Background

Superiority of 1L pembro monotherapy vs chemo in pts with metastatic NSCLC with PD-L1 TPS ≥50% and no sensitizing EGFR/ALK alterations was demonstrated in KEYNOTE-024 (NCT02142738). We report updated efficacy and safety from KEYNOTE-024 with 5 years follow-up.

Methods

Eligible pts were randomized to pembro (200 mg Q3W for up to 35 cycles [∼2 years]) or chemo. Randomization was stratified by ECOG PS (0/1), histology (squamous/nonsquamous), and region (East Asia/other). Pts randomized to chemo who had PD and met eligibility criteria could cross over to pembro monotherapy. Pts randomized to pembro who completed 2 years of therapy or who stopped pembro after achieving CR and then had PD were eligible for a second course of pembro monotherapy. Endpoints included PFS (primary); OS, ORR, and safety (secondary); and duration of response (exploratory). For this analysis, response/PD was assessed by investigators per RECIST v1.1.

Results

305 pts were randomized (pembro, 154; chemo, 151). As of June 1, 2020, median (range) time from randomization to data cutoff was 59.9 (55.1–68.4) mo. 83 (55.0%) pts randomized to chemo crossed over to pembro. Efficacy in the ITT population and in 39/154 (25.3%) pts in the pembro arm who completed 35 cycles of pembro are shown in the Table. 12/154 pts started second course pembro; outcomes in these pts will be presented. Among all treated pts, incidence of treatment-related grade 3–5 AEs was 31.2% with pembro vs 53.3% with chemo. Table: LBA51

Efficacy

Conclusions

Pembro continues to show improvements in OS vs chemo as 1L treatment for metastatic NSCLC with PD-L1 TPS ≥50%. Despite the high crossover rate, 5-year OS was approximately doubled among pts who received pembro (31.9% vs 16.3%). Fewer pts who received pembro experienced grade 3−5 AEs vs those who received chemo. Long-term OS and durable responses were observed with pembro monotherapy.

Clinical trial identification

NCT02142738.

Editorial acknowledgement

Medical writing assistance was provided by Rozena Varghese, PharmD, CMPP, of ICON plc (North Wales, PA, USA). This assistance was funded by the study sponsor, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

J.R. Brahmer: Advisory/Consultancy: Merck. D. Rodriguez-Abreu: Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer. A.G. Robinson: Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Pfizer . R. Hui: Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche. N. Peled: Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self), Research grant/Funding (self): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (self): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (self): Eli Lilly; Honoraria (self), Research grant/Funding (self): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Pfizer; Honoraria (self), Research grant/Funding (self): NovellusDx; Honoraria (self), Research grant/Funding (self): Foundation Medicine; Honoraria (self), Research grant/Funding (self): Guardant360. S. Cuffe: Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Bristol-Myers Squibb; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Amgen. M. O'Brien: Advisory/Consultancy: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Roche. K. Hotta: Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Honoraria (self): Ono; Honoraria (self): Kayaku; Honoraria (self): Taiho; Honoraria (self): Chugai. T.A. Leal: Advisory/Consultancy: Takeda; Advisory/Consultancy: Novocure; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Genentech; Advisory/Consultancy: Inivata; Advisory/Consultancy: Merck; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: EMD Serono. J.W. Riess: Research grant/Funding (institution): Merck Sharp & Dohme Corp; Research grant/Funding (self): Spectrum; Research grant/Funding (institution): Revolution Medicines; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self): Blueprint Medicines; Honoraria (self): Medtronic; Advisory/Consultancy: Boehringer Ingelheim. E. Jensen: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. B. Zhao: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. M.C. Pietanza: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. M. Reck: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis. All other authors have declared no conflicts of interest.

Background

EMPOWER-Lung 1 is a multicentre, open-label, global, phase III study of cemiplimab, an anti–PD-1, in patients (pts) with treatment-naïve stage IIIB, IIIC, or IV squamous or non-squamous NSCLC with PD-L1 expressed in ≥50% of tumour cells.

Methods

Pts were randomised 1:1 to receive cemiplimab 350 mg Q3W IV or investigator’s choice of chemo. Crossover (CO) from chemo to cemiplimab was allowed following progression. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded Independent Review Committee. A prespecified interim analysis was performed after 50% of OS events. Data are presented per intention-to-treat (ITT) and in a PD-L1 ≥50% ITT population which comprised only pts with PD-L1 ≥50% by 22C3 per instruction for use (after recommended retesting in some pts). Data cut-off was 1 March 2020.

