Background: No meta-analysis has assessed the pooled frequencies of adverse events (AEs) induced by concomitant nivolumab plus ipilimumab regimen for anticancer-medications-naïve malignancies. Furthermore, no meta-analysis has compared detailed safety profiles between four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks (N3I1) and four doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (N1I3). Objectives of this study was estimating AE frequencies, and comparison of AE frequencies between N3I1 and N1I3 regimens. Methods: Four major electronic databases were searched; both interventional and observational studies were included. All primary cancer types were permitted. Patients should not have been previously treated with any anti-cancer medications. The frequency of AEs was pooled using a random-model meta-analysis using the generic inverse variance method. Protocol registration: UMIN000044090. Results: Forty articles representing 48 populations with 4,677 patients were included in the study. The pooled frequencies for key indicators were as follows: any AE, 81.3% (95% confidence interval (CI) 77.5-85.1); grade 3 or higher AE, 40.6% (95% CI: 35.7–45.5); serious AE, 32.7% (95% CI: 22.4–43.1); AE leading to discontinuation, 28.3% (95% CI: 23.7–32.8); and treatment-related death, 0.7% (95% CI: 0.4–1.1). AEs with the highest incidence were fatigue (27.9%, 95% CI: 22.6–33.3), followed by diarrhea (26.0%, 95% CI: 21.5–30.5), pruritus (24.6%, 95% CI: 20.3–28.8), rash (24.0% 95% CI: 19.3–28.7), and elevated aspartate aminotransferase (21.2%, 95% CI: 14.9–27.5). Subgroup analyses demonstrated that N3I1, compared to N1I3, less frequently induced any AE (N1I3 95.7%, N3I1 84.5%, p = 0.003), grade 3 or higher AE (N1I3 64.3%, N3I1 35.7%, p < 0.001), and serious AE (N1I3 61.4%, N3I1 47.8%, p = 0.004). Conclusions: Approximately 40% of patients had grade 3 or higher AE. The N3I1 regimen was substantiated to trigger fewer any AEs, high grade AEs, and serious AE than the N1I3 regimen.

Background Differences in the resistance mechanisms of epidermal growth factor receptor tyrosine kinase inhibitors in patients with non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor mutations are unknown. This meta‐analysis aimed to clarify the differences in resistance mechanisms after treatment with various epidermal growth factor receptor tyrosine kinase inhibitors. Methods We systematically searched PubMed, Cochrane, and Web of Science on July 29, 2020, for relevant studies on acquired resistance mechanisms against epidermal growth factor receptor tyrosine kinase inhibitors. The primary outcome measure was differences in the resistance mechanism between individual or generations of epidermal growth factor receptor tyrosine kinase inhibitors. Results In total, 33 trials involving 2418 individuals were included and analyzed. T790M was significantly less frequent after afatinib treatment (40.2%, 95% confidence interval [CI]: 31.7%–48.7%) than after gefitinib and erlotinib treatments (52.5%, 95% CI: 48.7%–56.3%, p = 0.005). There were no significant differences between Asian and non‐Asian patients in the incidence of T790M after gefitinib, erlotinib, and afatinib treatments. Regarding epidermal growth factor receptor pathway‐independent resistant mechanisms, the incidences of small cell lung cancer transformation (osimertinib: 7.9%, 95% CI: 3.6%–12.2%, others: 2.3%, 95% CI: 0.8%–3.8%) and Kirsten rat sarcoma (KRAS) viral oncogene homolog mutation (osimertinib: 4.6%, 95% CI: 1.5%–7.7%, others: 0.2%, 95% CI: 0.0%–1.7%) were significantly higher following osimertinib treatment than with others. Conclusions Significant differences in the incidence of resistance mechanisms among epidermal growth factor receptor tyrosine kinase inhibitors exist, which should be taken into consideration when choosing the treatment strategy.

