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Background We previously reported that PD-L1 polymorphisms are associated with the efficacy and immune-related adverse events of PD-1 blockade with nivolumab. However, the association between PD-L1 polymorphisms and survival outcomes under PD-1/PD-L1 blockade is still uncertain. Here, we aimed to investigate whether PD-L1 polymorphisms are associated with survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab. Methods PD-1/PD-L1 polymorphisms and survival outcomes were retrospectively analysed in two independent cohorts (133 patients treated with nivolumab and 96 patients with no treatment history of an immune checkpoint inhibitor (ICI) (the non-ICI cohort)) with advanced NSCLC. Results Among the 7 studied single-nucleotide polymorphisms, PD-L1 rs822339 and rs1411262 were associated with overall survival (OS) in patients treated with nivolumab. Patients with the A/A genotype of rs822339 had a significantly longer OS than those with A/G or G/G genotypes (not reached versus 12.0 months; hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.18–0.64; p = 0.0008). A similar survival benefit with the A/A genotype was observed regardless of driver mutation status. In multivariate analysis, performance status (PS) and PD-L1 rs822339 genotype were independent prognostic factors for OS. In the non-ICI cohort, the PD-L1 rs822339 genotype did not correlate with OS (HR, 0.77; 95% CI, 0.31–1.70; p = 0.55). The T/T genotype of rs1411262 also showed a significant prolongation of OS compared to that with the C/T or C/C genotypes in patients treated with nivolumab. Conclusions PD-L1 polymorphisms are associated with favourable OS in nivolumab-treated NSCLC patients and may be useful predictive biomarkers, regardless of driver mutation status.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Osimertinib is a key drug for cancer patients with EGFR mutations. However, there is little information about its safety in cancer patients who require hemodialysis (HD) for chronic renal failure, despite notable increases in their numbers. Herein, we examined osimertinib safety in such a patient via pharmacokinetics analysis. A 66-year-old man was diagnosed with relapsed stage IV non-small cell lung cancer with an EGFR mutation in exon 21 (L858R) 2 years after stereotactic body radiotherapy. He was undergoing HD three times a week owing to worsening diabetic nephropathy. We administered osimertinib (80 mg/day) as the first-line therapy. We measured osimertinib concentrations on multiple days, either before, after, or in the absence of HD. Maximum concentrations and areas under the curve were determined. We found that HD did not affect the pharmacokinetics of osimertinib. We conclude that osimertinib can be safely administered to cancer patients undergoing HD.

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39–91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0–1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50–74%, 75–89%, and 90–100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0–1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05–2.72; p = 0.03138), CRP/Alb (

Background Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. Methods We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. Results Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. Conclusions Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

Background Detailed differences in clinical information between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia (CP), which is the main phenotype of SARS-CoV-2 disease, and influenza pneumonia (IP) are still unclear. Methods A prospective, multicenter cohort study was conducted by including patients with CP who were hospitalized between January and June 2020 and a retrospective cohort of patients with IP hospitalized from 2009 to 2020. We compared the clinical presentations and studied the prognostic factors of CP and IP. Results Compared with the IP group (n = 66), in the multivariate analysis, the CP group (n = 362) had a lower percentage of patients with underlying asthma or chronic obstructive pulmonary disease (P < .01), lower neutrophil-to-lymphocyte ratio (P < .01), lower systolic blood pressure (P < .01), higher diastolic blood pressure (P < .01), lower aspartate aminotransferase level (P < .05), higher serum sodium level (P < .05), and more frequent multilobar infiltrates (P < .05). The diagnostic scoring system based on these findings showed excellent differentiation between CP and IP (area under the receiver operating characteristic curve, 0.889). Moreover, the prognostic predictors were different between CP and IP. Conclusions Comprehensive differences between CP and IP were revealed, highlighting the need for early differentiation between these 2 pneumonias in clinical settings.

Immune checkpoint inhibitors (ICIs) are effective for previously treated patients with advanced non-small cell lung cancer (NSCLC). However, an unconventional response pattern is sometimes encountered. A dissociated response (DR), characterized by some lesions shrinking and others growing, has been recognized with ICI treatment. In this study, we examined the characteristics and treatment outcomes of DR in previously treated NSCLC patients, receiving nivolumab monotherapy. We conducted a retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab. We assessed the tumor response of each organ using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria at the first radiologic evaluation. We investigated treatment outcome and compared overall survival using the Kaplan-Meier Method and log-rank tests. Further, we conducted the same analysis in patients who had previously received chemotherapy or tyrosine kinase inhibitor therapy in our hospital. Between April 2016 and September 2018, 107 patients who received nivolumab fulfilled the inclusion criteria. Of them, 5 (5%) patients showed a DR. There were no specific differences in characteristics between DR and non-DR cases. Patients showing DR had significantly longer overall survival than those showing concordant progressive disease (46.9 vs. 8.2 months, p = 0.038). The frequencies of DR in the ICI, chemotherapy, and tyrosine kinase inhibitor-treated cohorts were 5%, 1%, and 4%, respectively. DR was uncommon, but this presented a distinctive pattern of nivolumab response. Some patients might benefit from continuing nivolumab therapy and may achieve a longer overall survival.