Results

In the ITT population (median follow-up: 13.1 months), median OS was 22.1 months (95% CI: 17.7–not evaluable [NE]) with cemiplimab (n=356) vs 14.3 months (95% CI: 11.7–19.2) with chemo (n=354; HR, 0.68; 95% CI: 0.53–0.87; P=0.002). Median PFS was 6.2 months (95% CI: 4.5–8.3) with cemiplimab vs 5.6 months (95% CI: 4.5–6.1) with chemo (HR, 0.59; 95% CI: 0.49–0.72; P<0.0001). In the PD-L1 ≥50% ITT population (median follow-up: 10.8 months), median OS was not reached (95% CI: 17.9–NE) with cemiplimab (n=283) vs 14.2 months (95% CI: 11.2–17.5) with chemo (n=280; HR, 0.57; 95% CI: 0.42–0.77; P=0.0002). Median PFS was 8.2 months (95% CI: 6.1–8.8) with cemiplimab vs 5.7 months (95% CI: 4.5–6.2) with chemo (HR, 0.54; 95% CI: 0.43–0.68; P<0.0001). CO rate to cemiplimab was 73.9%. In the ITT population, cemiplimab was associated with higher response rate (36.5% vs 20.6%), longer median duration of response (21.0 months vs 6.0 months) and lower rates of Grade ≥3 adverse events regardless of attribution (37.2% vs 48.5%) compared to chemo.

Conclusions

In this study, 1L cemiplimab monotherapy significantly improved OS and PFS vs chemo in pts with advanced NSCLC with PD-L1 ≥50%, despite high CO rate, providing rationale for cemiplimab as a new treatment option for this patient population.

Clinical trial identification

NCT03088540.

Editorial acknowledgement

Medical writing support was provided by Emmanuel Ogunnowo, PhD of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., and Sanofi.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc. and Sanofi.

Funding

Regeneron Pharmaceuticals, Inc. and Sanofi.

Disclosure

A. Sezer: Research grant/Funding (institution): Roche; Research grant/Funding (self): MSD Oncology; Research grant/Funding (self): Regeneron Pharmaceuticals, Inc.; Research grant/Funding (self): Novartis; Travel/Accommodation/Expenses: Bristol-Myers Squibb; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Lily; Research grant/Funding (institution): Johnson & Johnson; Research grant/Funding (institution): Sanofi. M. Gümüş: Honoraria (institution), outside the submitted work: Roche; Honoraria (institution), outside the submitted work: Merck Sharp & Dohme; Honoraria (institution), outside the submitted work: Gen İlaç; Honoraria (institution), outside the submitted work: Novartis. N. Rizvi: Advisory/Consultancy, outside the submitted work: AbbVie; Advisory/Consultancy, outside the submitted work: Apricity; Advisory/Consultancy, outside the submitted work: AstraZeneca; Advisory/Consultancy, outside the submitted work: Boehringer; Advisory/Consultancy, outside the submitted work: Calithera; Advisory/Consultancy, outside the submitted work: Dracen; Advisory/Consultancy, outside the submitted work: Editas; Advisory/Consultancy, outside the submitted work: EMD Sorono; Advisory/Consultancy, outside the submitted work: G1 Therapeutics; Advisory/Consultancy, outside the submitted work: Genentech; Advisory/Consultancy, outside the submitted work: Gilead; Advisory/Consultancy, outside the submitted work: GSK; Advisory/Consultancy, outside the submitted work: Illumina; Advisory/Consultancy, outside the submitted work: Lilly; Advisory/Consultancy, outside the submitted work: Merck; Advisory/Consultancy, outside the submitted work: Neogenomics; Advisory/Consultancy, outside the submitted work: Novartis; Advisory/Consultancy, Shareholder/Stockholder/Stock options, outside the submitted work: Brooklyn ImmunoTherapeutics; Advisory/Consultancy, outside the submitted work: Takeda; Advisory/Consultancy, Shareholder/Stockholder/Stock options, outside the submitted work: Bellicum; Licensing/Royalties, Patent (pending) filed by MSKCC, in the form of royalties, on “determinants of cancer response to immunotherapy, (PCT/US2015/062208)” licensed to Personal Genome Diagnostics: Personal Genome Diagnostics; Shareholder/Stockholder/Stock options, outside the submitted work: Gritstone. S. Li, S. Lee, G. Gullo: Shareholder/Stockholder/Stock options, Full/Part-time employment: Regeneron Pharmaceuticals, Inc. I. Lowy, P. Rietschel: Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment, Patents pending: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

