Abstract 1271: In vitro and in vivo characterization of BI 1823911 - a novel KRASG12C selective small molecule inhibitor

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-07, Vol.81 (13_Supplement), p.1271-1271
• Main Authors: Savarese, Fabio, Gollner, Andreas, Rudolph, Dorothea, Lipp, Jesse, Popow, Johannes, Hofmann, Marco H., Arnhof, Heribert, Rinnenthal, Jörg, Trapani, Francesca, Gmachl, Michael, Gerlach, Daniel, Broeker, Joachim, Ettmayer, Peter, Mantoulidis, Andreas, Phan, Jason, Smethurst, Christian A., Treu, Matthias, Waterson, Alex G., Lu, Hengyu, Machado, Annette, Daniele, Joseph, Fesik, Stephan W., Vellano, Christopher P., Heffernan, Timothy P., Marszalek, Joseph R., McConnell, Darryl B., Petronczki, Mark, Kraut, Norbert, Waizenegger, Irene C.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-1271

KRASG12C mutations are predominantly found in non-small cell lung cancer (NSCLC, 13%), in colorectal cancer (CRC, 3%), and with a lower prevalence in pancreatic ductal adenocarcinoma (PDAC, 1%). The amino acid exchange at position 12 from glycine to cysteine renders RAS insensitive to GAP-catalyzed hydrolysis but not to intrinsic hydrolysis and consequently, KRASG12C is still dependent on GEF stimulation to achieve full activation. The active GTP-loaded form of KRASG12C is favored and leads to activation of downstream signaling and proliferation. A number of recent publications has shown that targeting this mutant form of KRAS, using several covalent KRASG12C inhibitors binding to the inactive GDP-KRASG12C form, leads to anti-proliferative effects and induction of apoptosis in KRASG12C mutant cancer cell lines, CDX and PDX models. Early clinical data for AMG 510 and MRTX849 revealed a response rate of 35-45% in NSCLC and of 7-17% in CRC patients. Here, we show that BI 1823911 has potent anti-proliferative activity in a panel of KRASG12C mutant cancer cell lines with higher or similar potency compared to these two most advanced compounds in clinical development. In a panel of KRASG12C NSCLC cell lines, treatment with BI 1823911 results in downregulation of MAPK pathway-responsive genes, such as DUSP6 and CCND1, and the extent of pathway modulation correlates with sensitivity. Likewise, we observe strong and sustained inactivation of the MAPK pathway at the protein level using p-ERK as a pharmacodynamic (PD) biomarker. A MIA PaCa-2 cell line-derived pancreatic cancer xenograft model was selected for extensive PK/PD/efficacy analyses in vivo. Briefly, BI 1823911 tested at 60 mg/kg showed similar anti-tumor activity compared to both competitor compounds dosed at clinically relevant exposures. Results of the ongoing in-depth PK/PD/efficacy analysis will be shared. Furthermore, BI 1823911 was tested with a daily oral dose of 60 mg/kg in a panel of NSCLC or CRC CDX or PDX mouse models and showed comparable efficacy to AMG 510 and MRTX849, respectively. Preclinical and clinical data suggest that monotherapy with a KRASG12C inhibitor will not be sufficient to achieve durable response. Combination therapy of a KRASG12C inhibitor may therefore lead to enhanced anti-tumor efficacy and may address adaptive resistance mechanisms. Therefore, we selected a panel of KRASG12C mutant cancer cell lines and tested a large set of compounds in combination with BI 1823911 to iden