LBA44 - Primary results of a randomized phase II study of osimertinib plus bevacizumab versus osimertinib monotherapy for untreated patients with non-squamous non-small cell lung cancer harboring EGFR mutations: WJOG9717L study

Background

Osimertinib (Osi) has been a standard treatment for untreated patients (pts) with non-small-cell lung cancer (NSCLC) harboring an EGFR mutation. Previous studies showed that the addition of anti-VEGF inhibitors to erlotinib prolonged progression-free survival (PFS) in EGFR mutated non-squamous NSCLC (Ns-NSCLC) pts. This phase II, open-label, randomized trial was conducted to compare Osi plus bevacizumab (Bev) with Osi monotherapy for untreated pts with advanced EGFR mutated Ns-NSCLC.

Methods

This study enrolled untreated pts with advanced Ns-NSCLC harboring an EGFR sensitizing mutation (Del19 or L858R), and without symptomatic brain metastases. 122 eligible pts were randomized in a 1:1 ratio to receive either Osi (80 mg, daily) plus Bev (15 mg/kg, every 3 weeks) (OB arm) or Osi monotherapy (O arm), and stratified according to sex, stage and EGFR mutation status. The primary endpoint was PFS, assessed by blinded, independent central radiologic reviewer (BICR). Assuming that the median PFS in the OB arm and the O arm were 27 and 18 months, planned sample size was 120 in total to give a power of 80% with a one-sided alpha of 20%, with an accrual period of 1.5 years and a follow-up period of 2 years.

Results

Between January 2018 and September 2018, 122 pts were enrolled (OB arm, 61 pts O arm, 61 pts). At a median follow-up of 19.8 months, median PFS by BICR was 22.1 months for OB arm and 20.2 months for O arm, with a hazard ratio (HR) of 0.862 (60% CI, 0.700–1.060; 95% CI, 0.531–1.397; one-sided stratified log-rank p=0.213). In subgroup analysis, ex-smoker (HR 0.481) and pts with 19del (HR 0.622) showed better trend of PFS in OB arm. Objective response rate was 82% in OB arm and 86% in O arm. Grade 3-4 adverse events were observed in 34 pts (56%) for OB arm and in 29 (48%) for O arm. Any grade paronychia, rash acneiform, hypertension, epistaxis and proteinuria were frequently observed in OB arm. Among them, 3% and 18% experienced any grade pneumonitis, and grade 3 pneumonitis in 1 pt for each arm.

Conclusions

This study failed to show the efficacy of OB arm for improving PFS in untreated pts with EGFR mutated Ns-NSCLC.

Clinical trial identification

UMIN000030206.

Editorial acknowledgement

Legal entity responsible for the study

West Japan Oncology Group.

Funding

AstraZeneca.

