Search

A recent study suggested that proton pump inhibitor (PPI) use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) was associated with poor clinical outcomes. However, the clinical impact of PPI use on the outcome of patients receiving ICIs for postoperative recurrent NSCLC is unknown. The outcomes of 95 patients with postoperative recurrence of NSCLC receiving ICIs at 3 medical centers in Japan were analyzed. We conducted adjusted Kaplan-Meier survival analyses with the log-rank test, a Cox proportional hazards regression analysis, and a logistic regression analysis using inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves revealed that the progression-free survival (PFS), but not the overall survival (OS), was significantly longer in patients who did not receive PPIs than in those who did receive them. The IPTW-adjusted Cox regression analysis revealed that PPI use was an independent poor prognostic factor for the PFS and OS. Furthermore, in the IPTW-adjusted logistic regression analysis, PPI non-use was an independent predictor of disease control. In this multicenter and retrospective study, PPI use was associated with poor clinical outcomes in patients with postoperative recurrence of NSCLC who were receiving ICIs. PPIs should not be prescribed indiscriminately to patients with postoperative recurrence of NSCLC who intend to receive ICIs. These findings should be validated in a future prospective study., Competing Interests: The authors have declared that no competing interests exist.

Immune checkpoint inhibitors (ICIs) have become standard pharmacological therapies in patients with non-small-cell lung cancer (NSCLC). Because elderly patients with NSCLC are often excluded from clinical trials as a result of lower functional capacity or comorbidities, the prognostic impact of chronological age on the efficacy of ICIs is unclear. The National Cancer Database was queried for stage IV NSCLC patients between 2014 and 2015. Associations between ICI therapy and clinical characteristics were assessed using chi-squared tests. Kaplan-Meier curves were compared using the log-rank test. A Cox proportional hazards model was used to identify clinical characteristics predictive of overall survival (OS). This study included 24 136 patients with stage IV NSCLC aged ≥75 years and 62 037 patients with stage IV NSCLC aged <75 years. Patients aged ≥75 years treated with ICIs had significantly longer OS than those not treated with ICIs (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.58-0.64, p < 0.0001). The corresponding HR in patients aged <75 years was 0.67 (95% CI 0.65-0.68, p < 0.0001). Cox modeling confirmed the survival benefit of ICI therapy in patients aged ≥75 years (HR for patients not receiving ICIs 1.63 [95% CI: 1.55-1.71], p < 0.0001). The corresponding HR in patients aged <75 years was 1.47 (95% CI 1.43-1.51, p < 0.0001). Chronological age does not appear to negatively impact the survival benefit of ICI therapy in patients with stage IV NSCLC according to this large real-world database analysis., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have markedly improved the prognosis of many patients with advanced non-small cell lung cancer (NSCLC). However, the relationship between the patient's nutritional/immunologic status and the outcomes of ICI treatment remains unclear. In previous retrospective studies, we reported that the controlling nutritional status (CONUT) score, skeletal muscle area, and neutrophil-to-lymphocyte ratio were independent predictors of the response of NSCLC patients to anti-PD-1 drugs. The aim of this prospective multi-center study is to investigate the clinical impact of pre-treatment nutritional/immunologic indices and early post-treatment changes in the indices on treatment outcomes in advanced NSCLC. The main inclusion criteria are: (1) stage IV NSCLC, or stage III NSCLC not applicable for definitive chemoradiotherapy; (2) treatment with ICIs (monotherapy or combined with chemotherapy) as first-line therapy; and (3) available data on PD-L1 expression on tumor cells. A total of 300 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2025., Competing Interests: The authors declare no conflicts of interest in association with the present study.

