Abstract 524P
Background
BI 1701963 is a small-molecule protein–protein interaction inhibitor, which prevents KRAS activation by binding to the catalytic site of SOS1. This multicentre phase I first-in-human trial is evaluating BI 1701963 as monotherapy (mono tx) or in combination with trametinib in adults with KRAS-mutated solid tumours. Here, we report preliminary results from the mono tx arm, which aims to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of BI 1701963, based on dose-limiting toxicities (DLTs).
Methods
Pts are receiving BI 1701963 mono tx in 2 parts: dose escalation (Part A) and confirmation (Part B). The starting dose in Part A is 50 mg once-daily orally; dose cohorts will include ≥3 pts. In Part B, pts will be assigned to receive a therapeutic relevant dose. Primary endpoints are the MTD (Part A) and number of pts with DLTs during Cycle 1 (Parts A and B).
Results
To date, 28 pts have been treated (all Part A; 50/100/200/400/800 mg: 3/7/6/6/6 pts): 16 (57%) female; median age 57 yrs; 20 (71%) with ECOG PS of 1. All pts experienced adverse events (AEs); most commonly fatigue (n=11, 39%) and abdominal pain (n=7, 25%). Drug-related AEs occurred in 18 (64%) pts; most commonly diarrhoea, fatigue and decreased platelet count (all n=4, 14%). Three drug-related ≥G3 AEs were observed: G3 hypertension, G3 duodenal obstruction, G4 decreased platelet count. One DLT was reported: G4 decreased platelet count (800 mg). BI 1701963 was rapidly absorbed, with a tmax of 0.5–3 hrs post first dose. Exposure increased proportionally with increasing doses post first dose; dose-normalised Cmax and AUC0-24h values were 22.1 nmol/L/mg and 222.6 nmol*h/L/mg, respectively. Apparent terminal half-life is 12–26 hours. At 800 mg, exposure (AUC0-24h) is above the predicted therapeutic active exposure seen in xenograft models. Analysis of RAS/MAPK pathway target gene expression in paired tumour biopsies (n=12) showed signs of pathway inhibition at 800 mg (n=2).
Conclusions
These preliminary data suggest that BI 1701963 mono tx is generally well tolerated and indicate signs of signalling modulation. Recruitment is ongoing in mono tx and combination cohorts; updated data will be presented.
Clinical trial identification
NCT04111458.
Editorial acknowledgement
Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Hannah Simmons MSc, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.
Legal entity responsible for the study
Boehringer Ingelheim.
Funding
Boehringer Ingelheim.
Disclosure
M.L. Johnson: Financial Interests, Institutional, Advisory Board: Abbvie; Financial Interests, Institutional, Advisory Board: Amgen; Financial Interests, Institutional, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Editas Medicine; Financial Interests, Institutional, Advisory Board: Eisai; Financial Interests, Institutional, Advisory Board: G1 Therapeutics; Financial Interests, Institutional, Advisory Board: GlaxoSmithKline; Financial Interests, Institutional, Advisory Board: Ideaya Biosciences; Financial Interests, Institutional, Advisory Board: Incyte; Financial Interests, Institutional, Advisory Board: Ribon Therapeutics; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Principal Investigator: Abbvie; Financial Interests, Institutional, Principal Investigator: Acerta; Financial Interests, Institutional, Principal Investigator: Adaptimmune; Financial Interests, Institutional, Principal Investigator: Amgen; 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E. Gort: Financial Interests, Personal, Other, Travel/accomodation/expenses: Boehringer Ingelheim. S. Pant: Financial Interests, Personal, Other, Honoraria (self): 4D Pharma; Financial Interests, Personal, Advisory Role: Tyme; Financial Interests, Institutional, Research Grant: Mirati Therapeutics; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Redhill Biopharma; Financial Interests, Institutional, Research Grant: Xencor; Financial Interests, Institutional, Research Grant: Five Prime Therapeutics; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Rgenix; Financial Interests, Institutional, Research Grant: Sanofi/Aventis; Financial Interests, Institutional, Research Grant: ArQule; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Onco Response; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Personal, Advisory Role: Xencor; Financial Interests, Personal, Advisory Role: Zymeworks. M.P. Lolkema: Other, Personal, Advisory Board, Ph III study steering cie: Amgen; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: JnJ; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Janssen Cilag B.V.; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: INCa; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Sanofi Aventis; Financial Interests, Personal, Advisory Role: Netherlands BV; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Merck Sharp and Dome; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Julius Clinical. M. Sebastian: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Invited Speaker: Janssen-Cilag; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Sanofi-Aventis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Merck-Serono; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Janssen-Cilag; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sanofi-Aventis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Merck-Serono; Financial Interests, Institutional, Research Grant: AstraZeneca. M. Scheffler: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Writing Engagements: Amgen; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal and Institutional, Research Grant: Amgen; Financial Interests, Personal and Institutional, Research Grant: Dracen Pharmaceuticals; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Personal and Institutional, Project Lead: Dracen Pharmaceuticals; Financial Interests, Personal, Member: ESMO Lung Cancer Faculty; Financial Interests, Personal, Member: EORTC Lung Cancer Group; Financial Interests, Personal, Member: ESMO Climate Change Task Force; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Novartis. 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Hwang: Financial Interests, Personal, Advisory Role: Genentech/Roche; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Caris Centers of Excellence; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Speaker’s Bureau, Speaker bureau/expert testimony: BMS; Financial Interests, Personal, Speaker’s Bureau, Speaker bureau/expert testimony: Deciphera; Financial Interests, Personal, Speaker’s Bureau, Speaker bureau/expert testimony: Incyte; Financial Interests, Institutional, Research Grant, Research grant/Funding: Caris Centers of Excellence; Financial Interests, Institutional, Research Grant, Research grant/Funding: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: QED. U. Dünzinger: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. K. Riemann: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. T. Kitzing: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. P.A. Jänne: Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Merrimack; Financial Interests, Personal, Advisory Role: Chugai Pharma; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: LOXO; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: Araxes Pharma; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Biocartis; Financial Interests, Personal, Advisory Role: Voronoi Health Analytics; Financial Interests, Personal, Advisory Role: SFJ Pharmaceuticals Group; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Biocartis; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Transcenta; Financial Interests, Personal, Advisory Role: Silicon Therapeutics; Financial Interests, Personal, Advisory Role: Syndax; Financial Interests, Personal, Advisory Role: Nuvalent; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Esai; Financial Interests, Personal, Research Grant, Research grant/Funding (self): AstraZeneca; Financial Interests, Personal, Research Grant, Research grant/Funding (self): Astellas Pharma; Financial Interests, Personal, Research Grant, Research grant/Funding (self): Daiichi Sankyo; Financial Interests, Personal, Research Grant, Research grant/Funding (self): Lilly; Financial Interests, Personal, Research Grant, Research grant/Funding (self): Boehringer Ingelheim; Financial Interests, Personal, Research Grant, Research grant/Funding (self): Puma Biotechnology; Financial Interests, Personal, Research Grant, Research grant/Funding (self): Takeda; Financial Interests, Personal, Research Grant, Research grant/Funding (self): Revolution Medicines; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: LOXO; Financial Interests, Personal, Royalties, I am a co-inventor of DFCI owned patent on EGFR mutations licensed to Lab Corp. I receive post-marketing royalties from this invention: DFCI - Lab Corp.