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Background: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC)., Patients and Methods: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC)., Results: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively., Conclusion: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC., Competing Interests: Disclosure SS reports a grant from Ono and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis, ONO, Pfizer, and Taiho. J-SL, J-HK, HRK, and KHL report a grant from Ono. NI reports grants from Chugai, Daiichi Sankyo, Eli Lilly, MSD KK, Nippon Boehringer Ingelheim, Novartis, and Taiho; personal fees from AstraZeneca, Chugai, Eli Lilly, MSD, Nippon Boehringer Ingelheim, Novartis, Ono, and Taiho. TH reports grants from AbbVie, Astellas, AstraZeneca, Bristol-Meyers Squibb, Chugai, Daiichi Sankyo, Eisai, Ignyta, Janssen, Kissei, Merck Serono, MSD, Nippon Boehringer Ingelheim, Novartis, ONO, Pfizer, Taiho, and Takeda; personal fees from AstraZeneca, Bristol-Meyers Squibb, Chugai, Kissei, MSD, Nippon Boehringer Ingelheim, Novartis, Ono, Pfizer, Taiho, and Takeda. TY reports grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, MSD, Ono, and Takeda; personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, and Novartis. HT reports grants from Astra Zeneca, Boehringer Ingelheim, Chugai, Eli Lilly, MSD, Ono, and Taiho; personal fees from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eli Lilly, MSD, Novartis, Ono, Pfizer, and Taiho. C-TY reports personal fees from Boehringer Ingelheim, Chugai, MSD, Ono, Pfizer, and Roche. MN reports grants from AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Novartis, ONO, Pfizer, Taiho, and Takeda; personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Merck Biopharma, MSD, Novartis, ONO, Pfizer, Taiho, Takeda, and TEIJIN. YO reports grants from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Ignyta, Janssen, Kyorin, Kyowa Hakko Kirin, MSD, Nippon Kayaku, Novartis, Ono, Taiho, and Takeda; personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Chugai, Eli Lilly, Janssen, Kyorin, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho, and Takeda. TT reports grant from Ono and personal fees from Chugai and Lilly. NY reports grants from Astellas, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Ono, Pfizer, Shionogi, Taiho, Terumo, Toppan Printing, Tosoh, and Tsumura; personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho, Takeda, and Thermo Fisher Scientific. C-JY reports other support from Ono. HA reports grants from Chugai and MSD; personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, MSD, and Ono. YN and NS are employees of Ono. KN reports grants from A2 Healthcare, AbbVie, Astellas, AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, CMIC Shift Zero, Eisai, Eli Lilly, EP-CRSU, EPS, EPS International, GRITSONE ONCOLOGY, ICON Japan, inVentiv Health, Kissei, Kyowa Hakko Kirin, Linical, Merck Serono/Merck Biopharma, MSD, Nippon Boehringer Ingelheim, Novartis, Ono, Otsuka, PAREXEL International, Pfizer, Pfizer R&D Japan, Quintiles/IQVIA Services JAPAN, Symbio, Syneos Health, Taiho, and Takeda; personal fees from 3H Clinical Trial, AbbVie, Astellas, AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Care Net, Chugai, Clinical Trial, Daiichi Sankyo, Eli KYORIN, Lilly, Medical Mobile Communications, Medical Review, MEDICUS SHUPPAN Publishers, Merck Serono/Merck Biopharma, MSD, NANZANDO, Nichi-Iko, Nikkei Business Publications, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono, Pfizer, Reno. Medical, Roche Diagnostics, Symbio, Taiho, Takeda, Thermo Fisher Scientific, YODOSHA, and YOMIURI TELECASTING; other supports from Eli Lilly, KYORIN, Ono, Pfizer, and Takeda., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non-squamous NSCLC., Methods: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum-containing chemotherapy, were treated with nivolumab 3 mg/kg, intravenously every 2 weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety., Results: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8 months (95% CI 1.4 to 3.4) and 17.1 months (95% CI 13.3 to 23.0), respectively. The OS rate at 1 year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab., Conclusions: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression., Trial Registration Number: JapicCTI-132073., Competing Interests: Competing interests: MN received honoraria from Pfizer, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical and AstraZeneca. MN also has been a consultant/advisor for Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Pfizer, Bristol-Myers Squibb and Daiichi Sankyo, and received research funding from Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Eli Lilly, Pfizer, Astellas Pharma and AstraZeneca. THid received honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb and Clovis. THid also received research funding from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Taiho Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Clovis, Eisai, Takeda Pharmaceutical, Dainippon Sumitomo Pharma, Abbvie, Merck Serono, Kyowa Hakko Kirin, Daiichi Sankyo and Astellas Pharma. SA received honoraria from Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, and Bristol-Myers Squibb. SA also received funding from AstraZeneca and Taiho Pharmaceutical for participating in a speakers' bureau. SA also received research funding from Chugai Pharmaceutical, Pfizer, Ono Pharmaceutical, Merck Serono, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Yakult and Eli Lilly. HSakai received honoraria and funding to participate in a speakers' bureau from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly and Bristol-Myers Squibb. KN received honoraria from Astellas Pharma, AstraZeneca, EPS Holdings, Ono Pharmaceutical, Kyowa Hakko Kirin, Showa Yakuhin Kako, SymBio Pharmaceuticals, Daiichi Sankyo, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Pfizer and Bristol-Myers Squibb. KN also received research funding from Chugai Pharmaceutical, MSD, Ono Pharmaceutical, EPS Associates, Quintiles, Daiichi