Background: Serum levels of KL-6 are useful biomarkers for diagnosis of interstitial lung diseases (ILDs). However, its diagnostic utility in the setting of acute respiratory failure (ARF) is unknown. Aims and Objectives: We investigated how high serum KL-6 levels contributed to the differential diagnosis of ARF. Methods: We retrospectively examined consecutive 138 patients who were admitted to our department for the treatment of ARF with bilateral pulmonary infiltrates and were evaluated for serum KL-6 levels, from April 2015 to July 2018. Patients with apparent preexisting pulmonary fibrosis were excluded. Results: KL-6 values were high (≥ 500 U/mL) in 52 patients. Pulmonary diseases responsible for high KL-6 levels were detected in all patients of the high KL-6 group; ILDs associated with connective tissue diseases in 11 patients, latent chronic ILDs in 10 patients, drug-induced ILDs in 9 patients, pneumocystis pneumonia in 5 patients, radiation pneumonitis in 4 patients, and other etiologies in 13 patients. These KL-6-elevating diseases were the direct causes of ARF in 40 (77%) patients in the high KL-6 group compared to 22 (26%) patients in the normal KL-6 group (p Conclusions: In ARF with bilateral pulmonary shadows and no apparent chronic fibrotic lesions, elevated serum KL-6 levels could be a marker of causative diseases other than bacterial pneumonia that often require steroid therapy.

Background Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR-mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing. Methods We examined 132 patients with EGFR-mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR-positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide. Results The positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection. Conclusions Cobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.

Introduction Previous studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non–small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes. Patients and Methods We prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS). Results In the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts. Conclusion Our results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.

BACKGROUND/AIM The expression of programmed cell death ligand 1 (PD-L1) determined by immunohistochemistry (IHC) may be associated with tissue formalin fixation time in non-small cell lung cancer (NSCLC) samples. We investigated the association between the PD-L1 expression and formalin fixation time, and clarified the optimal duration of fixation for accurate PD-L1 evaluation. MATERIALS AND METHODS We collected 55 tumor specimens from resected NSCLC patients. The samples were halved and immediately fixed in 10% buffered formalin for 12-24 h (normal fixation), or 96-120 h (prolonged fixation). Each specimen was stained using two assay systems (22C3 and SP263) for PD-L1. RESULTS The mean PD-L1 tumor proportion score was not significantly different between normal and prolonged fixation groups for either 22C3 or SP263 (normal fixation: 18.8%; prolonged fixation: 16.3%, p=0.277; normal fixation: 16.2%; prolonged fixation: 17.6%, p=0.560, respectively). CONCLUSION Formalin fixation duration for up to 120 h does not affect PD-L1 IHC expression. PD-L1 tumor proportion score of tumor specimens can be evaluated by IHC even if these have been fixed in formalin outside the recommended duration in clinical practice.

Recently, based on results of the PACIFIC trial, durvalumab after chemoradiotherapy (CRT) became the standard therapy for unresectable stage III non-small cell lung cancer (NSCLC). However, in the PACIFIC trial, patients were recruited and randomized after CRT, and certain patients were considered ineligible after CRT in the real world. No study has been conducted on the patients who were ineligible for the PACIFIC trial, and hence, we conducted a retrospective study on them. We identified 82 patients with stage III NSCLC who received definitive platinum-based concurrent CRT and had World Health Organization performance status of 0–1. We investigated the proportion, clinical characteristics, and prognoses of patients who became ineligible for the PACIFIC trial after CRT. After CRT, 19 of 82 patients (23%) became ineligible for the PACIFIC trial. Comparison between eligible and ineligible patients revealed that old age (p = 0.042), male gender (p = 0.031), and radiation therapy with V20 ≥ 35% (p = 0.032) were associated with ineligibility after CRT. Moreover, ineligible patients showed shorter PFS (6.6 vs. 15.7 months, hazard ratio [HR] 2.61, 95% confidence interval [CI] 1.16–5.89, p = 0.016) and shorter OS (18.6 vs. 44.3 months, HR 3.03, 95% CI 1.29–7.10, p = 0.007) than eligible patients. Our study revealed the clinical characteristics and prognoses of patients who became ineligible for the PACIFIC trial after CRT. Physicians should be careful while prescribing CRT for patients with characteristics such as old age, male gender, and radiation therapy with V20 ≥ 35%.

