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Introduction: Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1—predictive markers for response to various immune checkpoint inhibitors in NSCLC—have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. Methods: In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. Results: The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. Conclusions: In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.

Introduction: EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. Methods: We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab. Results: Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab. Conclusions: Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.

Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma. Methods: This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry. Results: The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1–positive groups than in TTF-1–negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1–positive groups than in TTF-1–negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1–positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02). Conclusions: TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.

Introduction: In recent years, programmed cell death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy was found to have favorable clinical outcomes in patients with extensive-stage SCLC (ES-SCLC). The usefulness of early tumor shrinkage (ETS) has been reported in various types of cancers. Nevertheless, there have been few reports evaluating ETS in ES-SCLC. Therefore, this study aimed to evaluate the role of ETS in the clinical outcomes of patients with ES-SCLC receiving chemoimmunotherapy. Methods: We prospectively identified 46 patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy at 10 institutions in Japan between September 2019 and October 2021. Of them, 35 patients were selected for analyses. Results: The responders (progression-free survival [PFS] ≥ 6.0 mo) had significantly greater tumor shrinkage at the first evaluation than the nonresponders (PFS < 6.0 mo) (65.0% versus 53.7%, p = 0.03). We defined the cutoff value for ETS as a 57% change from the baseline on the basis of the receiver operating characteristic results to determine the optimal tumor shrinkage rate at the first evaluation for identifying responders. The patients with ES-SCLC who achieved ETS had longer PFS and overall survival than those who did not achieve ETS (5.6 versus 4.0 mo, log-rank test p = 0.001 and 15.0 versus 8.3 mo, log-rank test p = 0.02). In the multivariate analyses, ETS was significantly associated with PFS and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.12–0.63, p = 0.002 and hazard ratio = 0.34, 95% confidence interval: 0.13–0.85, p = 0.02). Conclusions: Our prospective observational study indicated that ETS was related to favorable clinical outcomes for patients with ES-SCLC receiving PD-L1 inhibitor plus platinum-etoposide chemotherapy.

Introduction: The use of immune checkpoint inhibitors (ICIs) with chemotherapy has increased the survival of patients with advanced NSCLC. Nevertheless, the efficacy of ICI treatment for NSCLC with EGFR mutations is limited. Previous studies have not evaluated the efficacy of ICI treatment after osimertinib treatment in real-world settings. Methods: This study performed a retrospective analysis of the association between clinical characteristics and ICI efficacy in patients with EGFR-mutant NSCLC treated with ICIs after osimertinib treatment at 12 institutions in Japan from March 2016 to March 2021. Results: Among 80 patients with EGFR-mutant lung cancer, 42 received ICI monotherapy and 38 received chemoimmunotherapy. In the chemoimmunotherapy group, the progression-free survival (PFS) was significantly longer in the group that exhibited PFS more than 10 months with osimertinib than in the group that exhibited PFS less than or equal to 10 months with osimertinib (8.4 mo versus 3.8 mo, p = 0.026). Nevertheless, there was no significant difference in PFS in the ICI monotherapy group (1.7 mo versus 1.5 mo, p = 0.45). Regardless of the EGFR mutation subtype, PFS of osimertinib treatment was a predictor of the PFS of chemoimmunotherapy (exon 19 deletion mutation: p = 0.03 and exon 21 L858R mutation: p = 0.001). Conclusions: The PFS of osimertinib might be a predictor of PFS of chemoimmunotherapy in patients with EGFR-mutant NSCLC. Further clinical investigations on the predictors of efficacy of administering ICIs after osimertinib treatment are required.

Introduction: To date, the efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy for patients with extensive-stage SCLC (ES-SCLC), with real-world evidence, stratified on the basis of age and performance status (PS), have not been fully investigated. The aim of this study was to evaluate the efficacy and safety of PD-L1 inhibitor plus platinum-etoposide chemotherapy in patients with ES-SCLC. Methods: This multicenter prospective study evaluated patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy between September 2019 and October 2021. Results: A total of 45 patients with ES-SCLC received the aforementioned treatment, including 18 elderly (≥75 y old) patients and six patients with a PS of 2. Multivariate analysis indicated that a PS of 2 was a significant independent prognostic factor for progression-free survival and overall survival (p = 0.008 and p = 0.001, respectively). Of patients with PS of 2 at the initial phase, those that achieved PS improvement during treatment had significantly longer progression-free survival and overall survival than those who did not (p = 0.02 and p = 0.02, respectively). The incidence of adverse events accompanied with treatment discontinuation was significantly higher in the elderly patients than in the non-elderly patients (p = 0.03). Conclusions: This real-world prospective study found that PD-L1 inhibitor plus platinum-etoposide chemotherapy had limited efficacy in patients with ES-SCLC with a PS of 2, except for cases with improvement of PS during treatment. Owing to the emergence of adverse events and treatment discontinuation, this treatment should be administered with caution in elderly patients with ES-SCLC.

Introduction This study aimed to describe the course of patients with lung cancer from treatment initiation to end-of-life. Methods This retrospective cohort study used Claims Data from the National Health Insurance and Advanced Elderly Medical Service System. We analyzed data from patients newly diagnosed with lung cancer between April 2013 and March 2021 who had been hospitalized at our University Hospital in urban area. We evaluated (1) treatment courses of these patients, and (2) end-of-life care and clinical factors related to end-of-life care. Results A total of 818 patients who were diagnosed with lung cancer and received lung cancer treatment were included, of whom 200 were assessed for end-of-life. During the study period, 464 patients underwent surgery, while 308 received chemotherapy without undergoing surgery. The patients generally received lung cancer treatment within 2 years. The median time from initial treatment to death was 13 months for deceased patients. Patients in the palliative care unit (PCU) constituted 9% at 30 days before death, 25% at 7 days before death, and 40.5% on the day of death, whereas only 15% died at home. The prevalence of end-of-life care in the home/PCU was elevated among patients receiving molecular targeted drugs and in the female group. Conclusion This study highlighted the patterns of end-of-life care following lung cancer treatment by using Claims Data. PCU utilization was concentrated in the period shortly before death, with fewer patients passing away at home. End-of-life care may be influenced by clinical factors, including the type of lung cancer treatment received, which may change the place of care.