Efficacy and Safety of Salvage-line Nivolumab Monotherapy for Advanced Esophageal Squamous Cell Carcinoma: Comparison of 240 mg Versus 480 mg Doses.

BACKGROUND: Nivolumab monotherapy is the standard second-line treatment for advanced esophageal squamous cell carcinoma (ESCC) after failure of platinum-based chemotherapy without anti-PD-1 antibody. Fixed dosing with 240 mg every 2 weeks was approved initially, followed by fixed dosing with 480 mg every 4 weeks based on pharmacokinetics data. However, information on the comparative efficacy and safety of the two doses remains limited. METHODS: We compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) between the two doses in 117 patients who received second-line (n = 85) or later-line (n = 32) nivolumab monotherapy at our institution between January 2016 and December 2021. RESULTS: In the second-line group, patient characteristics for the 240 mg and 480 mg groups were as follows (240 mg vs. 480 mg): performance status (PS) 0/1/2 was 34/61/5% vs. 54/42/4%, and prior fluoropyrimidine plus platinum therapy (FP) was 81.3% vs. 42.3%. In the later-line group, the characteristics were: PS 0/1/2 was 28/60/12% vs. 14/86/0%, and prior FP was 60.0% vs. 42.8%. ORR was 11.9 vs. 24.0% in the second-line group (p = 0.19) and 0 vs. 14.3% in the later-line group (p = 0.22). Median PFS was 1.7 vs. 4.1 months on second-line (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35-1.01, p = 0.056) and 1.4 vs. 1.8 months on later-line (HR 0.58, 95% CI 0.23-1.46, p = 0.25); AEs of any grade were observed in 58.3 vs. 69.7%, respectively. CONCLUSIONS: The efficacy and safety of the two doses of nivolumab monotherapy were comparable in patients with advanced ESCC.

BRAF V600E-mutant colorectal cancer with CNS metastases treated successfully with encorafenib, binimetinib and cetuximab.

This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.

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Impact of immune checkpoint inhibitors on survival outcomes in advanced gastric cancer in Japan: A real-world analysis.

BACKGROUND: Nivolumab was approved for the treatment of advanced gastric cancer in 2017 in Japan. The aim of this study was to assess the impact of nivolumab in a real-world clinical setting. METHODS: This single-institutional retrospective study included patients with advanced gastric or esophagogastric junction adenocarcinoma and a history of first-line chemotherapy with platinum-based doublet or triplet regimens between 2010 and 2020. To assess the impact of nivolumab on survival, the patients were divided based on the year of nivolumab approval into a pre-2017 (2010-2016) group and a post-2017 (2017-2020) group. RESULTS: From a total of 1918 patients, 1093 were excluded. There were 533 patients in the pre-2017 group and 292 in the post-2017 group. Immune checkpoint inhibitors were used significantly more often in the post-2017 group than in the pre-2017 group (8.6% vs. 47.9%). Median overall survival was significantly longer in the post-2017 group (16.9 vs. 13.9 months; hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.63-0.90; p < 0.01). The proportion of patients transitioning to third-line treatment was higher in the post-2017 group than in the pre-2017 group (56.3% vs. 43.8%, p < 0.01). Median survival outcomes following progression on second-line treatment were significantly longer in the post-2017 group (4.3 vs. 3.2 months; HR 0.70, 95% CI 0.57-0.86; p < 0.01). CONCLUSION: The proportion of patients transitioning to third-line treatment and survival outcomes following progression on second-line treatment have improved since the approval of nivolumab. This drug might help to prolong overall survival in real-world practice.

Preoperative docetaxel, cisplatin, and 5-fluorouracil for resectable locally advanced esophageal and esophagogastric junctional adenocarcinoma.

BACKGROUND: Chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel is the standard perioperative treatment for resectable esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma (EGJ-AC) in Western countries. Meanwhile, preoperative chemotherapy consisting of docetaxel, cisplatin, and 5-fluorouracil (DCF) has been developed for esophageal squamous cell carcinoma in Japan. However, there are few reports on the safety and efficacy of preoperative DCF for resectable EGJ-AC in the Japanese population. METHODS: Patients with histologically confirmed resectable EGJ-AC who received preoperative DCF (docetaxel 70 mg/m2 and cisplatin 70 mg/m2 on day 1 and continuous infusion of 5-fluorouracil 750 mg/m2/day on days 1-5 every 3 weeks with a maximum of three cycles) between January 2015 and April 2020 were retrospectively evaluated. We assessed the rates of completion of ≥ 2 courses of DCF and R0 resection, histopathological response, progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Thirty-two patients were included. Median follow-up was 28.7 (range, 5.2-70.8) months and median age was 63 (range, 42-80) years. Twenty-one patients (66%) had a performance status of 0. The proportions of clinical stage IIA/IIB/III/IVA/IVB disease were 3%/0%/44%/44%/9%, respectively. The treatment completion rate was 84%. A histopathological response of grade 1a/1b/2/3 was obtained in 58%/26%/13%/3% of cases. Median PFS was 40.7 months (95% confidence interval 11.8-NA). Median OS was not reached (80.8% at 3 years). Grade ≥ 3 adverse events were observed in 63% of cases (neutropenia, 44%; febrile neutropenia, 13%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative DCF for resectable EGJ-AC was well tolerated and has promising efficacy.