Background It would be useful to have criteria for predicting long-term treatment responses to immune checkpoint inhibitors (ICIs). Maximum depth of response correlates with treatment outcomes among patients receiving programmed death protein 1 axis inhibitors for non-small cell lung cancer (NSCLC). We investigated associations between early depth of response and survival outcomes among patients receiving nivolumab for NSCLC. Methods Using records from prospective observational cohorts, we identified 83 previously treated advanced patients with NSCLC who received nivolumab during 2016–2017. Thirty-one patients who achieved disease control were analyzed. Tumor assessments followed the Response Evaluation Criteria in Solid Tumors (RECIST). Using Kaplan-Meier and receiver operating characteristic (ROC) curve analyses, treatment outcomes were compared with percent tumor reductions from baseline to the first evaluation (8–12 weeks after starting nivolumab). Results Early depth of response was predictive of 6-month progression-free survival (area under the ROC curve, 0.848). Based on ROC results, early tumor shrinkage was defined as a > 10% reduction by the first evaluation. Early tumor shrinkage was associated with significantly longer median progression-free survival (early tumor shrinkage: 16.6 months, 95% confidence interval [CI] 8.5 months–not reached; no early shrinkage: 5.1 months, 95% CI 3.9–6.8 months; P

ROS1 gene arrangements occur in approximately 1% to 2% of non-small cell lung cancers. Crizotinib, the ROS1-tyrosine kinase inhibitor (TKI), has been approved for ROS1-rearranged lung cancer based on its dramatic therapeutic effect, but cures are usually not achieved. We have been focused on relationships between Yes associated protein1 (YAP1) and resistance to molecular target drugs. YAP1, a main mediator of the Hippo pathway, promotes cell proliferation and epithelial-mesenchymal transition and is associated with drug resistance in some cancer types. We previously demonstrated that YAP1 mediates survival against alectinib therapy in anaplastic lymphoma kinase-rearranged lung cancer cells. Then, in this study, we evaluated the role of YAP1 as an initial survival mechanism from lorlatinib in ROS1-rearranged lung cancer. We established a patient-derived EZR-ROS1-rearranged lung cancer cell line (KTOR71) from pleural effusion of a patient who acquired resistance to crizotinib. Subsequently, we conducted functional analysis of YAP1 involvement in drug-resistance, using this patient-derived cell line. DNA sequencing confirmed that KTOR71 cells harbored EZR-ROS1 fusion and ROS1 S1986F mutation, which is known crizotinib resistance mutation. KTOR71 cells were sensitive to lorlatinib, while resistant to crizotinib in cell viability assay (CVA). Nuclear localization of YAP1, which is an activation marker of YAP1, was assessed using immunofluorescence staining. In KTOR71 cells, YAP1 was activated after lorlatinib exposure. Then, to evaluate functional role of YAP1 in the initial survival against lorlatinib, the genetic inhibition of YAP1 in KTOR71 cells were performed using small interfering RNA (siRNA). Silencing of YAP1 by siRNA enhanced sensitivity to lorlatinib in KTOR71 cells in CVA. Furthermore, to confirm this functional role of YAP1 in vivo, we established the KTOR71 cell-derived xenograft model. The combination therapy with lorlatinib and verteporfin, an inhibitor of YAP1-TEAD interaction, sustained tumor remission significantly compared with lorlatinib monotherapy in vivo. Finally, we found that AKT was reactivated with activation of YAP1 and silencing of YAP1 by siRNA suppressed this AKT reactivation. These results suggest that YAP1 may be a potential drug target for ROS1-rearranged lung cancer. Citation Format: Masatoshi Yamazoe, Hiroaki Ozasa, Tetsuya Ohgimoto, Kazutaka Hosoya, Hitomi Ajimizu, Tomoko Funazo, Yuto Yasuda, Takahiro Tsuji, Hironori Yoshida, Ryo Itotani, Yuichi Sakamori, Young Hak Kim, Hirai Toyohiro. Activation of YAP1 confers ROS1 inhibitor resistance in ROS1-rearranged lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1098.

Background/aim While the PD-L1 22C3 pharmDx assay is an FDA-approved diagnostic assay for pembrolizumab use, not every pathology laboratory has the Dako Autostainer to use this assay. Since Ventana BenchMark platforms are more common, the Ventana SP263 assay can be used to inform treatment decisions involving nivolumab and pembrolizumab in non-small cell lung cancer (NSCLC). However, some studies have shown discordant results between the two assays. This study aimed was to compare PD-L1 expression using these two assays. Materials and methods A total of 100 samples from consecutive cases of resected NSCLC were tested using the two PD-L1 assays. Results The agreement rates of the two assays were 88-97% at various cut-offs. There was no significant difference between 22C3 and SP263 in tumour proportion score (p=0.455). Conclusion The SP263 assay can be used in the place of the 22C3 assay for PD-L1 testing, for guiding therapy with PD-1 axis inhibitors in NSCLC.

Background: Usual gait speed over 4-meter (4mGS) is a simple functional performance measure in older adults. The reliability and validity of the 4mGS has recently been demonstrated in patients with COPD, but there are few data in interstitial pneumonia (IP). Object: To evaluate the correlation between the 4mGS and 6-minute walk test (6MWT) in IP patients. Their underlying physiological factors were also examined. Method: In 52 IP patients, the 4mGS and 6MWT were prospectively performed. Other measurements included the health-related quality of life, modified Medical Research Council (MRC) score, arterial blood gas analyses, pulmonary function tests, muscle strength of skeletal muscle index, and physical activity. Result: 35 patients were male (68.6%) and 34 patients had IPF (66.7%). There was a significant correlation between the 4mGS and 6-minute walk distance (6MWD) (r = 0.57, P Conclusions: The 4mGS was a simple and reliable measure for IP patients.