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Introduction: Osimertinib is used as the first-line treatment for EGFR mutation-positive NSCLC. Nevertheless, its efficacy and safety in clinical practice remain to be fully elucidated and the pattern of progression and the optimal subsequent treatment after osimertinib remains unclear. Methods: This was a multicenter prospective observational study. EGFR mutation-positive patients with NSCLC who started first-line osimertinib from September 2018 to August 2020 were enrolled and followed up until August 2022. Results: A total of 583 patients received osimertinib. The median progression-free and overall survival were 20.0 (95% confidence interval [CI]: 17.6–21.7) months and 41.0 (95% CI: 37.1–44.1) months, respectively. Grade 3 or worse adverse events were observed in 136 patients (23.3%). Progression patterns were categorized as central nervous system only, oligo-progression, and multiple organs on the basis of the Response Evaluation Criteria in Solid Tumors—progressive disease and occurred in 37 (10.8%), 156 (45.4%), and 151 patients (43.9%). The patient’s condition on progression was asymptomatic in 195 patients (56.7%). Osimertinib was continued in 163 patients (47.4%) after confirming progression. In clinically stable population with progressive disease (n = 247), survival after progression was 13.3 (95% CI: 10.9–16.4) months for those who continued osimertinib beyond progressive disease (n = 124), and 24.1 (95% CI: 17.7–34.0) months for those who discontinued osimertinib (n = 123) (hazard ratio = 2.01, 95% CI: 1.38–2.91, p = 0.0002). Platinum plus pemetrexed had the best overall survival benefits after osimertinib. Conclusions: First-line osimertinib was found to have good effectiveness comparable to that reported in pivotal studies. Nevertheless, osimertinib should be discontinued among those who develop progression. Trial registration number: UMIN000038683

Introduction: Although pretreatment autoantibodies have been associated with immune-related adverse events (irAEs) and immune checkpoint inhibitor treatment efficacy in some types of cancer, their importance has not been evaluated in patients with SCLC. Methods: A multicenter prospective observational study was conducted on a total of 52 patients with extensive-disease SCLC who received immune checkpoint inhibitors in combination with chemotherapy as the first-line treatment at either of the six participating centers in Japan. Pretreatment serum samples were collected and analyzed for autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid). Moreover, 12 antineuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD65, and Tr) were analyzed using immunoblot assays. The primary end point was the incidence of irAEs with or without autoantibodies. The secondary end points were progression-free survival (PFS) and overall survival (OS) on the basis of the presence or absence of autoantibodies. Results: PFS and OS were 4.4 and 25.3 months, respectively. Autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid antibodies) were detected in 29 patients (56%). In total, irAEs were observed in 18 patients (35%); irAE incidence was 48% in the autoantibody-positive group and 17% in the autoantibody-negative group (p = 0.039). There was no difference in PFS or OS between patients with and without autoantibodies (4.4 mo versus 4.6 mo, p = 0.36; 15.3 mo versus 18.2 mo, p = 0.36). Antineuronal antibodies were detected in 16 patients (31%). However, the development of neurologic irAEs was not observed in both groups. Conclusions: Vigilance is required against the development of irAEs in pretreatment antibody-positive patients.

Introduction: Pembrolizumab became available in Japan in February 2017 for first-line monotherapy of unresectable advanced and metastatic NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. This retrospective chart review study aimed to describe real-world clinical outcomes of first-line pembrolizumab monotherapy, including for patients 75 years or older, who are under-represented in clinical trials. Methods: We identified patients (≥20 y old) at 23 sites initiating first-line pembrolizumab monotherapy from July 1, 2017, to December 20, 2018, for stages IIIB, IIIC, and IV NSCLC with PD-L1 TPS greater than or equal to 50% and Eastern Cooperative Oncology Group performance status of 0 to 2 or unknown. Patients with actionable genomic alterations (EGFR, ALK, ROS1, BRAF) and clinical trial participants were excluded. Time-to-event outcomes were estimated using Kaplan-Meier, with data cutoff on September 30, 2019. Results: Of 441 eligible patients (78% men), 303 (69%) were younger than 75 years and 138 (31%) were 75 years or older; median age was 70 years. With median follow-up of 13.5 months, median overall survival (OS) was not reached (NR); 12- and 24-month OS rates were 72% and 58%, respectively. For ages younger than 75 and 75 years or older, median OS was NR and 23.5 months (95% confidence interval: 16.2–NR), respectively; 12-month OS rates were 74% and 67% and 24-month OS rates were 62% and 48%, respectively. Median real-world progression-free survival was similar in the two age groups (10.1 and 9.5 mo, respectively), as was median real-world time on treatment with pembrolizumab (5.7 and 5.6 mo). Conclusions: These findings complement clinical trial results, adding real-world evidence supporting benefits of first-line pembrolizumab monotherapy for advanced NSCLC with PD-L1 TPS greater than or equal to 50%, including for patients 75 years or older.

