Zongertinib in HER2-altered breast cancer: Preclinical activity and preliminary results from a phase Ia dose-escalation study.

Abstract

1023 Background: Preclinical studies have demonstrated that zongertinib, an irreversible TKI, selectively and potently inhibits oncogenic HER2 in a variety of cancer models. An ongoing Phase (Ph) Ia/Ib dose escalation/expansion trial (NCT04886804) has demonstrated preliminary clinical activity of zongertinib across a range of HER2-driven solid tumors. Here we present comparative preclinical data for zongertinib in breast cancer (BC) cell lines and cell line-derived xenograft (CDX) models, as well as clinical data from patients (pts) with HER2-driven BC who received zongertinib during Phase Ia dose escalation. Methods: Cell proliferation assays were undertaken in HER2 -amplified BC cell lines (relative copy numbers ranging from 3.2–10.1) exposed to serial dilutions of zongertinib and tucatinib. Antitumor activity of zongertinib (5–40 mg/kg QD) in vivo was assessed in three HER2 -amplified BC CDX models. Ph Ia of the trial enrolled pts with confirmed HER2 alterations (mutations, amplification or overexpression) who had exhausted all other treatment (Tx) options. In Ph Ia, zongertinib was administered at 15–150 mg BID or 60–360 mg QD in 21-day cycles . Primary endpoints were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Efficacy (objective response, OR) was evaluated as a secondary endpoint using RECIST v1.1. Results: Zongertinib inhibited tumor cell growth in vitro with greater potency (4.5–16.4-fold) than tucatinib (zongertinib IC 50 : 2.6–40.6 nM; tucatinib IC 50 : 13.2–664.0 nM). In mice, zongertinib was well tolerated and led to a dose-dependent inhibition of BC tumor growth , with tumor regressions at higher doses (≥ 20 mg/kg QD). As of August 29, 2024, 121 pts had been treated in the Ph Ia trial. Two DLTs occurred during the MTD evaluation period; the MTD was not reached. Treatment-related adverse events (TRAEs; all/grade ≥3) occurred in 82.6%/12.4% of pts; the confirmed OR rate was 31.4% across all doses and tumor types. In total, 15 pts with Stage IV BC (HER2 overexpression/amplification: n = 10; HER2 mutations: n = 4; both: n = 1) received zongertinib (100 mg BID: n = 1; 240–360 mg QD: n = 14). Most were white (60.0%) and had an ECOG PS of 1 (66.7%). Mean (standard deviation, SD) age was 58.1 (7.4) years. Mean (SD) Tx duration was 4.0 (3.4) months. TRAEs (any/grade ≥3) occurred in 93.3%/0.0% of pts. In pts with BC, the confirmed OR rate was 26.7% (4 partial responses). The confirmed disease control rate was 73.3%. Regardless of confirmation, the OR rate was 46.5%. At the time of data cut-off, 2 pts with responses were still on treatment, and an additional 3 patients had a response lasting longer than 4 months. Conclusions: Zongertinib potently inhibits HER2-driven BC growth in preclinical models in vitro and in vivo . Preliminary Ph Ia data indicate that zongertinib has encouraging clinical activity and manageable safety in pts with advanced, HER2-driven BC. Clinical trial information: NCT04886804 .