Disclosure

H. Kenmotsu: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co, Ltd.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co, Ltd.; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly K.K; Financial Interests, Personal, Invited Speaker: Kyowa Hakko Kirin Co., Ltd.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis Pharma K.K.; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Taiho Pharma; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical Co, Ltd.; Financial Interests, Institutional, Research Grant: Novartis Pharma K.K.; Financial Interests, Institutional, Research Grant: Daiichi Sankyo Co., Ltd.; Non-Financial Interests, Principal Investigator: AstraZeneca K.K.; Non-Financial Interests, Principal Investigator: Eli Lilly K.K; Non-Financial Interests, Principal Investigator: Boehringer Ingelheim. K. Wakuda: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Astrazeneca; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Astrazeneca; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: AbbVie. T. Kato: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Merck KGaA; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck KGaA; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Institutional, Funding: AbbVie; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Chugai; Financial Interests, Institutional, Funding: Eli Lilly; Financial Interests, Institutional, Funding: Merck biopharma; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Regeneron; Other, Personal, Other: Eli Lilly. S. Sugawara: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai Pharma; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly and Company; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: Kyowa Kirin; Financial Interests, Personal, Invited Speaker: Yakult Honsha. K. Kirita: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Personal, Funding: Chugai Pharmaceutical Co., Ltd. I. Okamoto: Financial Interests, Personal, Invited Speaker: AstraZenaca; Financial Interests, Institutional, Funding: AstraZenaca; Financial Interests, Personal, Advisory Board: AstraZenaca. K. Azuma: Financial Interests, Personal, Speaker’s Bureau: Astrazeneca; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Speaker’s Bureau: Ono Pharma; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharm; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Nippon Kayaku. K. Nishino: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co., Ltd; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim Co., Ltd.; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Shanghai Haihe Pharmaceutical Co., Ltd. S. Teraoka: Financial Interests, Personal, Invited Speaker: Chugai Pharma; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutica; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutica; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly. H. Hayashi: Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim Japan Inc.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb Co. Ltd.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co. Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K; Financial Interests, Personal, Invited Speaker: Kyorin pharmaceutical co. ltd; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co., Ltd.; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Novartis pharmaceuticals K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd.; Financial Interests, Personal, Invited Speaker: Shanghai Haihe Biopharm; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co. Ltd; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Advisory Board: AstraZeneca K.K.; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim Japan Inc.; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb Co. Ltd.; Financial Interests, Personal, Advisory Board: Chugai Pharmaceutical Co. Ltd.; Financial Interests, Personal, Advisory Board: Eli Lilly Japan K.K; Financial Interests, Personal, Advisory Board: Pfizer Japan Inc.; Financial Interests, Personal, Advisory Board: Shanghai Haihe Biopharm; Financial Interests, Personal, Advisory Board: Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Advisory Board: Merck Biopharma Co., Ltd.; Financial Interests, Institutional, Funding: AstraZeneca K.K.; Financial Interests, Institutional, Funding: Astellas Pharma Inc.; Financial Interests, Institutional, Funding: MSD K.K.; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Nippon Boehringer Ingelheim Co.,Ltd; Financial Interests, Institutional, Funding: Novartis Pharma K.K.; Financial Interests, Institutional, Funding: Pfizer Japan Inc.; Financial Interests, Institutional, Funding: Bristol Myers Squibb Company; Financial Interests, Institutional, Funding: Eli Lilly Japan K.K.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co.,Ltd; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd.,; Financial Interests, Institutional, Funding: Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd.; Financial Interests, Institutional, Funding: Takeda Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: SymBio Pharmaceuticals Limited.; Financial Interests, Institutional, Funding: AbbVie Inc; Financial Interests, Institutional, Funding: inVentiv Health Japan; Financial Interests, Institutional, Funding: ICON Japan K.K.; Financial Interests, Institutional, Funding: Gritstone Oncology Inc. Financial Interests, Institutional, Funding: Parexel International Corp.; Financial Interests, Institutional, Funding: Kissei Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: EPS Corporation.; Financial Interests, Institutional, Funding: Syneos Health.; Financial Interests, Institutional, Funding: Pfizer R&D Japan G.K.; Financial Interests, Institutional, Funding: A2 Healthcare Corp.; Financial Interests, Institutional, Funding: Quintiles Inc. / IQVIA Services Japan K.K.; Financial Interests, Institutional, Funding: EP-CRSU Co., Ltd.; Financial Interests, Institutional, Funding: Linical Co.,Ltd.; Financial Interests, Institutional, Funding: Eisai Co., Ltd.; Financial Interests, Institutional, Funding: CMIC Shift Zero K.K; Financial Interests, Institutional, Funding: Kyowa Hakko Kirin Co.,Ltd; Financial Interests, Institutional, Funding: