Molecule

Zongertinib (BI 1810631) is a novel, orally administered HER2 TKI that selectively and covalently binds to the TKD of both wild-type and mutated HER2 receptors, including those with an exon 20 insertion, while sparing wild-type EGFR.

Proposed MoA

Mutations of ErbB receptor tyrosine kinases, such as EGFR and HER2, can cause aberrant signaling in cancer cells through uncontrolled proliferation, inhibition of apoptosis, and promotion of tumor growth and spread.^3–6

Zongertinib (BI 1810631) may selectively and covalently bind to the tyrosine kinase domain of mutated HER2 receptors.¹ Selective binding has the potential to block aberrant downstream signaling, while sparing wt EGFR signaling, thereby avoiding wt EGFR-associated toxicity.¹

Pan-ErbB TKIs are impeded by wt EGFR-associated toxicity. Improved selectivity of HER2 TKI compared to second generation TKIs may result in better tolerability and potential for more effective dosing.¹

Clinical Development

Zongertinib (BI 1810631) is currently undergoing clinical investigation as a monotherapy in patients with HER2 aberrations for advanced or metastatic solid tumors.^1,2,7
 

Proposed MoA¹

Zoom

A Phase III, open-label, randomized, active-controlled, multicenter trial (Beamion LUNG-2) is evaluating orally administered zongertinib compared with SOC as first-line treatment in patients with unresectable, locally advanced or metastatic nonsquamous NSCLC harboring HER2 TKD mutations.⁷

Beamion LUNG-1 is a Phase I trial evaluating zongertinib in the treatment of advanced or metastatic solid tumors with HER2 alterations.

Beamion BCGC-1: A Phase Ib Dose Escalation and Phase II Dose Optimization, Randomized, Open-label, Multicenter Trial of Oral Zongertinib (BI 1810631) in Combination With Intravenous Trastuzumab Deruxtecan (T-DXd) or in Combination With Intravenous Trastuzumab Emtansine (T-DM1) for Treatment of Patients With Advanced HER2+ Metastatic Breast Cancer (mBC) and Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma (mGEAC).