The gastrointestinal microbiota was reported as an important factor for the response to cancer immunotherapy. Probiotics associated with gastrointestinal dysbiosis and bacterial richness may affect the efficacy of cancer immunotherapy drugs. However, the clinical impact of probiotics on the efficacy of cancer immunotherapy in patients with nonsmall cell lung cancer (NSCLC) is poorly understood. The outcomes of 294 patients with advanced or recurrent NSCLC who received antiprogrammed cell death-1 (PD-1) therapy (nivolumab or pembrolizumab monotherapy) at three medical centers in Japan were analyzed in our study. We used inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves showed that progression-free survival (nonuse vs use: hazard ratio [HR] [95% confidence interval {CI}] = 1.73 [1.42-2.11], log-rank test P = .0229), but not overall survival (nonuse vs use: HR [95%CI] = 1.40 [1.13-1.74], log-rank test P = .1835), was significantly longer in patients who received probiotics. Moreover, the IPTW-adjusted univariate analyses showed that nonuse or use of probiotics was significantly associated with disease control (nonuse vs use: odds ratio [OR] [95%CI] = 0.51 [0.35-0.74], P = .0004) and overall response (nonuse vs use: OR [95%CI] = 0.43 [0.29-0.63], P < .0001). In this multicenter and retrospective study, probiotics use was associated with favorable clinical outcomes in patients with advanced or recurrent NSCLC who received anti-PD-1 monotherapy. The findings should be validated in a future prospective study., (© 2021 UICC.)

Background: Immune checkpoint inhibitors (ICIs) have become a standard therapy in non-small cell lung cancer (NSCLC). Although lung cancer adjoining emphysematous bullae (Ca-ADJ) were reported to express higher programmed cell death-ligand 1 (PD-L1), the predictive impact of Ca-ADJ on the response to ICIs is unknown., Methods: Two hundred and fifty-seven advanced or recurrent NSCLC patients treated with ICI monotherapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed., Results: Of the 257 patients, 55 had Ca-ADJ. Patients with Ca-ADJ were significantly associated with younger age (P = 0.0343), male sex (P = 0.0070), and smoking (P = 0.0080). The objective response rate of cases with Ca-ADJ was significantly higher than that of those without Ca-ADJ (36.4% vs. 20.8%, respectively; P = 0.0167). The disease control rate of cases with Ca-ADJ was also significantly higher than tumors without Ca-ADJ (63.6% vs. 47.5%, respectively; P = 0.0341). The IPTW-adjusted Kaplan-Meier curves showed that patients with Ca-ADJ had significantly longer progression-free survival (PFS) and overall survival (OS) than those without Ca-ADJ (P = 0.0407 and P = 0.0126, respectively). On IPTW-adjusted Cox analysis, Ca-ADJ was an independent predictor of PFS and OS (P < 0.0001 and P < 0.0001, respectively)., Conclusions: Patients with Ca-ADJ may be good candidates for ICIs. These findings should be validated prospectively.

