Meng Qiao

Combination Strategies on the Basis of Immune Checkpoint Inhibitors in Non–Small-Cell Lung Cancer: Where Do We Stand?

Abstract The era of immune checkpoint inhibitors, especially programmed death‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) antibodies in the treatment of advanced non–small‐cell lung cancer (NSCLC) is coming. Because of the lack of the definite biomarkers to select the optimal responders, only approximately 20% of patients with advanced NSCLC would respond to single checkpoint inhibitors‐based immunotherapy. Moreover, primary or acquired resistance to conventional therapies is inevitable in most cases. Thus, combinations are pushed to move forward to be an alternative strategy and surely, it would be a future direction. Combination approaches on the basis of PD‐1/PD‐L1 inhibitors are currently designed to re‐energize the immune system with complementary/synergetic mechanisms and could achieve durable antineoplastic effects in NSCLC. Herein, we highlight the potential combinations on the basis of PD‐1/PD‐L1 inhibitors in NSCLC, with other immunotherapies, chemotherapy, radiotherapy, and targeted therapy in this current review.

Characterization of distinct types of KRAS mutation and its impact on first‑line platinum‑based chemotherapy in Chinese patients with advanced non‑small cell lung cancer

We performed this retrospective study to investigate whether the KRAS mutation status and its subtypes could predict the effect of first-line platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). Patients received who had KRAS mutations were enrolled. Correlations between KRAS mutations, specific mutant subtypes and responses to chemotherapy were analyzed using Kaplan-Meier and Cox proportional hazard methods. A total of 2,183 cases who received KRAS mutation detection were included. A total of 218 of these cases were indicated to have KRAS mutations. KRAS mutations were identified more commonly in males compared with females (P=0.035). The most common subtypes were G12C, G12D and G12V. Among 73 KRAS mutant patients and 100 EGFR/ALK/KRAS wild-type patients with advanced NSCLC, KRAS-mutant NSCLC patients had a significantly shorter progression-free survival (P=0.007) compared with NSCLC patients with KRAS wild-type. In addition, there was a shorter but marginally statistically significant progression-free survival (PFS) in KRAS mutant patients with adenocarcinoma compared with those with non-adenocarcinoma (P=0.051). In the KRAS mutant group, patients with the KRAS G12V mutation had the poorest PFS compared with non-G12V mutant cases (P=0.045). In conclusion, KRAS mutation was a negative predictive factor of PFS in Chinese patients with advanced NSCLC who received first platinum-based chemotherapy. Patients with KRAS G12V mutations exhibited the poorest PFS compared with those with other KRAS mutant types.

Effect of Combined Therapy Inhibiting EGFR and VEGFR Pathways in Non–Small-cell Lung Cancer on Progression-free and Overall Survival

Background To investigate the effect of combined epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway inhibitors on progression‐free survival (PFS) and overall survival (OS) in patients with non–small‐cell lung cancer (NSCLC). Materials and Methods We included 15 randomized clinical trials that had compared the combination of EGFR tyrosine kinase inhibitors and anti‐VEGF/VEGFR therapy with different control groups. Pooled estimates of treatment efficacy were calculated, and subgroup analyses were conducted according to treatment line and EGFR status. Results Ten of 15 trials involving 3317 NSCLC patients were included. For all settings, the combined regimen demonstrated no PFS (hazard ratio [HR], 0.82; P = .10) or OS (HR, 0.97; P = .54) benefit compared with the control groups. In the first‐line setting, combined therapy showed similar PFS (HR, 1.01; P = .99) but poor OS (HR, 1.36; P = .03) compared with the control groups. In the second‐line or subsequent settings, combined therapy resulted in significantly longer PFS (HR, 0.75; P < .01) but similar OS (HR, 0.93; P = .16) compared with the control groups. A subgroup analysis stratified by EGFR status suggested that combined treatment substantially improved PFS (HR, 0.57; P = .04) and OS (HR, 0.45; P < .01) in patients with EGFR mutations rather than EGFR wild type. Conclusion EGFR‐tyrosine kinase inhibitors plus anti‐VEGF/VEGFR therapy significantly prolonged PFS in the second‐line treatment of NSCLC patients. An EGFR mutation is a promising indication for this combination treatment. More data are required to confirm this strategy in first‐line therapy. Micro‐Abstract The effect of combined epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor pathway inhibitors on progression‐free survival and overall survival in patients with non–small‐cell lung cancer remains controversial. Our analysis showed that epidermal growth factor receptor tyrosine kinase inhibitors plus anti‐VEGF/VEGF receptor therapy significantly prolonged progression‐free survival in the second‐line treatment of non–small‐cell lung cancer. Epidermal growth factor receptor mutation is a promising indication for this combination treatment.

