Franziska Siegel, Stephan Siegel, Kristýna Kotýnková, Gizem Karsli Uzunbas, Daniel Korr, H Tomono, Sawyer Andersen, D.R. Denney, Markus Berger, Volker Schulze, Timothy A. Lewis, Bethany Kaplan, Sven Golfier, Jérémie Mortier, R.C. Hillig, Ulf Boemer, Kirstin Petersen, Knut Eis, Sybil M. Genther Williams, Dominik Rüttinger, Andrew D. Cherniack, Herbert H. Loong, Kōichi Goto, Paolo Grassi, Matthew Meyerson, Heidi Greulich
Exon 20 insertions of HER2, encoded by erb-b2 receptor tyrosine kinase 2 (ERBB2), and other activating HER2 mutations occur in 2% to 4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR-HER2 inhibitor that is selective with respect to wild-type EGFR. In this study, we report the preclinical activity of sevabertinib in lung cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of neuregulin-1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer. SIGNIFICANCE: Additional therapeutic options are needed for patients with lung cancer with HER2 activating mutations, including exon 20 insertions. Sevabertinib shows activity against ERBB2-encoded HER2 exon 20 insertions in preclinical models of lung cancer, corroborated by early data from a phase 1/2 clinical trial.