Pembrolizumab for first-line treatment of advanced unresectable or metastatic esophageal or gastroesophageal junction cancer.

Esophageal cancer (EC) is the seventh most common malignancy worldwide. Although systemic chemotherapy is the standard treatment for advanced EC, the available cytotoxic agents have limited efficacy. Pembrolizumab, a humanized monoclonal immunoglobulin G4 antibody that inhibits programmed cell death protein 1, has recently been developed for the treatment of patients with advanced EC. In the KEYNOTE-181 trial, pembrolizumab achieved a clinical meaningful overall survival benefit over chemotherapy alone when used as second-line treatment in patients with esophageal squamous cell carcinoma (ESCC) who had a combined positive score ⩾10 for expression of programmed death ligand 1. Furthermore, KEYNOTE-590 showed that pembrolizumab + chemotherapy was more effective than chemotherapy alone as first-line chemotherapy for patients with advanced EC. Accordingly, immune checkpoint inhibitor (ICI) chemotherapy has become the standard first-line treatment for advanced EC. The use of ICIs in primary therapy has helped to improve the prognosis, especially for ESCC. Moreover, in CheckMate 577, patients who received postoperative nivolumab therapy had a reduced risk of recurrence, and the ability of preoperative ICI chemotherapy to reduce the incidence of recurrence is now under investigation. This review outlines the evidence for use of pembrolizumab as a first-line treatment for advanced unresectable or metastatic EC, summarizes the ongoing research on ICI combination chemotherapy, and discusses the associated issues.

Safety and short-term efficacy of preoperative FOLFOX therapy in patients with resectable esophageal squamous cell carcinoma who are ineligible for cisplatin.

BACKGROUND: The standard preoperative treatment for resectable locally advanced esophageal squamous cell carcinoma (LAESCC) in Japan is docetaxel, cisplatin (CDDP), and 5-fluorouracil. However, patients with renal or cardiac dysfunction and elderly patients are ineligible for a CDDP-containing regimen because of toxicities. Oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) therapy has less renal toxicity than CDDP-containing regimens and does not require hydration. However, there are limited data on preoperative FOLFOX therapy in these patients. METHODS: This retrospective study analyzed patients with resectable LAESCC who were aged ≥ 75 years or had renal or cardiac dysfunction and received preoperative FOLFOX between 2019 and 2021. FOLFOX was administered every 2 weeks for 3 or 4 cycles and was followed by surgery. Adverse events associated with chemotherapy, the complete resection (R0) rate, relative dose intensity (RDI), and histopathological response were evaluated. RESULTS: Thirty-five patients were eligible. Median age was 77 (range 65-89) years; 68.6% were aged ≥ 75 years, 74.3% had renal dysfunction, and 17.1% had cardiac dysfunction. The RDI was 70.2% and 87.1% for bolus and continuous intravenous 5-fluorouracil, respectively and 85.2% for oxaliplatin. The most common grade ≥ 3 adverse events were neutropenia (60.0%) and leucopenia (28.6%). Two patients (5.7%) had febrile neutropenia and grade 3 pneumonia. Thirty-one patients underwent surgery. The R0 resection rate was 87.1%, and there was no histopathological evidence of residual tumor in 16.1%. There were no treatment-related deaths. CONCLUSIONS: Preoperative FOLFOX had a manageable safety profile and showed favorable short-term efficacy in patients with resectable LAESCC who were ineligible for CDDP-containing treatment.