Immunocheckpoint inhibitors (ICIs) have become a standard pharmacological therapy in non-small cell lung cancer (NSCLC). Because brain metastases (BMs) have historically been listed as exclusion criteria in previous clinical trials involving ICIs in advanced NSCLC, the survival benefit from ICI in NSCLC patients with BMs remains unclear. The National Cancer Database was queried for stage IV NSCLC patients with or without BMs between 2014 and 2015. Overall survival (OS) of stage IV NSCLC patients who received immunotherapy and that of stage IV NSCLC patients who did not receive immunotherapy were compared according to the presence or absence of BMs. Multivariable logistic analyses identified the clinical characteristics predictive of overall survival. A propensity score analysis was conducted with the aim of adjusting the potential biases arising from the clinical characteristics. This study included 42,512 patients with stage IV NSCLC; 11,810 patients with BMs and 30,702 patients without BMs. In univariate analysis, stage IV NSCLC patients with BMs treated with immunotherapy had a significantly longer OS than those without immunotherapy after propensity score matching (median OS: 12.8 vs 10.1 months, hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.72-0.89, p < 0.0001). Multivariable Cox modeling after propensity score matching confirmed the survival benefit from ICI for stage IV NSCLC patients with BMs (HR: 0.75, 95% CI: 0.67-0.83, p < 0.0001). The HR in NSCLC patients without BMs treated with ICI compared with those without ICI was 0.77 (95% CI: 0.73-0.82, p < 0.0001). Survival in stage IV NSCLC patients with BMs was significantly improved by ICI treatment at levels comparable to those without BMs using a retrospective database. ICI may be one of the promising treatment options for stage IV NSCLC patients with BMs. These findings should be validated in future prospective studies., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Immunotherapy targeting programmed death-1 or programmed death-ligand 1 has become the standard of care for advanced non-small cell lung cancer (NSCLC). Several recent clinical trials have investigated the efficacy of immune checkpoint inhibitors (ICIs) as neoadjuvant treatment for early NSCLC. However, the safety and feasibility of pulmonary resection after ICIs remain unclear. We herein report a patient in whom cohesion between the left main pulmonary artery and left upper bronchus was found during left upper lobectomy following neoadjuvant ICI combined with chemotherapy. After both central and peripheral sides of the left main pulmonary artery were clamped with the aim of controlling hemorrhage in case of vascular injury, the left main pulmonary artery and left upper bronchus were divided and individually cut with staplers. The thoracoscopic procedure was otherwise uneventful. The patient was discharged from our hospital with no postoperative complications. Thoracic surgeons should anticipate the possible need for management of cohesion between a pulmonary artery and bronchus in patients who have received immune checkpoint inhibitors preoperatively., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Because patients younger than 40 years are rarely enrolled in clinical trials in non-small cell lung cancer (NSCLC), their survival benefit of immune checkpoint inhibitors (ICIs) needs to be clarified. Methods: The National Cancer Database was queried for patients who were diagnosed with stage IV NSCLC between 2016 and 2018. ICIs were administered in the first-line setting. The overall survival (OS) of patients with stage IV NSCLC according to the receipt of ICIs was compared in different age groups (< 40, 40–49, 50–59, 60–69, 70–79, and ≥ 80 years). Multivariate analyses identified the clinical characteristics predictive of OS. Propensity score matching (PSM) was conducted to reduce the biases arising from clinical characteristics. Results: This study included 126,476 patients with stage IV NSCLC. In univariate analysis, ICI treatment was not associated with a survival benefit in patients younger than 40 years with stage IV NSCLC relative to their ICI-naïve counterparts after PSM (median OS: 24.2 months vs. 24.0 months, hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 0.81–1.27, P = 0.9031). Multivariate analysis revealed that ICI use was not an independent predictor of OS in patients with stage IV NSCLC < 40 years old (HR = 0.96, 95% CI = 0.76–1.21, P = 0.7230). Sequential improvement of the HR was observed with increasing age. Conclusion: Our study suggested a poor survival benefit of ICIs in stage IV NSCLC patients younger than 40 years old, which should be validated in prospective studies. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy has become a standard‐of‐care for patients with non‐small‐cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death‐1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first‐line ICI combined with or without chemotherapy. Materials and Methods: Two‐hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first‐line therapy. Cutoff value of the pretreatment PNI was set as 42.17. Results: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression‐free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51–0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32–0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively). Conclusion: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first‐line ICI therapy. [ABSTRACT FROM AUTHOR]

Introduction: Recently, several meta-analyses have investigated the association between sex and the efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC). However, this issue remains controversial, because the results have been inconsistent. Moreover, the effect of sex on outcomes in patients with NSCLC receiving combination chemoimmunotherapy as a first-line therapy is poorly understood. The aim of this study was to examine the association between sex and outcomes in patients with NSCLC receiving combination chemoimmunotherapy as a first-line therapy. Methods: We searched PubMed and Scopus from database inception to Feb 18, 2022 and performed a systematic review and meta-analysis of randomized and controlled clinical trials investigating ICI+non-ICI vs non-ICI as a first-line therapy in NSCLC. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) in male and female patients were calculated using common and random-effects models. Results: We analyzed 5,830 patients, comprising 4,137 (71.0%) males and 1,693 (29.0%) females, from nine randomized clinical trials. The pooled HR (95%CI) for OS comparing ICI+non-ICI vs non-ICI was 0.80 (0.72–0.87) for males and 0.69 (0.54–0.89) for females. The pooled HR (95%CI) for PFS comparing ICI+non-ICI vs non-ICI was 0.60 (0.55–0.66) for males and 0.56 (0.44–0.70) for females. Conclusions: In patients with NSCLC receiving combination chemoimmunotherapy as a first-line therapy, a greater improvement in OS and PFS was observed in female patients than in male patients. [ABSTRACT FROM AUTHOR]