PIONeeR aims to predict response/resistance to PD1/L1 ICIs in advanced NSCLC pts through comprehensive agnostic multiparametric and longitudinal biomarkers assessment. These ICIs significantly improve long-term outcome in 20% of advanced NSCLC pts but to date, no robust biomarker predicts primary or secondary resistance.

Methods

Advanced NSCLC pts with available archived tumor tissue treated with either nivolumab, pembrolizumab or atezolizumab, alone (2^nd line min) or combined with chemotherapy (1^st line), were systematically re-biopsied and blood-sampled at 6wks (V2) of treatment. ORR was assessed by RECIST 1.1 every 6wks. Quantification of circulating and tumor infiltrating immune cells and PD-L1 mediated inhibition (Immunoscore® IC) were performed by FACS and multiplex IHC coupled to digital pathology respectively. Endothelial activation, blood soluble factors, PK and TMB through WES were also assessed.

Results

The first 100 pts are mainly male (64%), smokers (91-8%), <65yrs (55%), with an ECOG PS0/1 (97%), treated in 2^nd line setting (86%). Tumors were mainly ADC (57%) with ≥1% PDL1 expression in 38% of the cases. 21% were still on treatment at data cut-off. V2 biopsy was available in 46% of cases; 33 pts progressed before the 6wks milestone, and 13 pts were considered as responders. Median PFS was 2.99 months (mo) [95%CI: 2.43 – 4.83] and median OS was 11.01 mo [95%CI: 8.21 - NA]. At baseline (VS), PD-L1 tumor cell percentage was significantly higher in responders, as well as tumor infiltration by cytotoxic lymphocytes (cTILs) (median: 160 vs 410 cells/mm²). Five non-responders presented high cTILs densities (up to 1800 cells/mm²), associated either to no PDL1 expression, high infiltration of Treg cells in the tumor or weak PD1 expression on cTILs. High immune cell densities at the periphery and in the tumor were associated with survival. Immune cell infiltration and PD-L1+ cell density increased from VS to V2, as well as proximity between these cells. Massive PK variability among patients was found.

Conclusions

Immune cells quantification and characterization add value to clinical factors to predict advanced NSCLC response/resistance to ICIs.

Clinical trial identification

NCT03493581, Release date: February 2018.

Legal entity responsible for the study

Assistance Publique Hôpitaux de Marseille (AP-HM).

Funding

French National Research Agency (ANR-17-RHUS-0007).

Disclosure

F. Barlesi: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): ACEA; Research grant/Funding (institution): Amgen; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Boehringer-Ingelheim; Research grant/Funding (institution): Eisai; Honoraria (self), Research grant/Funding (institution): Eli Lilly Oncology; Honoraria (self), Research grant/Funding (institution): F. Hoffmann-La Roche Ltd.; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Innate Pharma; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): MedImmune; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Sanofi-Aventis; Honoraria (self), Research grant/Funding (institution): Takeda. F. Monville: Full/Part-time employment: HalioDx. J. le treut: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Boehringer; Honoraria (self): Roche. C. Audigier-Valette: Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Lilly; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (institution), Advisory/Consultancy: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: AbbVie; Advisory/Consultancy: FoundationOne; Advisory/Consultancy: Takeda. S. Garcia: Travel/Accommodation/Expenses: MSD. J. Ciccolini: Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Institut Roche; Honoraria (self): Pierre Fabre; Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Ipsen. P. Outters: Full/Part-time employment: HalioDx. J. Mazieres: Honoraria (self), Research grant/Funding (self): Roche; Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self), Research grant/Funding (self): Pierre Fabre; Honoraria (self): Takeda; Honoraria (self), Research grant/Funding (self): BMS; Honoraria (self): MSD; Honoraria (self): Hengrui; Honoraria (self): Blueprint; Honoraria (self): Daiichi; Honoraria (self): Novartis. M. Pérol: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Speaker Bureau/Expert testimony: Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Takeda; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Chugai. E. Vivier: Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Innate Pharma. J. Fieschi: Officer/Board of Directors: HalioDx. All other authors have declared no conflicts of interest.

