665P - First-in-human, phase Ia/b, dose-escalation/expansion study of KRAS G12C inhibitor BI 1823911, as monotherapy and combined with anticancer therapies, in patients (pts) with advanced or metastatic solid tumours harbouring a KRAS G12C mutation

Background

BI 1823911, a mutant-selective KRAS G12C inhibitor, covalently binds to G12C mutant KRAS, irreversibly locking it in its inactive GDP form, interfering with cell signalling, causing tumour cell apoptosis and blocking cell proliferation. NCT04973163 is assessing BI 1823911 monotherapy and is designed to evaluate combinations with other anticancer therapies in pts with locally advanced/metastatic solid tumours with a KRAS G12C mutation.

Methods

The study has two arms (monotherapy; combination with anticancer therapies) and three parts (dose escalation, A; confirmation, B; expansion, C). Primary endpoint in Part A is number of pts with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period. Primary endpoint in Parts B and C is objective response (confirmed complete or partial response [PR]). Primary objective is to ascertain the MTD/recommended phase II dose of BI 1823911, alone and in combination.

Results

As of 23rd Jan 2023, 17 pts received monotherapy in Part A (50/100/200/400/600/900/1200 mg QD, n=1/1/1/3/3/3/5); 9 male, 8 female; median age 58 years. 8 discontinued treatment (progressive disease, n=4; adverse event [AE], n=2). 3 pts had DLTs in the MTD evaluation period: G3 gastrointestinal stoma complication (n=1; 900 mg) and G3 diarrhoea (n=2; 1200 mg; 1 serious AE [SAE]). All pts experienced AEs (G3, n=8), most commonly diarrhoea (n=14) and nausea (n=14). 16 had drug-related AEs (G3, n=3; G4, n=0), most commonly diarrhoea (n=12; G3, n=3), nausea (n=12; G3 n=0) and vomiting (n=10; G3 n=0). 1 had a DLT outside the MTD evaluation period (G3 diarrhoea; 600mg; SAE). 2 had AEs leading to discontinuation; 6 had AEs leading to dose reduction. During early dose escalation (≥100 mg), 11 pts had disease control, including 8 with stable disease and 3 with confirmed PR (600 mg, n=2, lung and unknown cancer, Day 53 and 55; 900 mg, n=1, small intestine, Day 50).

Conclusions

Preliminary data suggest BI 1823911 monotherapy is generally well tolerated and offers clinical activity. Recruitment is ongoing; updated data will be presented.

Clinical trial identification

NCT04973163.

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 Inizio Company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

J. Heymach: Financial Interests, Personal, Advisory Board: Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAlta, Sanofi, Spectrum Pharmaceuticals, GSK, EMD Serono, BluePrint Medicine, Chugai Pharmaceutical; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Financial Interests, Personal, Licencing Fees: Spectrum; Financial Interests, Personal, Royalties: Spectrum; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer-Ingelheim, Spectrum, Mirati, Bristol Myer Squibb, Takeda. N. Kotecki: Financial Interests, Personal, Other, Travel grant: OSE Immunotherapeutics, Byondis. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. C.R. Lindsay: Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, CBPartners; Financial Interests, Institutional, Research Funding: Revolution Medicines; Non-Financial Interests, Personal, Non-financial benefits: Amgen. C. Thamer, S. Eigenbrod-Giese, M.A. Marotti: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. All other authors have declared no conflicts of interest.