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Recent studies have reported that immune-checkpoint inhibitors (ICIs) cause various immune-related adverse events (irAEs) and irAEs are associated with antitumor effects of ICIs. However, it remains unclear whether the incidence of irAEs was associated with types of PD-1 inhibitors and treatment lines. We retrospectively evaluated data of advanced or recurrent NSCLC patients treated in 1st to 3rd line with PD-1 inhibitors at Niigata Lung Cancer Treatment Group between January 2016 and October 2017. Of 231 patients who received anti-PD-1 therapies, 176 patients received nivolumab and 55 patients received pembrolizumab, and 63 patients (36%) developed irAEs in nivolumab therapy and 30 patients (55%) developed irAEs in pembrolizumab therapy. In the univariate analysis, male (Odd Ratio: OR 2.38, p = 0.01), smoker (OR 3.29, p = 0.002), squamous cell carcinoma (OR 2.99, p = 0.0001), pembrolizumab therapy (OR 2.15, p = 0.01), 1st line anti-PD-1 treatment (OR 2.07, p = 0.04), EGFR gene mutation negative (OR 8.77, p = 0.03) were significant predictors of irAEs. Multivariate analysis identified younger age (<75) (OR 2.46, p = 0.02), squamous cell carcinoma (OR 2.94, p = 0.0006) as independent positive predictors of irAEs. In patients treated with nivolumab, irAEs were associated with better survival (not reached vs. 15.4 months, p < 0.0005); however, in patients treated with pembrolizumab, irAEs were not correlated with overall survival (20 months vs. not reached p = 0.338). MST in patients with steroid treatment was significantly shorter than that in those without steroid treatment (not reached vs. 20.6 months, p < 0.01). The proportion of patients who received systemic steroid therapy for irAEs was not significantly different between nivolumab and pembrolizumab (46.0% vs. 46.6%, p = 0.954). In the current study, pembrolizumab therapy and 1st line treatment were predictors of irAE onset in univariate analysis, but not in multivariate analysis. [ABSTRACT FROM AUTHOR]

Background Recent studies have reported that immune-checkpoint inhibitors (ICIs) cause various immune-related adverse events (irAEs) and irAEs are associated with antitumor effects of ICIs. However, it remains unclear whether the incidence of irAEs was associated with types of PD-1 inhibitors and treatment lines. Methods We retrospectively evaluated data of advanced or recurrent NSCLC patients treated in 1st to 3rd line with PD-1 inhibitors at Niigata Lung Cancer Treatment Group between January 2016 and October 2017. Results Of 231 patients who received anti-PD-1 therapies, 176 patients received nivolumab and 55 patients received pembrolizumab, and 63 patients (36%) developed irAEs in nivolumab therapy and 30 patients (55%) developed irAEs in pembrolizumab therapy. In the univariate analysis, male (Odd Ratio: OR 2.38, p = 0.01), smoker (OR 3.29, p = 0.002), squamous cell carcinoma (OR 2.99, p = 0.0001), pembrolizumab therapy (OR 2.15, p = 0.01), 1st line anti-PD-1 treatment (OR 2.07, p = 0.04), EGFR gene mutation negative (OR 8.77, p = 0.03) were significant predictors of irAEs. Multivariate analysis identified younger age (<75) (OR 2.46, p = 0.02), squamous cell carcinoma (OR 2.94, p = 0.0006) as independent positive predictors of irAEs. In patients treated with nivolumab, irAEs were associated with better survival (not reached vs. 15.4 months, p < 0.0005); however, in patients treated with pembrolizumab, irAEs were not correlated with overall survival (20 months vs. not reached p = 0.338). MST in patients with steroid treatment was significantly shorter than that in those without steroid treatment (not reached vs. 20.6 months, p < 0.01). The proportion of patients who received systemic steroid therapy for irAEs was not significantly different between nivolumab and pembrolizumab (46.0% vs. 46.6%, p = 0.954). Conclusion In the current study, pembrolizumab therapy and 1st line treatment were predictors of irAE onset in univariate analysis, but not in multivariate analysis. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) induced by anti‐programmed‐cell death‐1 (PD‐1) and anti‐PD‐ligand 1 (PD‐L1) is potentially life‐threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune‐related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti‐PD‐1/PD‐L1 therapies, the association between radiologic features and clinical outcomes remains unclear. Methods: Patients with advanced non‐small‐cell lung cancer who were treated with 1st to 3rd line anti‐PD‐1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD. Results: A total of 231 patients who received anti‐PD‐1 therapy were enrolled. Thirty‐one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2‐NE) versus not reached (95% CI: 13.2‐NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival. Conclusions: This study demonstrated that patients who developed GGO exhibited worse outcomes among non‐small‐cell lung cancer patients receiving anti‐PD‐1 therapies. [ABSTRACT FROM AUTHOR]

