MPM is an aggressive malignancy of increasing prevalence and poor prognosis. At relapse after platinum-based (pb) CT, single agent CT is commonly used and single arm trials of immune checkpoint inhibitors have demonstrated encouraging activity.
PROMISE-meso is an open-label 1:1 randomized phase III trial investigating the efficacy of P (200 mg/Q3W) vs institutional choice single agent CT (gemcitabine or vinorelbine) in relapsed MPM patients (pts) failing one previous line of pb CT. Pts were of PS 0-1 and unselected for PD-L1 status. P beyond progression (PD) for clinical benefit and crossover to P at PD on CT were allowed. Primary endpoint was progression-free survival (PFS, RECIST 1.1) by independent radiological review (IR). The trial was designed to detect an increase in median PFS from 3.5 months (ms) to 6ms with P (HR = 0.58, 80% power, 1-sided α = 0.025). 142 pts were needed to observe the required 110 events. Secondary endpoints were overall survival (OS), investigator assessed (IA) PFS, objective response rate (ORR), adverse events (AE), while efficacy by PD-L1 status was exploratory.
Between 09/17 and 08/18, 144 pts were randomized, 73 to P and 71 to CT. At 20/02/19 data lock, 70 pts were on follow-up (median 12ms). Pts were of median age 70 years, 82% males, 77% poor EORTC prognostic score, 50% never smokers, 89% epithelioid histology and 65% (of 102 available) TPS≥1%. ORRs were 22% in P, 6% in CT (p = 0.004). 62 IR PFS events were observed in P vs 56 in CT, median PFS 2.5ms (95%CI 2.1-4.2) vs 3.4ms (2.2-4.3), HR = 1.06 (0.73–1.53), p = 0.76. Median OS was 10.7ms for P vs 11.7ms for CT, HR = 1.05 (0.66-1.67), p = 0.85. 45 CT pts crossed over to P. Accounting for crossover yielded similar OS results. Treatment-related AEs grade ≥3 were experienced by 19% P vs 24% CT pts, one fatal per arm. Most common AEs were fatigue (19%) in P vs nausea (27%) and fatigue (31%) in CT.
This is the first randomized trial evaluating the efficacy of P vs single agent CT in MPM pts progressing after or on previous pb CT. In unselected pts, whilst associated with an improved ORR, P does not improve PFS or OS over single agent CT.
NCT02991482.
European Thoracic Oncology Platform (ETOP).
MSD Merck Sharp & Dohme AG.
S. Popat: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Research grant / Funding (institution): Epizyme; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): Clovis Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Chugai Pharma; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: AbbVie. A. Curioni-Fontecedro: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Takeda. R. Shah: Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Lilly. M. O’Brien: Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: BMS; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Pierre fabre; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Teaching role for Roche: Roche. P. Fisher: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme. D. Gilligan: Honoraria (self): Merck Sharp & Dohme. E. Nadal: Advisory / Consultancy: Merck Sharp & Dohme. R. López Castro: Honoraria (self), Travel / Accommodation / Expenses: Takeda; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Aristo. R. García Campelo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme. S. Peters: Honoraria (self): AbbVie; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Biocartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Clovis; Honoraria (self): Daiichi Sankyo; Honoraria (self): Debiopharm; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Foundation Medicine; Honoraria (self): Illumina; Honoraria (self): Janssen; Honoraria (self): Merck Sharp and Dohme; Honoraria (self): Merck Serono; Honoraria (self): Merrimack; Honoraria (self): Novartis; Honoraria (self): Pharma Mar; Honoraria (self): Pfizer; Honoraria (self): Regeneron; Honoraria (self): Sanofi; Honoraria (self): Seattle Genetics ; Honoraria (self): Takeda. R.A. Stahel: Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self): Merck Sharp & Dohme; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self): Takeda; Research grant / Funding (self): BMS; Research grant / Funding (self): Genentech. All other authors have declared no conflicts of interest.
The phase IIR trial IFCT-1501 (MAPS2) tested nivo or nivo+ipi in pts with relapsed MPM as second/third-line. This trial reached its primary endpoint with 40% or more of pts with disease control in both arms. We now focus on long-term survivals and specific patterns of progression.