Impact of clinicopathological features on the efficacy of PD-1/PD-L1 inhibitors in patients with previously treated non-small cell lung cancer

Micro‐Abstract The selection of the population who can benefit from programmed cell death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1)‐inhibitor monotherapy based on clinicopathologic features is economical and convenient. This study suggests that PD‐1/PD‐L1‐inhibitor monotherapy could significantly prolong both overall and progression‐free survival in patients with previously treated non–small‐cell lung cancer regardless of age, gender, smoking history, and histology. Whether patients with central nervous system metastasis could benefit from anti‐PD‐1/PD‐L1 monotherapy requires further validation. Background: The current study aimed to comprehensively investigate the impact of various clinicopathologic features on the efficacy of programmed cell death‐1 (PD‐1) and ligand (PD‐L1) inhibitors in patients with previously treated non–small‐cell lung cancer (NSCLC). Patients and Methods: Randomized controlled trials that compared PD‐1/PD‐L1‐inhibitor monotherapy with chemotherapy or placebo in patients with previously treated NSCLC were included. Results: Five trials were included (n = 3025). For all studies, PD‐1/PD‐L1 inhibitors significantly prolonged overall survival (OS) (hazard ratio [HR], 0.70; P < .001) and progression‐free survival (PFS) versus chemotherapy (HR, 0.86; P = .020). Subgroup analysis showed that anti‐PD‐1/PD‐L1 monotherapy could markedly improve OS in elderly patients (HR, 0.69; P < .001), female patients (HR, 0.70; P < .001), never‐smoking patients (HR, 0.73; P = .001), and patients with a histology of squamous cell carcinoma (HR, 0.67; P < .001), but not PFS in the elderly and female patient groups. Notably, PD‐1/PD‐L1 inhibitors cannot prolong both OS (HR, 0.76; P = .390) and PFS (HR, 0.74; P = .210) in patients with central nervous system (CNS) metastasis, whereas patients without CNS metastasis could benefit from anti‐PD‐1/PD‐L1 monotherapy on OS (HR, 0.71; P < .001). Conclusion: PD‐1/PD‐L1‐inhibitor monotherapy could significantly prolong both OS and PFS in patients with previously treated NSCLC. Subgroup analyses showed that most patients including elderly, females, never‐smokers, and patients with squamous cell carcinomas do benefit. However, whether patients with CNS metastasis could benefit from anti‐PD‐1/PD‐L1 monotherapy requires further validation.

Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers

BackgroundCD73 is one of the critical component in the formation of immunosuppressive microenvironment in cancers. We aimed to provide an overview of the current status of CD73 expression and its relationship with clinicopathlogical features and prognosis in different cancers.MethodsPubMed, Web of Science, EMBASE and Cochrane library were searched to identify the relevant studies. CD73 expression level in distinct cancers and its relationship with clinicopathlogical characteristics and prognosis were investigated using online database. Meta-analyses were conducted using RevMan v5.0 and STATA v12.0.ResultsFourteen publications with 2951 cases were included. The incidence of high CD73 expression was 0.50 (95% CI: 0.36–0.63). Data from Oncomine validated that median CD73 expression level in tumor tissues was markedly higher than that in normal tissues in most kinds of cancers except cecum adenocarcinoma and ovarian cancer (P < 0.05). High CD73 expression was significantly correlated with shorter overall survival (OS) in various cancers (high risk [HR] = 1.48; P < 0.05). Subgroup analysis using online database demonstrated that high CD73 expression was significantly correlated with poor OS in breast (HR = 1.23; P < 0.05) and ovarian cancer (HR = 1.14; P < 0.05), but favorable OS in lung (HR = 0.80; P < 0.05) and gastric cancer (HR = 0.71; P < 0.05). High CD73 expression was dramatically associated with lymph node metastases (OR = 2.61; P = 0.05).ConclusionHigh CD73 expression was significantly associated with lymph node metastases and a promising prognostic factor in different types of cancers.

Impact of serum vascular endothelial growth factor and interleukin-6 on treatment response to epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small-cell lung cancer

BACKGROUND Although EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC), responses vary within individuals. The current study aimed to investigate whether serum levels of several cytokines and their dynamic changes during TKI treatment could be used to predict the efficacy of EGFR-TKIs. MATERIALS AND METHODS Pre-treatment and one-month post-treatment serum levels of hepatocyte growth factor (HGF), interleukin-10 (IL-10), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), interferon gamma (IFN-γ) and monocyte chemotactic protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay and U-plex biomarker group assays in patients with EGFR-mutant NSCLC received first-line EGFR-TKIs. RESULTS Patients who had lower baseline serum levels of IL-6 had better object response rate (ORR) than those with high levels (74.2% vs 42.9%, p = 0.014). PFS was significantly longer in patients with low baseline level of IL-6 (19.57 vs. 13.73 months, p = 0.003) and in those with reduced serum VEGF and HGF levels after treatment (20.30 vs. 14.33 months, p = 0.009; 22.77 vs. 14.33 months, p =  0.002; respectively). Multivariate analyses showed that lower baseline serum IL-6 level was significantly associated with longer PFS (HR = 0.469, p = 0.022) and OS (HR = 0.181, p = 0.004). Reduction of serum VEGF and HGF levels after treatment was associated with significantly longer PFS (HR = 0.447, p = 0.017; HR = 0.365, p = 0.003; respectively). Lower pre-treatment serum VEGF level was associated with dramatically longer OS (HR = 0.277, p = 0.018). CONCLUSIONS Our study suggested that serum levels of HGF, IL-6 and VEGF and its dynamic change during TKI treatment could be used to predict the efficacy of EGFR-TKIs treatment in patients with EGFR-mutant NSCLC.