The safety and efficacy of pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Lung cancer is the leading cancer-related cause of death worldwide. The introduction of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has significantly improved the outcome of these patients. Pembrolizumab, a monoclonal IgG4-kappa antibody against programmed-death-1 (PD-1) protein, nowadays represents a standard of care for NSCLC patients. Although it has a favorable toxicity profile, some immune-related adverse events (irAEs) can be life-threatening, therefore its knowledge may help to optimize the care of these patients.

Areas covered: The authors review data regarding the efficacy and safety of pembrolizumab from the most relevant clinical trials as well as toxicities reported in the clinical use. Special considerations of use in special populations will be noted. Finally, its toxicity profile will be compared with other ICIs used in NSCLC.

Expert opinion: In the scenario of NSCLC, pembrolizumab shows a favorable safety profile with less than 10% serious immune-related adverse events (irAEs) when used in monotherapy and without adding relevant extra-toxicity to chemotherapy when used in combination. Monotherapy with pembrolizumab is associated with better health-related quality of life than chemotherapy. Early recognition and appropriate treatment of irAEs is of prime importance as most are reversible if correctly managed. Rechallenge with pembrolizumab is frequently feasible.     

Reduced expression of circRNA novel_circ_0005280 and its clinical value in the diagnosis of non-small cell lung cancer

BackgroundCircular RNAs (circRNAs) are a class of novel RNAs with important biologic functions. The aberrant expression of circRNAs has been implicated in human diseases; however, the clinical significance of circRNAs in non-small cell lung cancer (NSCLC) is still unclear. The aim of the present study was to evaluate the expression and clinical implications of novel_circ_0005280 in patients with NSCLC.MethodsWe evaluated differential circRNA expression in cancer and adjacent normal tissues from 3 patients with NSCLC via RNA sequencing. Among these circRNAs, 17 and 64 circRNAs showed higher and lower expressions, respectively. Novel_circ_0005280 expression in cancer tissues (n=41) was examined using quantitative real-time polymerase chain reaction, and the results are presented in the form of paired graph and scatter graph and its correlation with clinicopathological features and patient prognosis was analyzed by drawing receiver-operating characteristic (ROC) curve and Kaplan-Meier survival analysis.ResultsNovel_circ_0005280 expression was significantly decreased in NSCLC tumor tissues (n=41, obtained via biopsies), compared with adjacent normal tissues (n=27). Novel_circ_0005280 expression was correlated with tumor diameter and age. The area under the receiver-operating characteristic curve, cutoff, sensitivity, and specificity of novel_circ_0005280 were 0.944, 10.23, 85.2%, and 95.1%, respectively. Low novel_circ_0005280 expression was associated with a worse prognosis.ConclusionsNovel_circ_0005280 may be a useful biomarker for the diagnosis and prognosis of NSCLC.     

Surgical modality for stage IA non-small cell lung cancer among the elderly: analysis of the Surveillance,Epidemiology, and End Results database

BackgroundThe appropriate surgical modality for early-stage non-small cell lung cancer (NSCLC) among the elderly remains controversial; identifying appropriate modalities will be helpful in clinical practice.MethodsIt’s a cohort study and we explored the Surveillance, Epidemiology, and End Results (SEER) database for identifying patients aged ≥70 years with pathologic stage IA NSCLC. Three types of surgeries were compared (lobectomy, segmentectomy, and wedge resection) via survival and stratification analyses.ResultsOverall, 6,197 patients were enrolled. Among patients aged ≥76 years with tumor diameters ≤1 cm, significant differences in survival were noted for segmentectomy vs. lobectomy [hazard ratio (HR) =0.294, P=0.007] and wedge resection vs. lobectomy (HR =0.548, P=0.017) but not in those with tumors diameters >1 cm. Among patients aged 70–75 years with tumor diameters >1–2 cm, significant differences in survival were observed for segmentectomy vs. lobectomy (HR =0.671, P=0.037) and segmentectomy vs. wedge resection (HR =0.556, P=0.003) and for wedge resection vs. lobectomy (HR =1.283, P=0.003) among those with tumor diameters >2–3 cm but not in those with tumor diameters ≤1 cm.ConclusionsBoth age and tumor size should be considered when selecting the surgical modality. Lobectomy is not recommended for lesions ≤1 cm among patients aged ≥76 years. Segmentectomy was associated with superior prognosis for tumor diameters >1–2 cm and survival favored lobectomy rather than wedge resection for NSCLCs >2–3 cm among patients aged 70–75 years. Surgeons could rely on personal experience to determine the appropriate surgical modality for NSCLCs >1 cm among patients aged ≥76 years and NSCLCs ≤1 cm among patients aged 70–75 years.     

