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Background: In CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up. Methods: Adults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients. Results: At 62.1 months' minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%–75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed. Conclusions: At 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Patients with uncommon EGFR-mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR-mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety. Clinical trial registration: jRCTs071200002. [ABSTRACT FROM AUTHOR]

Introduction: MET exon 14 skipping mutation, observed in 3–4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years, immune checkpoint inhibitors (ICI) have been effective in treating several NSCLCs. Our research aimed to investigate the characteristics of patients with NSCLCs harboring MET exon 14 mutations and their response to ICI in Japan. Methods: Among the 1954 consecutive NSCLCs diagnosed at Saitama Cancer Center between 2010 and 2019, MET exon 14 skipping mutations were detected in 68 (3.5%) NSCLCs. We evaluated their characteristics such as programmed cell death ligand 1 (PD-L1) expression. Results: Median age of patients with NSCLCs harboring MET exon 14 skipping mutations was 73 years. PD-L1 was highly expressed in 17 (70.8%) of the 24 patients examined. Seven patients received ICI monotherapy, and three out of seven had a remarkable treatment response, resulted in objective response rate (ORR) of 42.9% and progression-free survival of 24.7 months. Three patients with donor splice-site mutations showed a long-term treatment response, despite the fact that two with acceptor splice-site mutations demonstrated no response and experienced early disease progression with ICI monotherapy. Conclusion: Our results indicated that patients with NSCLCs harboring MET exon 14 mutations presented with a high rate of positive PD-L1 expression. ICI treatment showed a high ORR and long-term efficacy for NSCLCs harboring MET exon 14 mutations. Variants of MET exon 14 splice-site mutations may be associated with ICI response. [ABSTRACT FROM AUTHOR]

Several features of Langmuir turbulence remain unquantified despite its potentially large impacts on ocean surface mixing. For example, its vertical velocity variance, expected to be proportional to based on numerical simulations, was proportional to in recent field observations, where is the friction velocity and is surface Stokes velocity. To investigate unquantified features of Langmuir turbulence, we conducted a field experiment around a marine observation tower in a shallow sea off the southern coast of Japan in early winter when winds and waves (often swells) were often misaligned. Coherent structures similar to Langmuir cells were successfully identified in the horizontal and vertical structures of turbulent flows measured with upward- and horizontally looking acoustic Doppler current profilers (ADCPs). ADCPs and several anemometers attached at the tower showed that turbulent vertical velocity variance was large when the Langmuir number and Hoenikker number (; where B is surface buoyancy flux and H is the water depth) were both small and that the orientation of the cells was generally aligned in the direction of Lagrangian current shear. These results agree well with the previous numerical results. As in the previous observations, however, the vertical velocity variance appeared to be proportional to . In our experiment, this curious feature was explained by compensatory effects between waves and convection. Misaligned wind with waves also seems to characterize the observed Langmuir turbulence, though further quantitative analysis is required to confirm this result. [ABSTRACT FROM AUTHOR]

This paper reports laboratory experiments and numerical simulations of river embankment failure due to overtopping flow for different sediment sizes and different saturation conditions of embankment body. The effects of saturation and sediment size of embankment materials on the erosion process are discussed based on the results of the laboratory experiments. A numerical model is proposed to simulate the erosion process of embankments by overtopping flows. The proposed model considered the effects of infiltration process and resisting shear stress due to suction of unsaturated sediment. To simulate the embankment erosion phenomenon, the numerical model consists of four modules: two-dimensional (2D) shallow-water flow, seepage flow, sediment transport using a non-equilibrium model framework, and 2D slope stability. The validity of the developed model is tested using experimental data on embankment erosion. The numerical results on progressive embankment erosion agree well with the results of the sandy river embankment experiments. [ABSTRACT FROM AUTHOR]