Background/Aim: Immune checkpoint inhibitors (ICIs) have an important role in lung cancer therapy. Although the programmed cell death protein-1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden are known prognostic factors, they are insufficient to predict clinical outcomes. This study was conducted to identify novel biomarkers for ICI treatment. Patients and Methods: We performed univariable and multivariable analyses of 110 patients with advanced non-small-cell lung cancer (NSCLC) who were treated with an ICI to identify novel biomarkers related to prognosis. We assessed their backgrounds, such as performance status (PS), PD-L1 TPS, smoking status, and peripheral white blood cell counts at baseline and on the day the second course of ICI administration. Results: In the multivariable analysis, PS, driver gene, immune-related adverse events, and post-treatment absolute neutrophil counts (post-ANCs) were significantly associated with progressionfree survival. Conclusion: A high level of post-ANCs was associated with poor outcome in ICI-treated NSCLC patients.Emergence of immune checkpoint inhibitors (ICIs), such as nivolumab, pembrolizumab, and atezolizumab, has led to a paradigm shift in the treatment of non-small-cell lung cancer (NSCLC). Although the combination of ICIs and cytotoxic agents has been recently adapted for first-line chemotherapy regardless of the programmed cell death protein-1 (PD-L1) tumor proportion score (TPS) (1), ICI monotherapy remains the standard therapy for NSCLC patients with PD-L1 high expression (2). The PD-L1 TPS and tumor mutational burden (TMB) are known major predictive markers for ICI (3-5). Among patients with ≥50% PD-L1 expression, the response rate to pembrolizumab monotherapy has been found to be 45.2%, whereas among patients with <1% PD-L1 expression, the response rate of pembrolizumab monotherapy was 7.8% (6). Although the PD-L1 TPS is an important biomarker for ICI, high expression of PD-L1 is not always observed in patients who are successfully treated with an ICI. In a certain number of patients with the risk of immune-related adverse events (irAEs), ICIs provide no clinical benefit. Thus, more effective and easily measurable biomarkers for ICI are needed for clinical use. Some biomarkers assessed in the peripheral blood of ICItreated patients have previously been reported. High lactate dehydrogenase (LDH) and high C-reactive protein (CRP) at baseline have been reported to be associated with poor outcome (7, 8). High neutrophil-lymphocyte ratio (NLR) (9, 10), high absolute lymphocyte counts (ALCs), high absolute eosinophil counts (AECs), and high absolute neutrophil counts (ANCs) prior to induction of ICI have been shown to be associated with progression-free survival (PFS) and overall survival (OS) in NSCLC patients (11). Clinical biomarkers, poor performance status (PS) (9, 12), appearance of any irAEs (13), and expression of driver gene mutation ( 14) have also been reported to be associated with poor prognosis in NSCLC patients.The aim of this study ...

Background: Pembrolizumab alone or in combination with chemotherapy is a standard treatment for patients with non-small-cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression. However, no study has compared the efficacies of these two regimens. Therefore, we aimed to compare the efficacy of pembrolizumab alone and in combination with chemotherapy in NSCLC patients with high PD-L1 expression. Methods: We conducted a multicenter retrospective trial involving patients with diagnosed unresectable or recurrent NSCLCs who had received pembrolizumab with or without chemotherapy in the first-line setting. Patients were divided into monotherapy and combination therapy groups. The progression-free survival (PFS), overall survival (OS), and response rate (RR) were analyzed and compared between the groups. Clinical characteristics of patients were analyzed to assess their possible relationship with treatment outcomes. Results: We enrolled 96 patients from five hospitals. Of these, 47 and 49 patients received monotherapy and combination therapy, respectively. The median PFS was 343 and 328 days in the monotherapy and combination therapy groups, respectively (hazard ratio 1.003, p = 0.99). No statistically significant differences were observed in the OS and RR between the two groups. However, in patients with metastases to the liver, lung, adrenal glands, bone, or lymph nodes, the PFS was longer in the monotherapy group than in the combination therapy group. Conclusion: Although the PFS, OS, and RR were not significantly different between patients treated with pembrolizumab alone and or with pembrolizumab in combination with chemotherapy, patients with NSCLC having metastases to specific sites may benefit more from monotherapy.

Background: Immune checkpoint inhibitors are a standard treatment for advanced lung cancer, although it remains important to identify biomarkers that can accurately predict treatment response. Immune checkpoint inhibitors enhance the antitumor T-cell response, and interferon-γ plays an important role in this process. Therefore, this study evaluated whether the number of interferon-γ-releasing peripheral T cells after phytohemagglutinin stimulation in the interferon-γ release assay might act as a biomarker for the response of non-small cell lung cancer to immune checkpoint inhibitor treatment. Methods: Data were retrospectively collected regarding 74 patients with non-small cell lung cancer who had received immune checkpoint inhibitors. Pretreatment screening tests had been performed using the T-SPOT.TB assay, which quantifies the number of interferon-γ-releasing T cells (as immunospots) in response to phytohemagglutinin and tuberculosis-specific antigen stimulation. Clinical factors and the number of spots in the T-SPOT fields were evaluated for associations with patient outcomes. The median number of spots was used to categorize patients as having high or low values, and the two groups were compared. Results: Relative to patients with a low ratio, patients with a high ratio of phytohemagglutinin/tuberculosis-specific antigen spots (i.e. more responsive T cells) had significantly better progression-free survival after immune checkpoint inhibitor treatment. When we only considered patients with negative T-SPOT results, a high number of phytohemagglutinin-stimulated spots corresponded to significantly longer progression-free survival. Conclusion:The T-SPOT.TB assay can be used to quantify the number of immunospots in response to antigen stimulation, which may predict the response to immune checkpoint inhibitors in patients with non-small cell lung cancer.