Background

Nivolumab has been approved as second or later line therapy for NSCLC. It is becoming evident that cytotoxic chemotherapy and angiogenesis inhibitors may enhance therapeutic benefits of immune checkpoint inhibitors such as nivolumab. ONO-4538-52/TASUKI-52 is the first randomized, double-blinded phase III trial of nivolumab plus platinum chemotherapy with bevacizumab for first-line treatment of non-squamous NSCLC.

Methods

Between May 2017 and June 2019, treatment-naïve stage IIIB/IV or recurrent nsq NSCLC patients without sensitizing EGFR or ALK alterations were randomized 1:1 to receive nivolumab (360 mg) or placebo in combination with carboplatin (AUC 6), paclitaxel (200 mg/m²), and bevacizumab (15 mg/kg) every 3 weeks for up to 6 cycles. Subsequently, the treatments with nivolumab/placebo and bevacizumab were maintained until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by the independent radiology review committee (IRRC).

Results

Of 550 patients in Japan, Korea, and Taiwan, and 273 (nivolumab) and 275 (placebo) received ≥ 1 dose of the study drugs. At the interim analysis on July 2020 where the median follow-up was 13.7 months, PFS was significantly longer in the nivolumab arm compared to the placebo arm with the median PFS of 12.12 vs 8.11 months (hazard ratio [HR], 0.56; 96.37% CI, 0.43-0.71; p<0.0001) and 12-month PFS rate of 50.1% vs 30.2%. IRRC assessed Objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. OS, while not mature, tended to be longer in the nivolumab arm compared to the placebo arm (HR, 0.85; 95% CI, 0.63-1.14). Treatment-related adverse events (TRAEs) with grade 3 or 4 and TRAEs leading to treatment discontinuation were observed in 73.6% and 16.5% in the nivolumab arm and 72.0% and 4.4% in the placebo arm, respectively. Most frequently-observed TRAEs were alopecia, peripheral sensory neuropathy, and decreased neutrophil count.

Conclusions

ONO-4538-52/TASUKI-52 met the primary endpoint; nivolumab in combination with carboplatin, paclitaxel, and bevacizumab significantly prolonged PFS with a manageable safety profile.

Clinical trial identification

NCT03117049.

Legal entity responsible for the study

Ono Pharmaceutical Co., Ltd.

Funding

Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb.

