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PurposeThis phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma.MethodsPembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review.ResultsForty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3–5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3–5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3–43.5) for cutaneous melanoma and 25.0% (95% CI 3.2–65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma.ConclusionThe safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.

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Human ␥-aminobutyric acid type A (GABA A ) receptors were expressed in the baculovirus/Sf-9 insect cell expression system using recombinant cDNA of ␣ 1 ␤ 2 ␥ 2s subunits. ؊6 M or higher, gradually suppressed the peak amplitude of GABA response. A protein kinase A inhibitor, a protein kinase C inhibitor, and a Ca 2؉ chelator did not modify the effects of DHA on GABA-induced chloride ion current. Six unsaturated fatty acids other than DHA were examined. Arachidonic acid mimicked the effect of DHA while e.g. oleic acid had no effect.The inhibition of the GABA response in the presence of DHA was also observed in cells expressing GABA A receptors of ␣ 1 and ␤ 2 subunit combinations. The data show that the ␥ subunit is essential for DHA and arachidonic acid to potentiate the GABA-induced Cl ؊ channel activity and to affect the desensitization kinetics of the GABA A receptor.Polyunsaturated fatty acids are essential fatty acids that are abundantly bound in the phospholipids of brain membranes. The fatty acids influence the membrane fluidity of the neuronal plasma membrane as well as the functional properties of integral membrane protein (1). Arachidonic acid (AA) 1 and docosahexaenoic acid (DHA) are polyunsaturated fatty acids localized in the 2-position of membrane phospholipids and are liberated by various intracellular enzymes such as phospholipase A 2 and diacylglycerol lipase (2).Recently, various actions of these free fatty acids on the functional properties of neuronal plasma membrane neurotransmitter receptors have been reported, such as N-methyl-Daspartic acid receptor (3, 4), kainate receptor (4), and potassium channel receptor (5, 6). As for the effect of unsaturated fatty acids on ␥-aminobutyric acid type A (GABA A ) receptors, an electrophysiological study demonstrated that AA and DHA potently suppressed the GABA A receptor-mediated current response in the rat substantia nigra neurons (7). Receptor binding studies have shown marked effects of unsaturated fatty acids on brain GABA A receptor complexes in vitro (8 -11), as well as on human recombinant GABA A receptors expressed in Sf-9 insect cells (12). These findings suggest a variety of actions of fatty acids on the GABA A receptor-channel complex. The diversity of effects induced by free fatty acids might be due to ontogenetic, phylogenetic, and regional differences of the GABA A receptor subunit composition in the brain regions studied (13). Furthermore, a recent study on recombinant human GABA A receptors (12) reported that the effect of unsaturated fatty acids was dependent on the subunit composition of the GABA A receptor complexes. In addition, various combinations of GABA A receptor subunits might be expressed in the same neuron, complicating the interpretation of data on the effect of free fatty acids on the GABA A receptor complex obtained at the level of single cells, as, for example, by whole cell patch clamp techniques.The insect cell Sf-9/baculovirus expression system in combination with electrophysiological techniques provide the means for t...

Pembrolizumab plus pemetrexed‐platinum significantly improved overall survival (OS) and progression‐free survival (PFS) with manageable safety compared with placebo plus pemetrexed‐platinum in patients with previously untreated metastatic nonsquamous non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double‐blind, phase 3 KEYNOTE‐189 study. We present results of Japanese patients enrolled in the KEYNOTE‐189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed‐platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed‐platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune‐mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first‐line therapy with pembrolizumab plus pemetrexed‐platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.