Bayer Yakuhin, Ltd.; Financial Interests, Institutional, Funding: EPS International Co.,Ltd,; Financial Interests, Institutional, Funding: Otsuka Pharmaceutical Co., Ltd. R. Toyozawa: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Novartis Pharm; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Institutional, Funding: AbbVie; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: Eli Lilly Japan; Financial Interests, Institutional, Funding: Pfizer Japan; Financial Interests, Institutional, Funding: Takeda Pharmaceutical. S. Miura: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma.; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharma; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Boehringer-Ingelheim Japan; Financial Interests, Personal, Speaker’s Bureau: Ono Pharma.; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo. Y. Sato: Financial Interests, Personal, Invited Speaker: Chugai Pham; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical CO; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Nippon Kayaku; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Kyowa Kirin Co.,Ltd. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co., Ltd.; Financial Interests, Personal, Invited Speaker: Amgen Inc.; Financial Interests, Personal, Invited Speaker: Kyowa Kirin Co., Ltd.; Financial Interests, Personal, Invited Speaker: akeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: 3H Clinical Trial Inc.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K.; Financial Interests, Personal, Invited Speaker: Medical Review Co., Ltd.; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Medical Mobile Communications co., Ltd; Financial Interests, Personal, Invited Speaker: Pfizer Japan Inc.; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim Co., Ltd.; Financial Interests, Personal, Advisory Board: Eli Lilly Japan K.K.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Parexel International Corp.; Financial Interests, Institutional, Funding: Eisai Co., Ltd.; Financial Interests, Institutional, Funding: PRA Health Sciences; Financial Interests, Institutional, Funding: AstraZeneca K.K.; Financial Interests, Institutional, Funding: EPS Corporation.; Financial Interests, Institutional, Funding: Mochida Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Kissei Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Covance Japan Inc; Financial Interests, Institutional, Funding: EPS International Co.,Ltd,.; Financial Interests, Institutional, Funding: Japan Clinical Research Operations; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Funding: Takeda Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: GlaxoSmithKline K.K.; Financial Interests, Institutional, Funding: MSD K.K.; Financial Interests, Institutional, Funding: Sanofi K.K.; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: PPD-SNBL K.K.; Financial Interests, Institutional, Funding: Nippon Boehringer Ingelheim Co.,Ltd.; Financial Interests, Institutional, Funding: SymBio Pharmaceuticals Limited.; Financial Interests, Institutional, Funding: Sysmex Corporation; Financial Interests, Institutional, Funding: IQVIA Services Japan K.K.; Financial Interests, Institutional, Funding: Medical Reserch Support; Financial Interests, Institutional, Funding: Syneos Health; Financial Interests, Institutional, Funding: /Eli Lilly Japan K.K. N. Yamamoto: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Thermo Fisher Scientific; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K.; Financial Interests, Personal, Invited Speaker: Boehringer-Ingelheim; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer Inc.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Nippon Kayaku; Financial Interests, Personal, Invited Speaker: GlaxoSmithKline K.K.; Financial Interests, Personal, Invited Speaker: Sanofi K.K.; Financial Interests, Personal, Invited Speaker: Hisamitsu Pharmaceutical Co.Inc.; Financial Interests, Personal, Invited Speaker: Merk biopharma; Financial Interests, Personal, Invited Speaker: Guardant Health Japan; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: MSD K.K.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Eli Lilly Japan K.K.; Financial Interests, Personal, Advisory Board: Boehringer-Ingelheim; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer Inc.; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Nippon Kayaku; Financial Interests, Personal, Advisory Board: Life Technologies Japan Ltd.; Financial Interests, Personal, Advisory Board: Amgen Inc.; Financial Interests, Personal, Advisory Board: Guardant Health Japan; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K.; Financial Interests, Personal, Research Grant: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Research Grant: Boehringer-Ingelheim; Financial Interests, Personal, Research Grant: Tosoh Life Science Research Laboratory; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Boehringer-Ingelheim; Financial Interests, Institutional, Funding: Otsuka Pharmaceutical CO., Ltd.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Shionogi & Co., Ltd.; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Funding: Eli Lilly Japan K.K.; Financial Interests, Institutional, Funding: Tsumura & CO.; Financial Interests, Institutional, Funding: Nippon Kayaku; Financial Interests, Institutional, Funding: Asahi Kasei Pharma; Financial Interests, Institutional, Funding: Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Sanofi K.K.; Financial Interests, Institutional, Funding: Amgen Inc. T. Takahashi: Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Pfizer Japan Inc.; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim Japan; Financial Interests, Personal, Invited Speaker: Roche Diagnostics K.K.; Financial Interests, Institutional, Funding: AstraZeneca K.K.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Eli Lilly Japan K.K; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: MSD K.K.; Financial Interests, Institutional, Funding: Pfizer Japan Inc.; Financial Interests, Institutional, Funding: Amgen inc.; Financial Interests, Institutional, Funding: Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.