125 pts were randomized to receive Nivo 3 mg/kg q2w or Nivo 3 mg/kg q2w+Ipi 1mg/kg q6w, until progr or unacceptable toxicity. Median follow-up for OS is 32.5 months (Mar. 1st2019). HPD was defined by calculating the tumor growth rate before and during i.o. with determining the variation per month (ΔTGR) (Ferrara, JAMA Oncol 2018) or by measuring the tumor growth kinetics (TGK)on i.o. and on last treatment before, with TGK ratio (TGKr) calculation (Saâda-Bouzid, Ann. Oncol. 2017). HPD was defined as disease progression (assessed by BICR) with ΔTGR exceeding 50% or with a TGKr>2.
Median OS was 11·9 mo. (6·7–17·4) in the nivo arm and 15·9 mo. (10·7–22.2) in the nivo+ipilimumab arm. 52 (82%) /63 pts in the nivo group and 49 (79%)/62 patients in the combo group had died by data cutoff. 1 & 2-year survivals were 49·2% (36·4–60·8) & 25·4% (15·5–36·6) in the nivo arm, and 58·1% (44·8–69·2) & 31·7% (20·5–43·4) in the Nivo +Ipi arm. With ΔTGR method, 4 and 2 patients in Nivo and combo group had HPD respectively, while 7 and 4 patients had HPD by using TGKr. HPD pts with TGKr had a poorer OS than pts with standard progression only in the nivolumab arm (median OS = 1.6 mo [0.8-7.7] vs. 4.4 mo [2.4-10.8], (p = 0.02 in Cox model), while no difference was seen with ΔTGR definition.When both arms were analyzed together, only HPD pts defined with the TGKr had significantly worse survival: HR (progressive pts vs HPD): 0.37 [0.19-0.75], p = 0.006, with HR (pts with DCR vs. HPD)= 0.12 [0.06-0.25], p < 0.0001 and 2.6, 5.5 and 23.1 mos of median OS for HPD, progressive and pts with DCR respectively. All HPD patients with available IHC data (n = 8/11) had PDL1-neg expression at 1% cut-off (p = 0.001).
The durable efficacy of Nivo & Nivo+Ipi in MPM in confirmed, with 1/4 and 1/3 of pts alive at 2 yrs respectively. HPD pattern of progression did exist in both arms, associated with significantly worse survival when the TGKr definition of HPD is used.
NCT02716272.
IFCT: French Cooperative Thoracic Intergroup.
BMS.
G. Zalcman: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Inventiva; Honoraria (self), Advisory / Consultancy: Merck (MSD); Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche-France; Travel / Accommodation / Expenses: AbbVie. J. Mazieres: Honoraria (institution), Research grant / Funding (self): Roche-France; Honoraria (institution): BMS; Honoraria (institution), Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. L. Greillier: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Non-remunerated activity/ies: Novartis; Honoraria (self), Non-remunerated activity/ies: Lilly; Honoraria (self), Non-remunerated activity/ies: Pfizer; Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Boerhinger-Ingelheim; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: AbbVie; Honoraria (self), Non-remunerated activity/ies: MSD. S. Lantuejoul: Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (self), Non-remunerated activity/ies: Roche-Diagnostics; Honoraria (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: BMS. O. Bylicki: Honoraria (self), Non-remunerated activity/ies: MSD; Non-remunerated activity/ies: Roche. I. Monnet: Travel / Accommodation / Expenses: BMS. R. Corre: Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Audigier-Valette: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Boerhinger-Ingelheim; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Sysmex; Honoraria (self): MSD; Honoraria (self): Clovis Oncology; Honoraria (self): AbbVie. O. Molinier: Honoraria (self): BMS. F. Guisier: Honoraria (self), Non-remunerated activity/ies: 3MS; Honoraria (self): MSD US; Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Boerhinger-Ingeheim; Non-remunerated activity/ies: Chugai. D. Planchard: Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): BMS; Honoraria (self): Celgene; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche. E. Amour: Full / Part-time employment: IFCT. F. Morin: Full / Part-time employment: IFCT. D. Moro-Sibilot: Honoraria (self), Non-remunerated activity/ies: BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Boerhinger Ingelheim; Honoraria (self): Takeda; Honoraria (self): Leurquin Mediolanum. A. Scherpereel: Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Boerhinger Ingelheim. All other authors have declared no conflicts of interest.
MPM is an aggressive cancer with poor prognosis. Platinum/pemetrexed regimen is the standard 1°-line chemotherapy (CHT) in advanced disease.