Background: Pneumonitis can be triggered by anti-cancer therapies: cytotoxic chemotherapy, tyrosine kinase inhibitors, and immune checkpoint inhibitors. There are few treatment options for patients who develop such pneumonitis and their treatment including chemotherapy is generally difficult thus would limit patient's prognosis. In this study, we investigated the clinical course of patients with lung cancer who developed anti-cancer therapy-related pneumonitis. Patients and methods: We retrospectively examined data of patients who had developed pneumonitis triggered by anti-cancer agents and required hospitalization from January 2014 to March 2019 and analyzed their subsequent clinical course and prognosis. Results: The median age of the 58 study patients was 68 years and 82.8% were men. The median interval between first receiving the responsible agent and drug-induced pneumonitis was 7.4 weeks. Approximately 38% of patients were subsequently able to receive some anti-cancer therapy. The median post-pneumonitis overall survival (OS) from commencement of anti-cancer treatment was 13.2 months. No significant differences were found in survival time between treatment agents. However, patients who received some anticancer therapy after pneumonitis had significantly longer survival times than those did not (HR = 4.11, p = 0.0003) and patients who took longer to develop pneumonitis had a longer survival (HR = 2.28, p = 0.0148). Multivariate analysis revealed that short interval to onset and no post-pneumonitis anticancer therapy were independent predictors of short survival. Conclusion: Although patients who developed pneumonitis had relatively short survival times, the interval between initial therapy and pneumonitis had survival impact. Survival can be prolonged by administering further cancer treatment after resolution of pneumonitis. [ABSTRACT FROM AUTHOR]

Purpose: Anti-programmed death 1 (PD-1) antibodies have emerged as frontline treatments for patients with advanced non-small cell lung cancer (NSCLC) on the basis of global Phase III trials. However, current data regarding responses to anti–PD-1 therapy in older patients with NSCLC or those with poor performance status (PS) are limited. Therefore, we examined the therapeutic effect of anti PD-1 antibody in these patients. Patients: We retrospectively examined consecutive patients treated with anti–PD-1 monotherapy (pembrolizumab or nivolumab) from January 2016 to September 2018. Results: We enrolled 125 patients (median age, 60 years), 80.8% of whom were men. Patients aged ≥ 75 years were considered older patients (n = 15), and those with PS 2– 3 were regarded as having poor PS (n = 11). The objective response and disease control rates were 15.4% and 46.2%, respectively, in older patients and 9.1% and 27.3%, respectively, in those with poor PS. Progression-free survival (PFS) and overall survival (OS) did not significantly differ between older and younger patients. However, poor PS was significantly associated with poor survival. High programmed death ligand 1 (PD-L1) expression in tumor specimens (≥ 50%) was associated with favorable survival in the entire cohort as well as patients with poor PS. Safety analyses demonstrated no significant difference in the occurrence of any adverse event, including grade ≥ 3 adverse events, between patients with poor PS or older age and the remaining patients. Conclusion: Anti–PD-1 therapy had similar efficacy in older and younger patients with NSCLC, whereas survival was significantly worse in patients with poor PS. However, immune checkpoint inhibitors may be considered for patients with poor PS harboring positive PD-L1 expression. [ABSTRACT FROM AUTHOR]

