524P A phase I, open-label, dose-escalation trial of BI 1701963 in patients (pts) with KRAS mutated solid tumours: A snapshot analysis

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). 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). 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). 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.