The RAMES Study evaluated the 2°-line efficacy of gemcitabine/ramucirumab treatment vs. gemcitabine/placebo. From December 2016 to July 2018 (end of enrolment), 164 pts were admitted to this study. We evaluated by NGS the mutational profile of a panel of 34 genes (gs) (ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6). We reported the results of the 103 pts (63%) of both arms with specimen available for molecular analysis. Median age was 63 years (45-81), 24.3% (n = 25) were females and 75.7% (n = 78) males. Histotype was 83.5% (n = 86) epithelioid and 16.5% (n = 17) non-epithelioid. 37.8% (n = 39) were stage IV, 60.2% (n = 62) were stage III, and 1.9% (n = 2) were unknown. In 1°-line platinum/pemetrexed CHT treated pts, the median PFS was 5.75 months (ms) (C.I. 95% 4.75-6.76). 50 pts had PFS <6 ms, while 50 pts had PFS >6 ms (n = 3 not available).
260 functional somatic mutations were identified in 28 of the 34 gs analyzed. 75pts (72.8%) displayed mutations in 1 to 3 gs while 17 pts (16.5%) showed mutations in at least 4 gs. No mutated gs were detected for 11 pts (10.7%). The number of mutated gs was positively associated with higher stage and metastatic behavior (p = 0.025) and increased 1°-line PFS (p = 0.011). RDX (42.7%), MXRA5 (23.3%), BAP1 (13.6%), PIK3CB (10.7%) and NF2 (10.7%) were the most frequently mutated gs in our pts. Mutations in RAPGEF6 (p = 0.013) and ACTG1 (p = 0.01) were associated with non-epithelioid, while mutations in BAP1 (p = 0.041) were associated with PFS >6 months. A positive trend of association was also observed between mutations in COL3A1 (p = 0.052) and NFRKB (p = 0.052) and stage IV.
In MPM the identification of molecular gene alterations could be an important starting point for understanding the main pathways involved in prognosis and sensitivity/resistance to therapy. In the RAMES Study, the mutation of gene BAP1 is related to a prolonged PFS at the 1°-line CHT (p = 0.041).
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Available systemic 2nd or 3rd line options for MPM show a median progression-free survival (mPFS) of less than 2 months (mo) and median overall-survival (mOS) of 6-9 mo. Lurbinectedin (PharmaMar) is a novel compound with a dual role of binding to the DNA minor groove and inhibiting cytokine transcription of tumor-associated macrophages. Single MPM pts treated with lurbinectedin in early clinical trials showed encouraging outcome. The aim of current trial was to provide further data on safety and efficacy of lurbinectedin in progressive MPM.
MPM pts (all histologies) not amenable for local treatment and progressing after first-line platinum-pemetrexed chemotherapy +/- immunotherapy (IO) received 2nd or respectively 3rd line lurbinectedin. Lurbinectedin 3.2 mg/m2 every 3 weeks was given i.v. until progression or unacceptable toxicity. Primary endpoint was PFS at 12 weeks (PFS12wks) and would be met if achieved by at least 21 pts (p0 ≤ 35%; mPFS 2 mo). Secondary endpoints were mPFS, mOS and adverse events (AEs).
6 Swiss and 3 Italian centers recruited 42 pts (33 epithelioid, 4 biphasic, 5 sarcomatoid). 10/42 (23.8%) pts also received prior IO. At cut-off date (31st January 2019) PFS12wks was met by 22/42 pts (52.4%; 95%CI [38.7%; 63.5%]; p = 0.015) for mPFS of 4.1mo (95% CI [2.6; 5.5]) and mOS of 11.9mo (95% CI [9.2; 14.7]). 1 pt had complete, 1 pt partial response and 20 pts stable disease as best response. No significant difference in PFS12wks, mPFS and mOS was observed in epithelioid vs non-epithelioid MPM and prior-IO vs non-prior IO pts. All pts experienced AEs. Grade 3-4 toxicity was seen in 33 pts with most common being leuco-/lymphopenia (60.6%) and fatigue (24.2%). Febrile neutropenia was 9.1%. No pt discontinued treatment due to toxicity.
The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity compared to historical data. Neither histology nor prior IO seems to affect efficacy of lurbinectedin, but respective pts numbers are small for definitive conclusions. Further evaluation of lurbinectedin in a large randomized trial is warranted.
NCT03213301.
Swiss Group for Clinical Cancer Research.
PharmaMar; State Secretariat for Education, Research and Innovation (SERI).
