HER2 mutations are potent oncogenic drivers in various cancer indications. In NSCLC, about 2% of patients carry either a HER2 exon20 insertion mutation or a HER2 point mutation. With the recent approval of fam-trastuzumab deruxtecan-nxki, the first targeted treatment option became available for HER2 mutant NSCLC patients. However, there remains a high unmet need for more effective and better tolerated therapies with the potential to improve response rates and response durability. BAY 2927088 is a reversible small molecule inhibitor that is currently being evaluated in a first-in-human, phase I clinical trial in patients with EGFR mutant NSCLC (NCT05099172). Here, we present the preclinical activity profile of BAY 2927088 in HER2 mutant NSCLC. BAY 2927088 shows strong antiproliferative activity in an isogenic Ba/F3 cell line panel of HER2 exon20 insertion mutations as well as HER2 point mutations. BAY 2927088 is highly potent on the most frequent HER2 exon20 insertion mutations A775insYVMA and G776del insVC, as well as in the HER2 point mutations S310F, S335C, and L755S, among others. In addition, the compound was active in a subset of endogenously HER2 mutant cancer cell lines. The in vitro activity of BAY 2927088 was validated in vivo in a patient-derived xenograft model carrying the HER2 exon20 insertion mutation A775insYVMA. The strong preclinical activity of BAY 2927088 in HER2 mutant NSCLC supports clinical evaluation in this indication and might offer a novel targeted therapy option for NSCLC patients that carry HER2 mutations. Citation Format: Franziska Siegel, Gizem Karsli-Uzunbas, Kristyna Kotynkova, Quinn McVeigh, Stephan Siegel, Daniel Korr, Volker Schulze, Markus Berger, Georg Beckmann, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. Preclinical activity of BAY 2927088 in HER2 mutant non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4035.
Molecular therapies targeting EGFR-mutant non-small cell lung cancer (NSCLC) have dramatically improved prognosis for patients with the classical activating mutations, L858R and exon 19 deletion. Tumors harboring EGFR exon 20 insertions do not respond to inhibitors of classical activating mutations. Agents such as amivantamab and mobocertinib have been approved for treatment of lung cancer patients with exon 20 insertions, but agents with an improved selectivity profile versus wild-type EGFR are still needed. BAY 2927088, currently in phase I clinical trials, is a novel reversible inhibitor that targets EGFR exon 20 insertion mutations with decreased activity towards wild-type EGFR. Although most patients with advanced EGFR-mutant NSCLC eventually progress due to acquired resistance to EGFR inhibitors, the mechanisms of resistance to BAY 2927088 are currently unknown. Using two different methods of in vitro resistance generation, we identified mechanisms of intrinsic and acquired resistance to BAY 2927088 and other EGFR inhibitors. With the first method, involving initial incubation with a high concentration of inhibitor, we isolated drug-tolerant persister cells that underwent a transcriptional state transition resembling EMT. With the second method, involving gradual escalation of inhibitor concentrations, we identified NRAS hotspot mutations as a mechanism of resistance to BAY 2927088 and other EGFR inhibitors. As a parallel approach, we are developing a deep-scanning mutagenesis assay of the EGFR kinase domain to identify mutations that could cause resistance. Understanding these resistance mechanisms will help to identify second-line treatments for exon 20 insertion patients who develop resistance to EGFR inhibition. Citation Format: Gizem Karsli Uzunbas, Quinn McVeigh, Akansha Gupta, Stephanie Hoyt, Andrew Cherniack, Franziska Siegel, Stephan Siegel, Matthew Meyerson, Heidi Greulich. Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 433.
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