Abstract 2667: Trial in progress: Phase 1 study of BI 1823911, an irreversible KRASG12C inhibitor targeting KRAS in its GDP-loaded state, as monotherapy and in combination with the pan-KRAS SOS1 inhibitor BI 1701963 in solid tumors expressing KRASG12C mutation
Authors: Waizenegger Irene C. , Lu Hengyu , Thamer Claus , Savarese Fabio , Gerlach Daniel , Rudolph Dorothea , Vellano Christopher P. , Marotti Marcelo , Heymach John , Kopetz Scott , Heffernan Timothy P. , Marszalek Joseph R. , Petronczki Mark P. , Hofmann Marco H. , Kraut Norbert 
Published: June 2022

Inhibition of KRASG12C mediated signaling and the therapeutic impact in non-small cell lung cancer (NSCLC) whose tumors carry this mutation was demonstrated clinically by sotorasib and adagrasib leading to approval of sotorasib in KRASG12C mutant NSCLC. These encouraging data are currently changing the treatment paradigm for patients with KRASG12C-mutated tumors. However only a fraction of patients is initially responding to these compounds and patients who achieved an objective response ultimately progressed on-treatment. It became clear from these studies that KRASG12C inhibitors require a combination partner to either achieve a deeper response initially or to prevent development of resistance. Multiple rational combination approaches are currently investigated with the goal to prolong duration of response or to overcome KRASG12C inhibitor resistance. The KRASG12C inhibitor BI 1823911 is more potent compared to sotorasib or adagrasib and showed comparable in vivo efficacy at a dose of 60 mg/kg vs. 100 mg/kg of either sotorasib or adagrasib in preclinical studies. The pan-KRAS SOS1 inhibitor BI 1701963 is the first direct KRAS signaling modifier, which entered phase I clinical trials both as a monotherapy as well as in combination with KRASG12C inhibitors, MEK inhibitors and irinotecan. Pan-KRAS SOS1 inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. In the presented combination concept BI 1701963 shifts the balance of KRASG12C to its GDP-loaded form, which is the state to which BI 1823911 covalently binds to. Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition of BI 1823911 in combination with BI 1701963. Our preclinical results supported the start of a phase I trial (NCT04973163), investigating the safety, tolerability, recommended dose and preliminary efficacy of BI 1823911 alone and in combination with the pan-KRAS SOS1 inhibitor BI 1701963. The trial includes cohorts of patients with KRASG12C mutant solid tumors, such as NSCLC, CRC, cholangiocarcinoma, and pancreatic adenocarcinoma, both KRAS therapy naïve or KRAS therapy relapsed. The first patients in the trial were treated in the monotherapy arm, dose escalation started at a dose of 50 mg. The combination therapy part is expected to start in Q1 2022. Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic properties of combination regimens and preliminary efficacy.

Citation Format: Irene C. Waizenegger, Hengyu Lu, Claus Thamer, Fabio Savarese, Daniel Gerlach, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, John Heymach, Scott Kopetz, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Marco H. Hofmann, Norbert Kraut. Trial in progress: Phase 1 study of BI 1823911, an irreversible KRASG12C inhibitor targeting KRAS in its GDP-loaded state, as monotherapy and in combination with the pan-KRAS SOS1 inhibitor BI 1701963 in solid tumors expressing KRASG12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2667.