Y. Metaxas: Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: PharmaMar; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol Meyer Squibb; Honoraria (institution), Advisory / Consultancy: MSD; Research grant / Funding (institution): Krebsliga Graubünden; Research grant / Funding (institution): Suva Switzerland. M. Frueh: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Takeda. F. Grosso: Travel / Accommodation / Expenses: Novocure; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Boehringer Ingelheim; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Bristol-Meyer Squibb; Travel / Accommodation / Expenses: Amianto-Italia-Canada-Asbestos Committee; Honoraria (self): Merck; Honoraria (self): Italian Centro per la Prevenzione e Controllo delle Malattie; Research grant / Funding (self): Associazione Famigliari e Vittime Amianto. P.A. Zucali: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self): Pfizer; Honoraria (self): Ipsen; Honoraria (self): Tesaro. G.L. Ceresoli: Honoraria (self), Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self): Astellas; Honoraria (self): Pfizer; Travel / Accommodation / Expenses: Novocure. M.T. Mark: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Boehringer; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Takeda. M.R.A. Perrino: Honoraria (self): Astellas; Honoraria (self): Bristol Meyer Squibb; Honoraria (self): Novartis. S. Schmidt: Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Takeda. R. von Moos: Honoraria (institution), Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Elly Lilly; Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Bristol-Meyers ; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Vifor. All other authors have declared no conflicts of interest.
Thymic carcinoma is a rare malignant disease. Standard treatments have not been established for patients with advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy. Several trials reported the efficacy of multi-targeted inhibitors mainly targeting vascular endothelial growth factor receptor (VEGFR) for thymic carcinoma. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, fibroblast growth factor receptor (FGFR), RET, c-Kit etc.; it has shown anti-tumor activity with manageable toxicity profiles in several cancer types. We investigated the efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma (JMA-IIA00285).
An open-label, single-arm, multi-center phase II trial was conducted in patients with histologically confirmed thymic carcinoma. The eligibility criteria were disease progression after at least one prior platinum-based chemotherapy, ECOG-PS of 0 or 1, measurable lesions, and adequate organ functions. Patients received 24 mg of lenvatinib orally once daily until progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR) by independent radiological review. As per the SWOG two-stage design, the sample size of 40 had 80% power with one-sided alpha error of 5%; threshold ORR, 10%; and expected ORR, 25%.
Between May 2017, and Feb 2018, 42 patients were enrolled from 8 institutions in Japan. The median follow-up period was 15.5 months (IQR 13.1-17.5). The 42 assessable patients had ORR of 38.1% (90%CI, 25.6-52.0), indicating statistically significant improvement in ORR. Of them, 16 had partial response, and 24 achieved stable disease. The most treatment-related adverse events of any grade were hypertension, diarrhea, and hand-foot syndrome, proteinuria, hypothyroidism, and decreased platelet count.
The efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These encouraging results suggest that lenvatinib could become one of the standard treatment options in patients with advanced or metastatic thymic carcinoma.
JMA-IIA00285.
The authors.
Center for Clinical trials, Japan Medical Association and Eisai.
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), Research grant / Funding (institution): Pfizer; 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; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Ignyta. J. Sato: Speaker Bureau / Expert testimony: AstraZeneca K.K.. Y. Okuma: Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Takeda Pharmaceutical Company Ltd; Speaker Bureau / Expert testimony: AstraZeneca K.K.; Speaker Bureau / Expert testimony: Nippon Boehringer Ingelheim Co.; Speaker Bureau / Expert testimony: Bristol‐Myers Squibb Japan; Speaker Bureau / Expert testimony: MSD K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical.. S. Niho: Research grant / Funding (self): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Eli Lilly; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Shionogi. H. Mizugaki: Speaker Bureau / Expert testimony, Research grant / Funding (self): Boehringer Ingelheim; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Chugai Pharmaceutical. H. Murakami: Honoraria (self): AstraZeneca; Honoraria (self): Chugai pharma; Honoraria (self): Lilly Japan; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim. T. Kozuki: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical ; Honoraria (self), Research grant / Funding (self): Eli-Lilly; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical ; Honoraria (self): Ono Pharmaceutica; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self): Beohringer-Ingelheim; Honoraria (self): Kyowa-Hakko Kirin; Honoraria (self): Pfizer; Research grant / Funding (self): Merck Biopharma. K. Nakamura: Speaker Bureau / Expert testimony: Eisai. A. Kuchiba: Speaker Bureau / Expert testimony: Chugai. N. Yamamoto: Research grant / Funding (self): Astellas; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai; Advisory / Consultancy, Research grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Kyowa-Hakko Kirin; Advisory / Consultancy, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono; Research grant / Funding (self): Janssen Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Merck; Advisory / Consultancy: Otsuka; Advisory / Consultancy: Cimic. All other authors have declared no conflicts of interest.