Emerging data on nivolumab for esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal cancer (EC) is the seventh most common malignancy in the world. The standard treatment for advanced EC patients is systemic chemotherapy, but few effective cytotoxic agents are available. Recently, nivolumab, a human monoclonal immunoglobulin G4 antibody that inhibits programmed cell death protein 1, has been tested for the treatment of advanced squamous cell carcinoma (ESCC) patients. The ATTRACTION-1 trial showed a promising efficacy of nivolumab monotherapy for advanced ESCC patients after prior chemotherapy. The ATTRACTION-3 phase III trial showed the superiority of nivolumab monotherapy over taxane monotherapy for advanced ESCC patients as a second-line treatment. The CheckMate-577 trial also showed survival benefits of postoperative nivolumab monotherapy in patients with resectable EC. AREAS COVERED: This review mainly outlines emerging data on nivolumab for patients with advanced ESCC after prior chemotherapy. Additionally, this review includes data from the CheckMate-577 trial for patients with resectable EC. EXPERT OPINION: Nivolumab has been approved by the US Food and Drug Administration for treatment after prior chemotherapy in patients with advanced ESCC. Several trials evaluating nivolumab-containing treatments are ongoing in patients with not only advanced EC, but also locally advanced EC, and these investigational treatments might improve the clinical outcomes of EC patients.

The large-scale production of an artificial influenza virus-like particle vaccine in silkworm pupae.

We successfully established a mass production system for an influenza virus-like particle (VLP) vaccine using a synthetic H5 hemagglutinin (HA) gene codon-optimized for the silkworm. A recombinant baculovirus containing the synthetic gene was inoculated into silkworm pupae. Four days after inoculation, the hemagglutination titer in homogenates from infected pupae reached a mean value of 0.8 million hemagglutination units (HAU), approximately 2,000 µg HA protein per pupa, more than 50-fold higher than that produced with an embryonated chicken egg. VLPs ranging from 30 nm to 300 nm in diameter and covered with a large number of spikes were detected in the homogenates. The spikes were approximately 14 nm long, similar to an authentic influenza HA spike. Detailed electron micrographs indicated that the VLP spike density was similar to that of authentic influenza virus particles. The results clearly show that the expression of a single HA gene can efficiently produce VLPs in silkworm pupae. When chickens were immunized with the pupae homogenate, the hemagglutination inhibition titer in their sera reached values of 2,048-8,192 after approximately 1 month. This is the first report demonstrating that a large amount of VLP vaccine could be produced by single synthetic HA gene in silkworm pupae. Our system might be useful for future vaccine development against other viral diseases.

Interactions of phytoestrogens with estrogen receptors alpha and beta (III). Estrogenic activities of soy isoflavone aglycones and their metabolites isolated from human urine.

Two glucuronides (4'-O-, and 7-O-) and a glucuronyl (7-O-) sulfate (4'-O-) of genistein, two glucuronides (4'-O-, and 7-O-) and a glucuronyl (7-O-) sulfate (4'-O-) of daidzein, 7-O-glucuronides of glycitein, dihydrodaidzein and O-desmethylangolensin were isolated from the urine of volunteer subjects fed soy bean curds (Tofu). The estrogenic activities, i.e., i) the effect on the estrogen-dependent growth of MCF-7 cells, ii) the binding ability to human estrogen receptors (hERs) alpha and beta, and iii) the effect on hER-dependent beta-galactosidase induction, of these isoflavone metabolites were examined. Two synthetic isoflavone aglycones (dihydrodaidzein and O-desmethylangolensin) and four synthetic sulfates (4'-O- and 4'-, 7-di-O-) of genistein and daidzein were also studied for their estrogenic activities for the purpose of comparison. With respect to estrogenic acivity, the tested isoflavone metabolites were classified into three groups. The first group shows a very poor stimulatory effect toward the growth of MCF-7 cells, binding activity, and beta-galactosidase induction. The sulfates belong to this group. The second group shows a moderate binding activity but poor stimulation and beta-galactosidase induction. Some glucuronyl conjugates belong to this group. The last group shows a moderate stimulation and beta-galactosidase induction but poor binding activity. A mixed type of conjugates having glucuronyl and sulfony moieties belong to this group.

Interaction of phytoestrogens with estrogen receptors alpha and beta (II).

We investigated the estrogenic activities of isoflavone derivatives in competition binding assays with human estrogen receptor (hER) alpha or hER beta protein, and in a gene expression assay using a yeast system. Coumestrol binds as strongly as 17beta-estradiol to both hERs. Biochanin A, 5-OMe-genistein, formononetin, and tectorigenin bind well to hER beta, but significant binding to hER alpha is only observed with 5-OMe-genistein, formononetin and tectorigenin. The binding of 7-OMe-genistein and irisolidone is poor to both receptors. Among the glucosides, sissotorin binds both receptors and the binding is stronger than genistin. Coumestrol induces transcription as strongly as genistein. Tectorigenin also induces transcription with both hERs. Though biochanin A, 5-OMe-genistein, 7-OMe-genistein, irisolidone and formononetin slightly induce transcription with hER beta, they act as antagonists in the induction of transcription by 17beta-estradiol. The results show that methylation or glucosidation of isoflavones generally inhibits their phytoestrogenic activities.