Disclosure

J-S. Lee: Research grant/Funding (institution): Ono Pharmaceutical. S. Sugawara: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): Chugai Pharma; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly and Company; Honoraria (self): Novartis; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): AstraZeneca. J.H. Kang: Research grant/Funding (institution): Ono Pharmaceutical. H.R. Kim: Research grant/Funding (institution): Ono Pharmaceutical. N. Inui: Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd; Honoraria (self), Research grant/Funding (institution): MSD K.K; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd; Honoraria (self), Research grant/Funding (institution): Novarits Japan; Research grant/Funding (institution): Daiichi Sankyo Company, Ltd; Honoraria (self), Research grant/Funding (institution): Eli Lilly Japan K.K; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim Co., Ltd; Honoraria (self): AstraZeneca K.K. T. Hida: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Bristol-Meyers Squibb; Honoraria (self), Research grant/Funding (institution): Kissei; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Takeda Pharmaceutical Co., Ltd.; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Janssen Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca. K.H. Lee: Research grant/Funding (institution): Ono Pharmaceutical. T. Yoshida: Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Takeda; Honoraria (self): Chugai; Honoraria (self): Novartis; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie. H. Tanaka: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (institution): Chugai pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Boehringer Ingelheim. C.T. Yang: Honoraria (self): Ono Pharmaceutical; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche; Honoraria (self): Chugai. M. Nishio: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Bristol Myers Squibb; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self): Merck Biopharma; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant/Funding (institution): Takeda Pharmaceutical Company Limited; Honoraria (self): Teijin Pharma Limited.; Honoraria (self): AbbVie. Y. Ohe: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self), Research grant/Funding (institution): Nippon Kayaku; Honoraria (self), Research grant/Funding (institution): Kyorin; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Janssen; Honoraria (self): Pfizer; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Kyowa Hakko Kirin; Honoraria (self): Celtrion; Honoraria (self): Amgen. T. Tamura: Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Lilly. N. Yamamoto: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Thermo Fisher Scientific; Honoraria (self), Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self): Takeda; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant/Funding (institution): Boehringer-Ingelheim; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Nipponkayaku; Research grant/Funding (institution): Shionogi; Research grant/Funding (institution): Tsumura; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Terumo; Research grant/Funding (institution): Tosoh; Research grant/Funding (institution): Toppan Printing. C-J. Yu: Research grant/Funding (institution): Ono Pharmaceutical. H. Akamatsu: Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Chugai Pharmatheutical; Honoraria (self): Astrazeneca; Honoraria (self): Bristol-Myers Squibb. Y. Namba: Full/Part-time employment: Ono Pharmaceutical. N. Sumiyoshi: Full/Part-time employment: Ono Pharmaceutical. K. Nakagawa: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Astellas Pharma Inc.; Honoraria (self), Research grant/Funding (institution): MSD K.K.; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Novartis Pharma K.K.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant/Funding (institution): Bristol Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd.; Honoraria (self): Clinical Trial Co., Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co., Ltd.; Honoraria (self): Care Net, Inc; Honoraria (self): Reno. Medical K.K.; Honoraria (self), Advisory/Consultancy: Kyorin Pharmaceutical Co., Ltd.; Honoraria (self): Medical Review Co., Ltd.; Honoraria (self): Roche Diagnostics K.K.; Honoraria (self), Research grant/Funding (institution): Bayer Yakuhin, Ltd; Honoraria (self): Medical Mobile Communications Co., Ltd; Honoraria (self): 3H Clinical Trial Inc.; Honoraria (self): Nichi-Iko Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): SymBio Pharmaceuticals Limited; Honoraria (self): Nanzando Co., Ltd.; Honoraria (self): Yodosha Co., Ltd.; Honoraria (self): Nikkei Business Publications, Inc; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Yomiuri Telecasting Corporation; Honoraria (self): Nippon Kayaku Co., Ltd.; Honoraria (self), Research grant/Funding (institution): AbbVie Inc.; Research grant/Funding (institution): inVentiv Health Japan; Research grant/Funding (institution): Icon Japan K.K.; Research grant/Funding (institution): Gritsone Oncology.Inc; Research grant/Funding (institution): PAREXEL International Corp.; Research grant/Funding (institution): Kissei Pharmaceutical Co., Ltd.; Research grant/Funding (institution): EPS Corporation.; Research grant/Funding (institution): Syneos Health; Research grant/Funding (institution): Pfizer R&D Japan G.K.; Research grant/Funding (institution): A2 Healthcare Corp.; Research grant/Funding (institution): Quintiles Inc. / IQVIA Services Japan K.K.; Research grant/Funding (institution): EP-CRSU Co., Ltd.; Research grant/Funding (institution): Linical Co.,Ltd.; Research grant/Funding (institution): Eisai Co., Ltd.; Research grant/Funding (institution): CMIC Shift Zero K.K.; Research grant/Funding (institution): Kyowa Hakko Kirin Co.,Ltd; Research grant/Funding (institution): EPS International Co., Ltd.; Research grant/Funding (institution): Otsuka Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): AstraZeneca K.K.

Background

In the treatment of advanced NSCLC with PD-1/PD-L1 antibodies, PD-L1 expression in tumor cells is one of the predictive markers for their efficacy. In the first-line treatment for patients with high PD-L1 expression, pembrolizumab or Atez each has been shown to prolong overall survival compared with platinum doublet therapy. On the other hand, Bev enhances the efficacy of cytotoxic agents and EGFR-TKI in non-Sq NSCLC. In addition, preclinical models have shown that Bev also enhances the antitumor activity of PD-1/-PD-L1 antibodies.

Methods

We conducted a single-arm phase II study to investigate clinical benefits of adding Bev 15 mg/kg to Atez 1200 mg/body in the 1st line setting for patients with high PD-L1 expression. Both agents were administered on day 1 q3wk until disease progression. Patients were eligible if they had pathologically confirmed advanced non-Sq NSCLC without any EGFR/ALK/ROS1 alterations, had ECOG performance status 0-1, and PD-L1 expression≥50% detected by Dako 22C3 antibody. The primary endpoint was objective response rate (ORR) assessed by the central review committee (CRC). The sample size was set as 38 assuming that the threshold of ORR was 40% and the expected ORR was 62%. Secondary endpoints were progression free survival (PFS), duration of response, overall survival, and safety.