Sankyo, Japan Clinical Research Operations, Eisai, PPD-SNBL, Pfizer, Takeda Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Kyowa Hakko Kirin and OncoTherapy Science. TTak received honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Eli Lilly, Chugai Pharmaceutical and Ono Pharmaceutical. TTak also received research funding from AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, Takeda Pharmaceutical, Taiho Pharmaceutical and MSD. NN received honoraria from Astellas Pharma, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim and Pfizer. HSaka received research funding from AstraZeneca, Daiichi Sankyo, Ono Pharmaceutical, Eli Lilly, Bayer, Taiho Pharmaceutical, MSD, Linical, Bristol-Myers Squibb and Sanofi. MT received honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Kyowa Hakko Kirin, Ono Pharmaceutical and Taiho Pharmaceutical. MT also received research funding from Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Novartis and Ono Pharmaceutical. MM received honoraria from AstraZeneca, Chugai Pharmaceutical, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb and Eli Lilly. MM also received research funding from Boehringer Ingelheim. YO’s immediate family member is an employee of Chugai Pharmaceutical. YO also has an immediate family member with an ownership of interest with Ono Pharmaceutical. YO received honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, Nippon Kayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Clovis and Sanofi. YO has also been a consultant/advisor for AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Ono Pharmaceutical and Novartis, and received funding from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Kyorin Pharmaceutical, Dainippon Sumitomo Pharma, Pfizer, Taiho Pharmaceutical, Novartis and Merck Serono. YO has also been paid by AstraZeneca to provide expert testimony. HN received honoraria from AstraZeneca, Ono Pharmaceutical, Eli Lilly, Bristol-Myers Squibb and Chugai Pharmaceutical. HN also received research funding from Merck Serono, Pfizer, Taiho Pharmaceutical, Eisai, Chugai Pharmaceutical, Eli Lilly, Novartis, Daiichi Sankyo, GlaxoSmithKline, Yakult, Quintiles, Astellas Pharma, AstraZeneca, Boehringer Ingelheim and Ono Pharmaceutical. THir received research funding from MSD, AstraZeneca, Ono Pharmaceutical, Eisai, Daiichi Sankyo, Merck Serono, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Kyowa Hakko Kirin and Takeda Pharmaceutical. HT received research funding from Eli Lilly, AstraZeneca, MSD, Ono Pharmaceutical, Takeda Pharmaceutical, Daiichi Sankyo, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical and Boehringer Ingelheim. KT received honoraria from AstraZeneca, Ono Pharmaceutical, Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo and Kyowa Hakko Kirin. KT also has been a consultant/advisor for AstraZeneca, Eli Lilly and Novartis, and received research funding from AstraZeneca, Chugai Pharmaceutical, Eisai, Bristol-Myers Squibb, Eli Lilly, Ono Pharmaceutical, Kyowa Hakko Kirin, Boehringer Ingelheim and Merck Serono. KG received honoraria from Daiichi Sankyo, Nippon Kayaku, Kyowa Hakko Kirin, Bristol-Myers Squibb, AstraZeneca, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Eli Lilly and Boehringer Ingelheim. KG also has been a consultant/advisor for Taiho Pharmaceutical, Chugai Pharmaceutical, and Daiichi Sankyo, and received research funding from MSD, AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, GlaxoSmithKline, OxOnc, Dainippon Sumitomo Pharma, Takeda Pharmaceutical, Novartis, Daiichi Sankyo, Kyowa Hakko Kirin, Astellas Pharma, Eisai, Eli Lilly, Amgen Astellas BioPharma, Pizer, Riken Genesis and Bristol-Myers Squibb. MS received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Boehringer Ingelheim Novartis and MSD. MS also received research funding from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Pfizer, Novartis, MSD and Astellas Pharma. HI received funding to participate in a speakers' bureau from AstraZeneca, Bristol-Myers Squibb, Kyowa Hakko Kirin, Chugai Pharmaceutical and Boehringer Ingelheim. KM received research funding from Ono Pharmaceutical and Chugai Pharmaceutical. NS is an employee of Ono Pharmaceutical. TTam received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Eisai, Yakult, Novartis, Daiichi Sankyo and Astellas Pharma.

Cell surface heparan sulfate proteoglycans (HSPGs) play significant roles in the regulation of developmental signaling, including vascular endothelial growth factor (VEGF), fibroblast growth factor, Wnt and bone morphogenetic protein signaling, through modification of their sulfation patterns. Recent studies have revealed that one of the functions of heparan sulfate 6-O-endosulfatase (Sulf) is to remove the sulfate from the 6-O position of HSPGs at the cell surface, thereby regulating the binding activities of heparan sulfate (HS) chains to numerous ligands and receptors in animal species. In this study, we focused on the sea urchin Hemicentrotus pulcherrimus homolog of Sulf (HpSulf), and analyzed its expression pattern and functions during development. HpSulf protein was present throughout development and localized at cell surface of all blastomeres. In addition, the HS-specific epitope 10E4 was detected at the cell surface and partially colocalized with HpSulf. Knockdown of HpSulf using morpholino antisense oligonucleotides (MO) caused abnormal morphogenesis, and the development of MO-injected embryos was arrested before the hatched blastula stage, indicating that HpSulf is necessary for the early developmental process of sea urchin embryos. Furthermore, we found that injection of HpSulf mRNA suppressed the abnormal skeleton induced by overexpression of HpVEGF mRNA, whereas injection of an inactive form of HpSulf mRNA, containing mutated cysteines in the sulfatase domain, did not have this effect. Taken together, these results suggest that HpSulf is involved in the regulation of various signal transductions, including VEGF signaling, during sea urchin development., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)