Background: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) in EGFR‐mutant non‐small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR‐mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR‐TKIs in patients with EGFR‐mutant NSCLC with newly diagnosed brain metastases. Methods: We retrospectively analyzed the data of EGFR‐mutant NSCLC patients with CNS metastases who received EGFR‐TKIs as a first‐line therapy. Results: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR‐TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3–9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1–30.1). The overall response rate of the CNS was 37%. The median CNS progression‐free survival (PFS) was 13.2 months (95% CI: 10.0–16.2). Brain radiotherapy prior to EGFR‐TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS‐PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. Conclusion: EGFR‐TKI showed a favorable effect for EGFR‐mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS‐PFS were observed with upfront brain radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI.Methods: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25% from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or ≥ 1.5 times the baseline level.Results: Eighty of the 84 patients (95.2%) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4%). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95% confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95% CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI.Conclusions: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use. [ABSTRACT FROM AUTHOR]

The specific mechanisms how lung cancer cells harboring epidermal growth factor receptor (EGFR) activating mutations can survive treatment with EGFR-tyrosine kinase inhibitors (TKIs) until they eventually acquire treatment-resistance genetic mutations are unclear. The phenotypic diversity of cancer cells caused by genetic or epigenetic alterations (intratumor heterogeneity) confers treatment failure and may foster tumor evolution through Darwinian selection. Recently, we found DDX3X as the protein that was preferentially expressed in murine melanoma with cancer stem cell (CSC)-like phenotypes by proteome analysis. In this study, we transfected PC9, human lung cancer cells harboring EGFR exon19 deletion, with cDNA encoding DDX3X and found that DDX3X, an ATP-dependent RNA helicase, induced CSC-like phenotypes and the epithelial-mesenchymal transition (EMT) accompanied with loss of sensitivity to EGFR-TKI. DDX3X expression was associated with upregulation of Sox2 and increase of cancer cells exhibiting CSC-like phenotypes, such as anchorage-independent proliferation, strong expression of CD44, and aldehyde dehydrogenase (ALDH). The EMT with switching from E-cadherin to N-cadherin was also facilitated by DDX3X. Either ligand-independent or ligand-induced EGFR phosphorylation was inhibited in lung cancer cells that strongly expressed DDX3X. Lack of EGFR signal addiction resulted in resistance to EGFR-TKI. Moreover, we found a small nonadherent subpopulation that strongly expressed DDX3X accompanied by the same stem cell-like properties and the EMT in parental PC9 cells. The unique subpopulation lacked EGFR signaling and was highly resistant to EGFR-TKI. In conclusion, our data indicate that DDX3X may play a critical role for inducing phenotypic diversity, and that treatment targeting DDX3X may overcome primary resistance to EGFR-TKI resulting from intratumor heterogeneity. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that most solid malignancies consist of heterogeneous tumor cells and that a relatively small subpopulation, which shares biological features with stem cells, survives through potentially lethal stresses such as chemotherapy and radiation treatment. Since the survival of this subpopulation of cancer stem cells (CSC) plays a critical role in recurrence, it must be eradicated in order to cure cancer. We previously reported that vaccination with CD133 murine melanoma cells exhibiting biological CSC features induced CSC-specific effector T cells. These were capable of eradicating CD133 tumor cells in vivo, thereby curing the parental tumor. In the current study, we indicated that DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked (DDX3X) is an immunogenic protein preferentially expressed in CD133 tumor cells. Vaccination with DDX3X primed specific T cells, resulting in protective and therapeutic antitumor immunity. The DDX3X-primed CD4 T cells produced CD133 tumor-specific IFNγ and IL-17 and mediated potent antitumor therapeutic efficacy. DDX3X is expressed in various human cancer cells, including lung, colon, and breast cancer cells. These results suggest that anti-DDX3X immunotherapy is a promising treatment option in efforts to eradicate CSC in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron. Methods: Chemotherapy-naïve lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2-3 and the oral administration of 8 mg of dexamethasone on days 2-4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0-120 h). Results: The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0 %, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7 %, respectively. The most common adverse event was grade 1 or 2 constipation. Conclusions: Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC. [ABSTRACT FROM AUTHOR]