Immune correlates of talactoferrin alfa in biopsied tumor of relapsed/refractory metastatic non-small cell lung cancer patients

Context: Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.

Objective: Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.

Methods: Talactoferrin was administered orally at 1.5?g bid weeks 1–12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.

Results: Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.

Conclusion: Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF.     

A study of weekly docetaxel and carboplatin as first-line chemotherapy for advanced non-small cell lung cancer

Background

Weekly docetaxel demonstrated similar efficacy but better tolerability than standard triweekly docetaxel, and carboplatin was less nephrotoxic, neurotoxic and emetogenic than cisplatin. This study aimed to evaluate the efficacy and safety of weekly docetaxel with carboplatin as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC).

Methods

Forty-three Chinese patients have been included. Patients were administered docetaxel at a dose of 35 mg/m² on days 1, 8, 15 and carboplatin at an area under the curve (AUC) 5 on day 1 every 28-day cycle (maximum six cycles).

Results

Of the 43 eligible patients, the assessed overall response rate (RR) was 30.2% with 30.2% partial response (PR) in 13 patients, 48.8% stable disease (SD) in 21 patients and 20.9% progressive disease (PD) in 9 patients. The estimated median progression free survival and median overall survival (OS) time were respectively, 120 days (95% CI: 80-160 days) and 340 days (95% CI: 224-456 days) with the patients surviving of 46.5% (95% CI: 31.6-61.4%) at one year and 20.0% (95% CI: 7.1-33.3%) at two years. The major grade 3/4 hematological toxicities were included leucocytopenia in 6 patients (13.9%) and neutropenia in 8 patients (18.6%). One patient (2.3%) suffered grade 1 febrile neutropenia. All grade of the nonhematological toxicities, such as nausea, vomiting, alopecia and fatigue held the proportion of 48.8% (grade 3/4 4.6%), 27.9%, 55.8% and 53.5% (grade 3/4 9.3%), respectively.

Conclusions

The combination of weekly docetaxel and carboplatin showed feasible efficacy with acceptable hematologic toxicities for advanced lung cancer.     

Infrequent ERBB2 mutations in Chinese patients with non-small cell lung cancer

ERBB2 mutations have been reported to occur in a subset of patients with lung adenocarcinomas or lung squamous cell carcinomas for some ethnicities, but it is unclear for Chinese patients with lung squamous cell carcinomas up to now. We retrospectively evaluated the status of ERBB2 mutations in a large cross-sectional cohort of 212 Chinese patients with non-small cell lung cancer (NSCLC) diagnosed in several hospitals from southern China during a time period of 1.5 years by polymerase chain reaction (PCR)-based direct sequencing and PCR-single strand conformation polymorphism (PCR-SSCP) analysis. ERBB2 mutation was found in 1 of 49 lung adenocarcinomas (2.0%) and none in lung squamous cell carcinomas and lung adenosquamous carcinomas. It implies the occurrence of ERBB2 mutations is infrequent in Chinese patients with NSCLC, especially in lung squamous cell carcinomas.     

Predictive risk factors for lymph node metastasis in patients with small size non-small cell lung cancer

Background

Accurate clinical staging of non-small cell lung cancer (NSCLC) is essential for developing an optimal treatment strategy. This study aimed to determine the predictive risk factors for lymph node metastasis, including both N1 and N2 metastases, in clinical T1aN0 NSCLC patients.

Methods

We retrospectively evaluated clinical T1aN0M0 NSCLC patients who showed no radiologic evidence of lymph node metastasis, and who had undergone surgical pulmonary resection with systematic mediastinal node dissection or sampling at the First Affiliated Hospital of Zhejiang University between January 2011 and June 2013. Univariate and multivariate logistic regression analyses were performed to identify predictive factors for node metastasis.

Results

Pathologically positive lymph nodes were found in 16.2% (51/315) of the patients. Positive N1 nodes were found in 12.4% (39/315) of the patients, and positive N2 nodes were identified in 13.0% (41/315) of the patients. Some 9.2% (29/315) of the patients had both positive N1 and N2 nodes, and 3.8% (12/315) of the patients had nodal skip metastasis. Variables of preoperative radiographic tumor size, non-upper lobe located tumors, high carcinoembryonic antigen (CEA) levels and micropapillary predominant adenocarcinoma (AC) were identified as predictors for positive N1 or N2 node multivariate analysis.

Conclusions

Pathologically positive lymph nodes were common in small size NSCLC patients with clinical negative lymph nodes. Therefore, preoperative staging should be performed more thoroughly to increase accuracy, especially for patients who have the larger size, non-upper lobe located, high CEA level or micropapillary predominant ACs.