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Objectives: The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) in tumor tissue samples is an established clinical biomarker for non-small cell lung cancer (NSCLC). However, the significance of PD-L1 expression in other types of samples has not been fully investigated., Patients and Methods: We conducted a multicenter retrospective cohort study of advanced NSCLC patients who received ICI treatment during the clinical course and investigated the effects of ICIs according to PD-L1 expression in cytology samples, including cell block and endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) samples., Results: A total of 264 patients were included in this study: PD-L1 expression was determined in cell block or TBNA specimens in 55 patients, and in tissue samples in 209 patients. Among the former patients, the median progression-free survival (PFS) of those with a TPS for PD-L1 ≥ 50% was significantly longer compared to that of those with a TPS < 50% (6.5 vs. 1.9 months, respectively, p = 0.008). When the cutoff value was set at 1%, the median PFS was 4.2 months in patients with a TPS ≥ 1% and 1.5 months in patients with a TPS < 1% (p < 0.001)., Conclusion: PD-L1 expression determined using cytology specimens predicts the efficacy of ICIs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear., Methods: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model., Results: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort., Conclusions: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%., Competing Interests: Conflict of interest statement E.I. received honoraria from Boehringer Ingelheim and additional research funding from MSD. N.T. received honoraria and research funds from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, Boehringer Ingelheim and Ono Pharmaceutical. T.N. received honoraria from MSD, Bristol Myers Squibb and Eisai. N.T. received research funds from Kyowa Hakko Kirin, Nippon Kayaku, Takeda Pharmaceutical and Astellas Pharma. D.H. received research funds from Eli Lilly, MSD, Chugai, Pfizer, BMS, AstraZeneca, Novartis, Kissei and Takeda and honoraria from MSD, Ono Pharmaceutical, BMS, Kyowa Hakko Kirin, AstraZeneca, Boehringer Ingelheim and Lilly. S.H. received honoraria from Bristol Myers Squibb and MSD. T.S. received research funding from Ono Pharmaceutical and Shionogi Pharmaceutical. K.H. received honoraria from Taiho Pharmaceutical and Chugai Pharmaceutical. K.H. received additional research funding from MSD and Chugai Pharmaceutical. Y.M. received honoraria from Chugai Pharmaceutical and Bristol Myers Squibb. Y.M. received honoraria from Chugai Pharmaceutical and Bristol Myers Squibb. K.K. received honoraria from Chugai Pharmaceutical. All other authors declare no conflicts of interest with regard to this study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort., Patients and Methods: We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated., Results: A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008)., Conclusion: Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC., Patients and Methods: The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed., Results: In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26-5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025)., Conclusion: The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre‐enfortumab vedotin era, many patients could not receive third‐line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real‐world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third‐line treatment. Methods: We analyzed data for 1023 la/mUC patients diagnosed between January 2020 and December 2021 at 54 institutions from a Japanese nationwide cohort. Results: At the median follow‐up of 28.5 months, the median overall survival from first‐line initiation for 905 patients who received systemic anticancer treatment was 19.1 months. Among them, 81% and 32% received second‐ and third‐line treatment. Notably, 52% had their treatment terminated before the opportunity for third‐line treatment. Multivariate logistic regression analysis revealed that low performance status (≥1), elevated neutrophil‐to‐lymphocyte ratio (≥3), and low body mass index (<21 kg/m2) at the start of first‐line treatment were independent risk factors for not proceeding to third‐line treatment (p = 0.0024, 0.0069, and 0.0058, respectively). In this cohort, 33% had one of these factors, 36% had two, and 15% had all three. Conclusions: This study highlights the high frequency of factors associated with poor tolerance to anticancer treatment in la/mUC patients. The findings suggest the need to establish optimal sequential treatment strategies, maximizing efficacy within time and tolerance constraints, while concurrently providing strong supportive care, considering immunological and nutritional aspects. [ABSTRACT FROM AUTHOR]