• GPS is calculated based on serum albumin and C-reactive protein values. • GPS was associated with DCR in NSCLC patients treated with ICI. • GPS was an independent prognostic factor in NSCLC patients receiving ICI. • GPS was the most powerful prognostic factor of the GPS, mGPS, and CAR. Immune checkpoint inhibitors (ICIs) have become one of the standard therapies in non-small-cell lung cancer (NSCLC). Although inflammatory indices, including Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS), and C-reactive protein/albumin ratio (CAR) were reported to be reliable predictors for survival in cancer patients, their clinical utility in NSCLC patients treated with ICIs is unknown. Advanced or recurrent NSCLC patients (n = 304) treated with ICI monotherapy at the National Hospital Organization Kyushu Cancer Center and Kyushu University Hospital between January 2016 and December 2019 were analyzed. Information on patient demographics, GPS, mGPS, and CAR at diagnosis were collected. The time-dependent area under curves (AUCs) of receiver operating characteristic curves for the prediction of overall survival (OS) for each factor were compared. Of the three indices, GPS was the most significantly correlated with the degree of disease control rate (DCR) (DCR of GPS of 0, 1, and 2: 63.6 %, 49.4 %, and 41.4 %, respectively). The time-dependent AUC values of GPS for the prediction of OS were superior to those of mGPS and CAR (time-dependent AUC values of GPS, mGPS, and CAR for the prediction of 1-year OS: 0.7005, 0.6736, and 0.6565, respectively). GPS was significantly correlated with performance status (PS) (P < 0.0001) and clinical stage (P = 0.0139). GPS in combination with PS effectively predicted survival at 1 year ranging from 83.5 % (GPS = 0, PS = 0) to 25.0 % (GPS = 2, PS = 2, 3). A multivariable analysis revealed that GPS was an independent predictor of PFS and OS (P = 0.0009 and P = 0.0100, respectively). We report for the first time that GPS represents a simple and useful prognostic factor in NSCLC patients treated with ICIs and should be validated prospectively. [ABSTRACT FROM AUTHOR]

• dNLR is a novel serum inflammatory marker. • dNLR is calculated from white blood cell concentration and neutrophil count. • dNLR was associated with treatment response in NSCLC treated with anti-PD-1 drugs. • dNLR was an independent prognostic factor in NSCLC treated with anti-PD-1 drugs. • dNLR might be the most important factor for the efficacy of anti-PD-1 therapy. Several serum markers have been associated with treatment response and clinical outcome in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. We performed univariate and multivariate analyses on 226 patients with advanced or recurrent NSCLC treated with anti-programmed cell death-1 (PD-1) therapy. The cut-off values for body mass index (BMI), albumin (Alb), and serum inflammatory markers were determined by receiver operating characteristic curve analyses. Tumor response was assessed by computed tomography according to the Response Evaluation Criteria in Solid Tumors, version 1.1. BMI ≥ 19.1 kg/m2 and derived neutrophil-lymphocyte ratio (dNLR) < 2.79 were independent predictors of overall response, and Alb ≥ 3.5 g/dL and dNLR < 2.79 were independent predictors of disease control. Analyses of survival revealed that Alb < 3.5 g/dL, dNLR ≥ 2.79, lymphocyte-monocyte ratio < 2.12, and red blood cell distribution width ≥ 15.9 % were independent predictors of both progression-free and overall survival. Moreover, these markers tended to have a strong impact on survival, especially among patients with programmed cell death-ligand 1 tumor proportion score ≥ 50 %. dNLR might be the most important factor for predicting the efficacy in NSCLC patients treated with anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

The transformation of adenocarcinoma to small cell lung cancer has been reported as acquisition of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. We here report a patient who presented histologically confirmed transformation of adenocarcinoma to small cell lung cancer after treatment with immune checkpoint inhibitor. A 65-year-old man was treated with pembrolizumab as first-line therapy and achieved temporarily a stable disease with progression after six cycles of this agent. At that stage, a transbronchial biopsy showed small cell lung cancer, and he was found to have high serum concentrations of neuron-specific enolase despite concentrations of numerous tumor markers, including neuron-specific enolase, having been within normal limits at the time of presentation. The patient thereafter was treated as a small cell carcinoma patient using cisplatin plus irinotecan and amrubicin. [ABSTRACT FROM AUTHOR]

We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted. • Concomitant medications affect clinical outcomes from immune checkpoint inhibitors. • We previously validated a prognostic drug score in European patients with NSCLC. • We explored the prognostic ability of the drug score in Japanese patients with NSCLC. • The use of probiotics might mitigate the deleterious effect of antibiotics. • Racial differences should be considered when investigating this topic. [ABSTRACT FROM AUTHOR]