation of immunotherapy for small-cell lung cancer (SCLC) remains unclear, with a scarcity of systematic comparisons of therapeutic effects and safety of immunotherapy in these two major lung cancer subtypes. Herein, we aimed to provide a comprehensive landscape of immunotherapy and systematically review its specific efficacy and safety in advanced lung cancer, accounting for histological types.MethodsWe identified studies assessing immunotherapy for lung cancer with predefined endpoints, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAE), from PubMed, Embase, Medline, and Cochrane library. A random-effects or fixed-effect model was adopted according to different settings.ResultsOverall, 38 trials with 20,173 patients with lung cancer were included in this study. ICI therapy resulted in a significantly prolonged survival in both patients with NSCLC and SCLC when compared with chemotherapy (hazard ratio [HR] = 0.74; 95% confidence interval [CI], 0.70-0.79] and [HR = 0.82; 95% CI, 0.75-0.90], respectively). The magnitude of disease control and survival benefits appeared superior with ICI plus standard of care (SOC) when compared with SOC alone. OS and PFS advantages were observed only when immunotherapy was employed as the first-line treatment in patients with SCLC.ConclusionICI therapy is a promising therapeutic option in patients with NSCLC and SCLC. ICI plus SOC can be recommended as the optimal first-line treatment for patients with SCLC, and double-target ICIs combined with SOC are recommended in patients with NSCLC as both the first and subsequent lines of treatment. Additionally, non-first-line immunotherapy is not recommended in patients with SCLC.
Project description:Immune checkpoint inhibitors (ICI) have been applied to treat advanced stage hepatocellular carcinoma (HCC) and obtain promising effects. However, tumor response to treatment was unpredictable. A predicting biomarker of objective response or disease-control is an unmet need for patient selection. In this study, 45 advanced HCC patients who failed to sorafenib treatment and received nivolumab, 3 mg/kg bi-weekly, were included. Tumor responses to nivolumab treatment were assessed by the modified response evaluation criteria in solid tumors (mRECIST) criteria. Tumor responses were correlated to clinical characteristics to find out response predictors. In this small series, the prevalence of extrahepatic nodal metastasis, distant metastasis, and portal vein thrombus among the patients were 22.2% (n = 10), 48.9% (n = 22), and 42.2% (n = 19), respectively. The pre-treatment tumor size was 7.2 ± 4.2 cm in maximal diameter, and the calculated total tumor volume was 619.0 ± 831.1 cm3. Among 45 patients, 3 patients had partial response (PR), 11 had stable disease (SD), and the other 31 had progression of disease. By correlating clinical data to the patients with PR and SD, serum neutrophil-to-lymphocyte ratio (NLR) (hazard ratio (HR) = 2.04) and patient-generated subjective global assessment (PG-SGA) score (HR = 2.30) were the independent factors in multivariate analysis. By receiver operating characteristic curve analysis, pre-treatment NLR ≤ 2.5 and PG-SGA score < 4 were the cutoff points to predict tumor response to ICI treatment. In conclusion, biomarkers to predict tumor response for HCC are still lacking in this costly ICI therapy. In this study, NLR ≤ 2.5 and PG-SGA score < 4 indicated disease-control, and can be applied as biomarkers to select the right patients to receive this costly therapy.
Project description:Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.
Project description:Over the last decade, the treatment of advanced non-small cell lung cancer (NSCLC) has undergone rapid changes with innovations in oncogene-directed therapy and immune checkpoint inhibitors. In patients with epidermal growth factor receptor (EGFR) gene mutant (EGFRm) NSCLC, newer-generation tyrosine kinase inhibitors (TKIs) are providing unparalleled survival benefit and tolerability. Unfortunately, most patients will experience disease progression and thus an urgent need exists for improved subsequent lines of therapies. The concurrent revolution in immune checkpoint inhibitor (ICI) therapy is providing novel treatment options with improved clinical outcomes in wild-type EGFR (EGFRwt) NSCLC; however, the application of ICI therapy to advanced EGFRm NSCLC patients is controversial. Early studies demonstrated the inferiority of ICI monotherapy to EGFR TKI therapy in the first line setting and inferiority to chemotherapy in the second line setting. Additionally, combination ICI and EGFR TKI therapies have demonstrated increased toxicities, and EGFR TKI therapy given after first-line ICI therapy has been correlated with severe adverse events. Nonetheless, combination therapies including dual-ICI blockade and ICI, chemotherapy, and angiogenesis inhibitor combinations are areas of active study with some intriguing signals in preliminary studies. Here, we review previous and ongoing clinical studies of ICI therapy in advanced EGFRm NSCLC. We discuss advances in understanding the differences in the tumor biology and tumor microenvironment (TME) of EGFRm NSCLC tumors that may lead to novel approaches to enhance ICI efficacy. It is our goal to equip the reader with a knowledge of current therapies, past and current clinical trials, and active avenues of research that provide the promise of novel approaches and improved outcomes for patients with advanced EGFRm NSCLC.
Project description:The liver maintains a balance between immune tolerance and activation in its role as a filtration system. Chronic inflammation disrupts this immune microenvironment, thereby allowing for the rise and progression of cancer. Hepatocellular carcinoma (HCC) is a liver tumor generally diagnosed in the setting of chronic liver disease. When diagnosed early, the primary treatment is surgical resection, liver transplantation, or liver directed therapies. Unfortunately, patients with HCC often present at an advanced stage or with poor liver function, thereby limiting options. To further complicate matters, most systemic therapies are relatively limited and ineffective among patients with advanced disease. Recently, the IMbrave150 trial demonstrated that the combination of atezolizumab and bevacizumab was associated with better survival compared to sorafenib among patients with advanced HCC. As such, atezolizumab and bevacizumab is now recommended first-line therapy for these patients. Tumor cells work to create an immunotolerant environment by preventing the activation of stimulatory immunoreceptors and upregulating expression of proteins that bind inhibitory immunoreceptors. ICIs work to block these interactions and bolster the anti-tumor function of the immune system. We herein provide an overview of the use of ICIs in the treatment of HCC.