Introduction: The real-world effectiveness of combination treatment with cytotoxic chemotherapy and programmed cell death protein-1 or programmed death-ligand 1 inhibitor for NSCLC, especially for the elderly (aged ≥75 y) or those with poor performance status (≥2), has not been fully elucidated. We investigated the real-world effectiveness and safety of this combination therapy in these populations. Methods: This multicenter retrospective study evaluated patients who are chemo-naïve with advanced NSCLC who received a combination of platinum, pemetrexed, and pembrolizumab between December 2018 and June 2019. This was an updated prespecified secondary analysis with the primary objective of investigating the safety and effectiveness in this cohort. Results: Overall, 299 patients were included. Multivariate analysis identified performance status (0–1) and programmed death-ligand 1 tumor proportion score (≥50%) as significant independent predictors of progression-free survival (p = 0.007, and p = 0.003, respectively). The incidence of severe adverse events (AEs) was higher in the elderly and those with poor performance status than in their younger and good performance status counterparts. A total of 71 patients developed AEs that led to treatment discontinuation, and AE-related treatment discontinuation occurred at a significantly higher rate in older patients (median [range]) (70 [46–82] y) than in younger patients (68 [31–84] y) (p

Abstract: Lysophosphatidic acid (LPA) is a potent signaling lipid, and state-dependent alterations in plasma LPA make it a promising diagnostic marker for various diseases. However, plasma LPA concentrations vary widely among reports, even under normal conditions. These variations can be attributed, at least in part, to the artificial metabolism of LPA after blood collection. Here, we aimed to develop an optimized plasma preparation method that reflects the concentration of LPA in the circulating blood. The main features of the devised method were suppression of both LPA production and degradation after blood collection by keeping whole blood samples at low temperature followed by the addition of an autotaxin inhibitor to plasma samples. Using this devised method, the LPA level did not change for 30 min after blood collection. Also, human and mouse LPA levels were found to be much lower than those previously reported, ranging from 40 to 50 nM with minimal variation across the individual. Finally, the increased accuracy made it possible to detect circadian rhythms in the levels of certain LPA species in mouse plasma. These results demonstrate the usefulness of the devised plasma preparation method to determine accurate plasma LPA concentrations.

Lysophosphatidic acids (LysoPAs) and lysophosphatidylserine (LysoPS) are emerging lipid mediators proposed to be involved in the pathogenesis of acute coronary syndrome (ACS). In this study, we attempted to elucidate how LysoPA and LysoPS become elevated in ACS using human blood samples collected simultaneously from culprit coronary arteries and peripheral arteries in ACS subjects. We found that: 1) the plasma LysoPA, LysoPS, and lysophosphatidylglycerol levels were not different, while the lysophosphatidylcholine (LysoPC), lysophosphatidylinositol, and lysophosphatidylethanolamine (LysoPE) levels were significantly lower in the culprit coronary arteries; 2) the serum autotaxin (ATX) level was lower and the serum phosphatidylserine-specific phospholipase A1 (PS-PLA1) level was higher in the culprit coronary arteries; 3) the LysoPE and ATX levels were significant explanatory factors for the mainly elevated species of LysoPA, except for 22:6 LysoPA, in the peripheral arteries, while the LysoPC and LysoPE levels, but not the ATX level, were explanatory factors in the culprit coronary arteries; and 4) 18:0 and 18:1 LysoPS were significantly correlated with PS-PLA1 only in the culprit coronary arteries. In conclusion, the origins of LysoPA and LysoPS might differ between culprit coronary arteries and peripheral arteries, and substrates for ATX, such as LysoPC and LysoPE, might be important for the generation of LysoPA in ACS.