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Background Osimertinib is one of the standard first-line treatments for advanced non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) mutations, because it achieves significantly longer progression-free survival (PFS) than conventional first-line treatments (hazard ratio: 0.46). However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remain unclear. Methods This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. The primary endpoint was 1-year PFS rate; secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Results Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%), which did not meet the primary endpoint (the threshold 1-year PFS rate of 50% predicted using data from the NEJ003 study). The most common grade 3/4 adverse events were rash/dermatitis acneiform/ALT increased/hypokalemia (2 patients, 5%). Seven patients developed pneumonitis (17.5%). There were no other cases of treatment discontinuation due to adverse events other than pneumonitis. Conclusion Although this study did not meet the primary endpoint, osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer. (Japan Registry of Clinical Trials [JRCT] ID number: jRCTs071180007).

Purpose The primary objective of this study was to identify the potential predictors to assess impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). Methods We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at eight hospitals in Japan between January 2019 to December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune-checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. Results Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). Conclusions This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

BackgroundIn recent years, immune checkpoint inhibitors (ICIs) in combination with chemotherapy have increased survival in patients with advanced non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF), which plays a key role in tumor angiogenesis, is an immunological modulator; therefore, it is expected that anti-VEGF therapy in combination with ICIs enhances the antitumor effect of ICIs. In the present study, we investigated the impact of VEGF inhibition on clinical outcomes of NSCLC patients, including the efficacy of ICI treatment.MethodsA total of 105 patients with advanced NSCLC who had been treated with ICIs were retrospectively analyzed to examine the relationship between the history of treatment with anti-VEGF agents and the clinical outcomes with ICI monotherapy.ResultsPatients who had received anti-VEGF therapy prior to ICIs showed shortened progression-free survival of ICI treatment and a decreased overall response rate to ICI treatment. By contrast, anti-VEGF therapy after ICI treatment was associated with increased survival, especially in patients who had also received anti-VEGF therapy prior to ICI therapy.ConclusionsThese retrospective observations suggest that anti-VEGF therapy prior to ICIs might be a negative predictor of response to ICIs. The sequence of anti-VEGF therapy might play a role in its ability to predict survival in NSCLC patients. Further investigation is warranted to identify the role of VEGF inhibition in altering clinical outcomes after immunotherapy.

BackgroundThe immunotherapy plus chemotherapy combination is one of the most promising treatments in advanced non-small-cell lung cancer (NSCLC). Immunotherapy often causes immune-related adverse events (irAEs), which have been reported to be associated with the good clinical outcomes. However, the effects of immunotherapy plus chemotherapy remain unknown. In this study, we investigated the association between irAEs caused by immunotherapy plus chemotherapy and clinical efficacy in patients with advanced NSCLC.Materials and MethodsWe retrospectively analyzed the data of patients with advanced NSCLC, who received a combination of immunotherapy plus chemotherapy at six institutions in Japan between January 2019 and September 2019. We examined the effect of irAEs on various clinical outcomes.ResultsWe included 70 patients with advanced NSCLC. Patients were divided into two groups: patients with irAEs and patients without irAEs. Patients with irAEs had significantly longer progression-free survival than those without irAEs on univariate (hazard ratio 0.53, 95% confidence interval 0.30–0.93, p = 0.026) and multivariate (hazard ratio 0.53, 95% confidence interval 0.29–0.97, p = 0.041) analyses. In addition, patients with grade 1–2 irAEs (mild irAEs) had significantly longer progression-free and overall survival than those with grade 3-5 irAEs (severe irAEs) or without irAEs on univariate (398 days versus 189 days, respectively; p = 0.0061) and multivariate (not reached versus 412 days, respectively; p = 0.021) analyses.ConclusionPatients with NSCLC who experienced mild irAEs showed better response to treatment with immunotherapy plus chemotherapy than those with severe irAEs or without irAEs. Further large-scale research is warranted to confirm these findings.

Combined immunotherapy and chemotherapy is a promising standard treatment in patients with advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the relationship between the combined therapy and pretreatment serum antinuclear antibody (ANA) levels as a prognostic indicator in patients with NSCLC. We retrospectively analyzed patients with advanced NSCLC who were treated with combinatorial immunotherapy and chemotherapy between January and December 2019 at six institutions in Japan. Relationship between ANA status and patients’ characteristics were reviewed. A total of 77 patients with advanced NSCLC were enrolled in the study. Patients were divided into ANA-positive (ANA ≥ 1:160) and ANA-negative (ANA

The (2R,5S)-trans- and (2S,5S)-cis-stereoisomers 1a and 1b of 4(5)-(5-aminotetrahydropyran-2-yl)imidazole, which have two chiral centers and adopt a stable chair conformation, were synthesized via cyclization of diol intermediates 7 using L-glutamine as the starting material. Their enantiomers, (2S,5R)-trans-1c and (2R,5R)-cis-1d, were synthesized by the same methodology from D-glutamine. Stereo isomers 1a-d were converted into cyanoguanidines 11a-d, and into N-isopropyl and N-3,3-dimethylbutyl derivatives 12a-d and 13a-d, respectively. The results of in vivo brain microdialysis of the derivatives apparently indicated that only (2S,5R)-isomers increased the release of neuronal histamine. Among the many (2S,5R)-N-alkyl derivatives, 13c (OUP-133) and 18 (OUP-153) increased histamine release to 180-190% and 180-200% of basal levels, respectively, and were found to be novel histamine H(3) antagonists.