The relationships between the therapeutic effects of immune checkpoint inhibitors (ICIs) and the intestinal flora have attracted increasing attention. However, the effects of oral probiotics on the efficacies of ICIs used to treat non‐small‐cell lung cancer (NSCLC) remain unclear. We investigated the effects of probiotics on the efficacies of ICIs in patients treated with and without chemotherapy. We investigated patients with advanced NSCLC on ICI monotherapy or combination ICI and chemotherapy using the Okayama Lung Cancer Study Group Immunotherapy Database (OLCSG‐ID) and the Okayama Lung Cancer Study Group Immunochemotherapy Database (OLCSG‐ICD). In total, 927 patients (482 on ICI monotherapy, 445 on an ICI + chemotherapy) were enrolled. Most were male, of good performance status, smokers, and without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutations. Probiotics were administered to 19% of patients on ICI monotherapies and 17% of those on ICIs + chemotherapy. Of the former patients, progression‐free survival (PFS) and overall survival (OS) were significantly better in the probiotics group (PFS 7.9 vs. 2.9 months, hazard ratio [HR] 0.54, p <.001; OS not attained vs. 13.1 months, HR 0.45, p <.001). Among patients receiving ICI and chemotherapy, there were no significant differences in PFS between those on probiotics and not but OS was significantly better in the probiotics group (PFS 8.8 vs. 8.6 months, HR 0.89, p =.43; OS not attained vs. 22.6 months, HR 0.61, p =.03). Patients on probiotics experienced better outcomes following ICI treatment. [ABSTRACT FROM AUTHOR]

Background: Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown. Methods: We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020. Results: After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was < 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%). Conclusion: Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration. [ABSTRACT FROM AUTHOR]

Background: COVID‐19 incidence is high in patients with cancer. The fatality rate was high for the Delta variant, necessitating infection prevention by vaccination. This study evaluated the safety of a SARS‐CoV‐2 vaccine in patients with advanced lung cancer receiving anticancer therapy. Methods: We prospectively enrolled patients receiving anticancer drugs for advanced lung cancer and planning SARS‐CoV‐2 vaccination. Early side effects within 7 days of vaccination were evaluated using patient‐reported outcome (PRO) surveys. Chi‐square test and multivariate logistic regression analyses were used. Results: Post‐vaccination PROs were collected from 406 patients (252 were males). The mean age was 72 years. Treatment at the time of initial vaccination included chemotherapy, immune checkpoint inhibitors (ICI), a combination of chemotherapy and ICI, targeted therapy including tyrosine kinase inhibitors, and others in 115, 93, 45, 147, and six cases, respectively. The vaccines administered were BNT162b2 and mRNA273 in 361 and three cases, respectively and unknown in 42 cases. A total of 16.1% of patients developed fever (38°C) after the second mRNA vaccination (95% confidence interval: 12.6%–20.1%). This rate is comparable to data previously reported in 120 patients and slightly higher than that of healthy participants of the BNT162b2 study. Patients receiving treatment with cytotoxic anticancer agents were more likely to have high fever. Multivariate analysis showed no correlation between fever frequency and patient background. No serious initial adverse events due to vaccination were observed. Conclusions: Anti‐SARS‐CoV‐2 mRNA vaccination is safe; however, post‐vaccination fever is more common in patients undergoing lung cancer treatment than in healthy individuals. [ABSTRACT FROM AUTHOR]

Simple Summary: Minimal data exists on pleural effusion (PE) for non-small cell lung cancer (NSCLC) patients undergoing combined ICI and chemotherapy. We retrospectively investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival and overall survival than those without PE. In addition, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. In conclusion, PE was associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy. Objectives: Combined immune checkpoint inhibitor (ICI) therapy and chemotherapy has become the standard treatment for advanced non-small-cell lung cancer (NSCLC). Pleural effusion (PE) is associated with poor outcomes among patients with NSCLC undergoing chemotherapy. However, minimal data exists on PE for patients undergoing combined ICI and chemotherapy. Therefore, we investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. Methods: We identified patients with advanced NSCLC undergoing chemotherapy and ICI therapy from the Okayama Lung Cancer Study Group–Immune Chemotherapy Database (OLCSG–ICD) between December 2018 and December 2020; the OLCSG–ICD includes the clinical data of patients with advanced NSCLC from 13 institutions. Then, we analyzed the treatment outcomes based on the presence of PE. Results: We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without PE (median PFS: 6.2 months versus 9.1 months; p < 0.001; median OS: 16.4 months versus 27.7 months; p < 0.001). The negative effect of PE differed based on the patient's programmed cell death-ligand 1 (PD-L1) expression status; with the effect being more evident in patients with high PD-L1 expression. In addition, PFS and OS did not differ between patients who did and did not undergo bevacizumab treatment; thus, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. Conclusion: PE is associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy. [ABSTRACT FROM AUTHOR]