Results

From August 2018 to January 2020, 40 patients were enrolled from 14 institutions. Of the 40 patients, 33 (83%) were male with a median age of 68 (range: 41-75), 36 (90%) had a history of smoking. One patient was ineligible and did not receive protocol treatment. As of 31 March 2020, none and 25 of the 39 patients were judged as CR and PR, indicating that ORR was 64.1% (95%CI: 47.2-78.8). One year PFS rate was 54.9%. The median number of treatment cycles was 12 (1-27). The treatment was discontinued in 19 patients, 17 and 2 of whose reasons were disease progression and immune-related adverse events, such as sclerosing cholangitis and encephalopathy, respectively. The number of serious adverse events was 23 in 12 patients, but no grade 4/5 toxicity was observed.

Conclusions

This positive result supports Atez with Bev as a potential treatment option for non-Sq NSCLC with high PD-L1 expression.

Legal entity responsible for the study

West Japan Oncology Group.

Funding

Chugai Pharma.

Disclosure

T. Seto: Honoraria (self): Astellas Pharma; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant/Funding (institution): Eli Lilly Japan; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Novartis Pharma; Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Pfizer Japan; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Takeda Pharmaceutical; Honoraria (self): Thermo Fisher Scientific; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Bayer Yakuhin; Research grant/Funding (institution): Kissei Pharmaceutical; Research grant/Funding (institution): Loxo Oncology; Research grant/Funding (institution): Merck Serono; Full/Part-time employment: Precision Medicine Asia. K. Nosaki: Honoraria (self), Honoraria (institution), Research grant/Funding (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd. R. Toyozawa: Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Nippon Kayaku; Honoraria (self): Novartis Pharma; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Pfizer Japan; Research grant/Funding (institution): Takeda Pharmaceutical. S. Sugawara: Honoraria (self): Chugai Pharma; Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Eli Lilly and Company; Honoraria (self): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Novartis; Honoraria (self): Kyowa Hakko Kirin. H. Hayashi: Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Boehringer Ingelheim Japan Inc; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb Co. Ltd.; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant/Funding (institution): Eli Lilly Japan K.K; Honoraria (self): Kyorin pharmaceutical co. ltd; Honoraria (self): Merck Biopharma Co., Ltd.; Honoraria (self), Research grant/Funding (institution): MSD K.K; Honoraria (self), Research grant/Funding (institution): Novartis pharmaceuticals k.k; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Ono Pharmaceutical Co. Ltd; Honoraria (self), Research grant/Funding (institution): Pfizer Japan Inc; Honoraria (self): Shanghai Haihe Biopharm; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co. Ltd; Research grant/Funding (institution): Astellas Pharma Inc; Research grant/Funding (institution): Daiichi Sankyo Co., Ltd; Research grant/Funding (institution): Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd; Research grant/Funding (institution): Takeda Pharmaceutical Co., Ltd.; Research grant/Funding (institution): SymBio Pharmaceuticals Limited; Research grant/Funding (institution): AbbVie Inc; Research grant/Funding (institution): inVentiv Health Japan; Research grant/Funding (institution): Icon Japan K.K.; Research grant/Funding (institution): Gritsone Oncology.Inc; Research grant/Funding (institution): Parexel International Corp; Research grant/Funding (institution): Kissei Pharmaceutical Co., Ltd.; Research grant/Funding (institution): EPS Corporation; Research grant/Funding (institution): Syneos Health; Research grant/Funding (institution): Pfizer R&D Japan G.K; Research grant/Funding (institution): A2 Healthcare Corp; Research grant/Funding (institution): Quintiles Inc. / IQVIA Services Japan K.K.; Research grant/Funding (institution): EP-CRSU Co., Ltd., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co., Ltd., Bayer Yakuhin, Ltd., EPS International Co., Ltd,., Otsuka Pharmaceutical Co., Ltd.,. H. Murakami: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Chugai pharma; Honoraria (self), Research grant/Funding (institution): Lilly Japan; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): MSD; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): IQVIA. T. Kato: Honoraria (self), Research grant/Funding (institution): Chugai. S. Niho: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self): MSD; Honoraria (self): Boehringer Ingelheim; Research grant/Funding (institution): Merck Biopharma; Research grant/Funding (institution): Chugai. H. Saka: Honoraria (self): Chugai; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Ono; Honoraria (self): Boehringer Ingelheim Japan; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Taisho-Toyama. H. Yoshioka: Honoraria (self), Lecture fee: Chugai pharmaceutical. I. Okamoto: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Chugai. H. Daga: Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self): MSD; Honoraria (self), Research grant/Funding (institution): Astrazeneca; Honoraria (self): Ono. K. Azuma: Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Chugai phrma; Speaker Bureau/Expert testimony: Bristol-meiers squib; Speaker Bureau/Expert testimony: Ono Pharma. H. Tanaka: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bristol Myers Squibb; Honoraria (self), Research grant/Funding (institution): Boehringer-ingelheim; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical; Research grant/Funding (institution): Ono Pharmaceutical; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Pfizer. K. Nishino: Honoraria (self): AstraZeneca; Honoraria (self): Chugai; Honoraria (self): Eli Lilly Japan; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Ono; Honoraria (self): Nippon Boehringer Ingelheim. M. Satouchi: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self): Taiho; Honoraria (self): Nippon kayaku; Honoraria (self), Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Ono; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Takeda. N. Yamamoto: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): MSD K.K.; Honoraria (self), Research grant/Funding (institution): AstraZeneca K.K; Honoraria (self): Ono Pharmaceutical Co., Ltd; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly Japan K.K; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Japan Boehringer-Ingelheim Co., Ltd; Honoraria (self), Research grant/Funding (institution): Nipponkayaku; Honoraria (self), Research grant/Funding (institution): Novartis Pharma K.K.; Honoraria (self), Research grant/Funding (institution): Pfizer Inc.; Research grant/Funding (institution): Astellas Amgen BioPharma; Research grant/Funding (institution): Tsumura; Research grant/Funding (institution): Daiichi Sankyo Company; Research grant/Funding (institution): Shionogi; Research grant/Funding (institution): Toppan printing; Research grant/Funding (institution): Tosoh Corporation. K. Nakagawa: Honoraria (self), Research grant/Funding (institution): AstraZeneca K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co., Ltd; Honoraria (self), Research grant/Funding (institution): Astellas Pharma Inc; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda Pharmaceutical Co.,Ltd; Honoraria (self), Research grant/Funding (institution): MSD K.K.; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Bristol Myers Squibb Company; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant/Funding (institution): Novartis Pharma K.K; Honoraria (self), Research grant/Funding (institution): SymBio Pharmaceuticals Limited; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer Japan Inc; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo Co., Ltd; Honoraria (self), Advisory/Consultancy: Kyorin Pharmaceutical Co., Ltd.; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Roche Diagnostics K.K.; Honoraria (self): Nippon Kayaku Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Bayer Yakuhin, Ltd; Honoraria (self), Research grant/Funding (institution): Merck Biopharma Co., Ltd; Honoraria (self), Research grant/Funding (institution): AbbVie Inc; Research grant/Funding (institution): Eisai Co., Ltd; Research grant/Funding (institution): Kissei Pharmaceutical Co., Lt; Research grant/Funding (institution): Kyowa Hakko Kirin Co., Ltd; Research grant/Funding (institution): Otsuka Pharmaceutical Co., Ltd.; Research grant/Funding (institution): Pfizer R&D Japan G.K.; Honoraria (self): Clinical Trial Co., Ltd., Nanzando Co., Ltd., Medicus Shuppan, Publishers Co., Ltd., Yodosha Co., Ltd., Care Net, Inc, Nikkei Business Publications, Inc, Reno, Medical K.K. Medical Review Co., Ltd., Yomiuri Telecasting Corporation, Medical Mobile Communications; Research grant/Funding (institution): A2 Healthcare Corp., inVentiv Health Japan, Quintiles Inc., IQVIA Services Japan K.K./icon Japan K.K./ EP-Crsu Co., Ltd./Gritsone Oncology.Inc, Linical Co., Ltd./Parexel International Corp., CMIC Shift Zero K.K./ EPS Corporation, Syneos Health, EPS Interna. All other authors have declared no conflicts of interest.