BAY 1436032 (BAY) inhibits R132X-mIDH1, which aberrantly generates oncometabolite 2-hydroxyglutarate (2-HG). In animal studies, BAY decreased 2-HG levels in mIDH1 tumours and showed brain penetration (brain/plasma ratio ∼0.2). Plasma 2-HG levels are increased in pts with mIDH1 tumours like intrahepatic cholangiocarcinoma (IHCC), but not in mIDH1 gliomas.
In this ongoing phase I dose-escalation and expansion study, BAY was administered orally (150-1500 mg BID) to pts with advanced mIDH1-R132X solid tumours. 4 expansion cohorts (1500 mg BID) enrolled pts with anaplastic and advanced grade 2 gliomas, glioblastoma (GBM), IHCC and other tumours. Response was assessed by RECIST (solid tumours) and RANO criteria (gliomas). Plasma BAY and 2-HG levels were measured.
29 pts were treated in the escalation part in 5 dose-escalation cohorts and 52 in the expansion part. Pts had glioma (n = 55), IHCC (n = 16), chondrosarcoma (n = 7) and other tumours (n = 3). As of the 8 Nov 2018 preliminary cut-off, the most common all-cause treatment-emergent AEs reported in ≥ 10% of pts were: headache (20%), vomiting, diarrhoea and fatigue (19% each), nausea (16%), ALT increased (12%) and blood bilirubin increased (11%). There was 1 DLT (grade 3 rash maculopapular, 1500 mg BID). MTD was not reached; RP2D was 1500 mg BID. BAY exposure increased broadly dose proportionally from 150-1200 mg, with high variability. Consistent with short half-life, no accumulation was observed. Plasma 2-HG reduction occurred in nearly all non-glioma pts, with up to 98% inhibition. A pt with anaplastic astrocytoma (AA) (1200 mg BID) achieved complete response and is still on treatment (>23 months at cut-off); 2 glioma pts (AA and oligodendroglioma, both 1500 mg BID) had a partial response. 6 additional pts remained on treatment with stable disease at cut-off (3 gliomas, 2 GBM, 1 IHCC; treatment duration 4-11 months). Updated safety, efficacy and PK/PD analyses will be presented.
BAY is well tolerated as anticipated due to specificity for mIDH1. BAY inhibited mIDH1-R132X activity as evidenced by a PD effect in pts with measurable 2-HG, with objective response in 3 pts (all gliomas).
NCT02746081.
Medical writing assistance was provided by Laura Valenzo, PhD, of Complete Health Vizion and funded by Bayer AG.
Bayer AG.
Bayer AG.
W. Wick: Non-remunerated activity/ies, patent: IDH vaccine; Non-remunerated activity/ies, patent: IDH diagnostic; Non-remunerated activity/ies, patent: APG diagnostic. G. Tabatabai: Research grant / Funding (self): Roche Diagnostics; Research grant / Funding (self): Medac; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Novocure; Travel / Accommodation / Expenses: Medac; Speaker Bureau / Expert testimony: Medac; Speaker Bureau / Expert testimony: Novocure; Advisory / Consultancy: AbbVie; Advisory / Consultancy: BMS; Advisory / Consultancy: TIGER NIS (Novocure); Advisory / Consultancy: ON-TRK NIS (Bayer). M. Schuler: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Honoraria (self): Abbvie; Honoraria (self): Alexion; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene; Honoraria (self): Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol Myers-Squibb; Research grant / Funding (institution): Novartis. K. Rorhberg: Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche; Research grant / Funding (self), Non-remunerated activity/ies: Loxo Oncology; Research grant / Funding (self), Non-remunerated activity/ies: Orion Pharma; Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: PUMA; Research grant / Funding (self), Non-remunerated activity/ies: Cantargia; Research grant / Funding (self), Non-remunerated activity/ies: Genmab; Research grant / Funding (self), Non-remunerated activity/ies: Novartis; Research grant / Funding (self), Non-remunerated activity/ies: Incyte; Research grant / Funding (self), Non-remunerated activity/ies: Symphogen; Research grant / Funding (self), Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (self), Non-remunerated activity/ies: Alligator; Research grant / Funding (self), Non-remunerated activity/ies: Merck; Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (self), Non-remunerated activity/ies: BMS. S.P. Chawla: Research grant / Funding (self): Amgen; Research grant / Funding (self): Roche; Research grant / Funding (self): Threshold Pharmaceuticals; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Immune Design; Research grant / Funding (self): TRACON Pharma; Research grant / Funding (self): SARC; Research grant / Funding (self): Karyopharma Therapeutics; Research grant / Funding (self): Jansen. F. Janku: Research grant / Funding (self): Novartis; Research grant / Funding (self): Genentech; Research grant / Funding (self): Bayer; Research grant / Funding (self): BioMed Valley Discoveries; Research grant / Funding (self): Astellas; Research grant / Funding (self): Agios; Research grant / Funding (self): Plexxikon; Research grant / Funding (self): Deciphera; Research grant / Funding (self): Piqur; Research grant / Funding (self): Symphogen; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Asana; Research grant / Funding (self): Upsher-Smith Laboratories; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: IFM Therapeutics; Advisory / Consultancy: Synlogic; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Trovagene; Advisory / Consultancy: Immunomet; Shareholder / Stockholder / Stock options: Trovagene. Y. Narita: Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Abbvie; Speaker Bureau / Expert testimony, Research grant / Funding (self): Dainippon-Sumitomo; Speaker Bureau / Expert testimony, Research grant / Funding (self): Daiichi-Sankyo; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eisai; Speaker Bureau / Expert testimony, Research grant / Funding (self): Stella-pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ohtuka; Speaker Bureau / Expert testimony, Research grant / Funding (self): Meiji-seika; Speaker Bureau / Expert testimony, Research grant / Funding (self): SBI pharma. Y. Ando: Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Kyowa Hakko Kirin Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Nippon Kayaku Co., Ltd.; Honoraria (self), Research grant / Funding (self): Yakult Honsha Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (self): Mochida Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Ono Pharmaceutical Co.,Ltd.; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical Co.,Ltd.; Honoraria (self): Novartis Pharma K.K.; Honoraria (self): Merck Serono Co.,Ltd.; Honoraria (self): Bayer Holding Ltd.; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Otsuka Holdings Co.,Ltd.; Honoraria (self): Sawai Pharmaceutical Co., Ltd; Honoraria (self), Research grant / Funding (self): Daiichi Sankyo Company, Ltd.; Research grant / Funding (self): Eisai Co.,Ltd.; Research grant / Funding (self): Hisamitsu Pharmaceutical Co., Inc.; Research grant / Funding (self): Takeda Pharmaceutical Co.,Ltd.; Honoraria (self): Tsumura & Co.; Honoraria (self): Shionogi & Co.,Ltd; Honoraria (self): Janssen Pharmaceutical K.K.; Honoraria (self): Pharma International Inc. H.J. Lenz: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck KG. M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eisai; Honoraria (self), Advisory / Consultancy: MSD; Research grant / Funding (self): Ono; Advisory / Consultancy, Research grant / Funding (self): ASLAN; Honoraria (self), Research grant / Funding (self): Yakult; Research grant / Funding (self): J-Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Honoraria (self), Research grant / Funding (self): Sumitomo Dainippon; Research grant / Funding (self): Kowa; Honoraria (self): Abbott; Honoraria (self): EA Pharma; Advisory / Consultancy, Research grant / Funding (self): Chugai; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Advisory / Consultancy, Research grant / Funding (self): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (self): NanoCarrier; Advisory / Consultancy: Shire; Honoraria (self), Research grant / Funding (self): Taiho; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Baxalta; Research grant / Funding (self): Merck Serono; Advisory / Consultancy, Research grant / Funding (self): Takara Bio; Research grant / Funding (self): Zeria; Honoraria (self): Nobelpharma; Honoraria (self), Advisory / Consultancy: Otsuka; Honoraria (self): Kaken Pharmaceutical; Honoraria (self): Gilead; Advisory / Consultancy: Astellas Pharma; Research grant / Funding (self): Takeda Pharmaceutical; Advisory / Consultancy: Micron. I. Genvresse: Full / Part-time employment: Bayer AG. C. Rentzsch: Full / Part-time employment: Bayer AG. S. Reschke: Full / Part-time employment: Bayer AG. C. Cyris: Full / Part-time employment: CHRESTOS Concept GmbH & Co. KG. C. Cai: Full / Part-time employment: Bayer HealthCare Pharmaceuticals, Inc. M. Jeffers: Full / Part-time employment: Bayer HealthCare Pharmaceuticals, Inc. C. Peña: Full / Part-time employment: Bayer HealthCare Pharmaceuticals, Inc. O. Bähr: Honoraria (self): Novocure; Honoraria (self): Medac Pharma; Honoraria (self): BMS. All other authors have declared no conflicts of interest.