Zongertinib in HER2-altered colorectal cancer: A pooled analysis of colorectal cancer patients from two clinical trials.

3538 Background: Zongertinib, an irreversible TKI, selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Here, we present a pooled analysis of a subgroup of patients (pts) with HER2-positive colorectal cancer (CRC) who received zongertinib monotherapy in Phase Ia of a dose-escalation/expansion trial (NCT04886804) or in the ongoing Phase II Beamion PANTUMOR-1 trial (NCT06581432), as well as supporting preclinical data. Methods: Preclinical antitumor activity of zongertinib as monotherapy or in combination with other HER2-directed agents was assessed in commercially available HER2 -amplified mouse PDX models of CRC. Phase Ia of NCT04886804 enrolled pts with advanced solid tumors and HER2 alterations (mutations, amplification, or overexpression) who had exhausted all other standard treatment options. Beamion PANTUMOR-1 includes pts with previously treated HER2-positive (amplification or overexpression) or HER2 -mutant solid tumors. Pts in NCT04886804 received escalating doses of zongertinib (15 mg BID or 180–360 mg QD); pts in Beamion PANTUMOR-1 received zongertinib 120 mg QD. Efficacy (investigator-assessed objective response rate ORR; RECIST v1.1) and safety (incidence of adverse events AEs; CTCAE v5.0) were assessed. Results: In HER2 -amplified PDX CRC models, zongertinib monotherapy and in combination with other HER2-directed agents led to tumor growth inhibition or regression, with greater antitumor activity observed with the combinations. A total of 20 pts with HER2-positive CRC (10 from each trial) received zongertinib. Pts had a median age of 53 years (range: 36–70) and had received a median of 2.5 lines of prior systemic therapy. A total of 8 pts (6 from NCT04886804 and 2 from Beamion PANTUMOR-1) had received ≥1 prior HER2-directed therapy, including trastuzumab, pertuzumab, or T-DXd. Median treatment duration with zongertinib was 5.1 months (range: 0–18). The confirmed ORR was 45% (n = 9; all partial responses). A further 9 (45%) pts achieved stable disease, giving a disease control rate of 90%. At the time of analysis, 7 (35%) pts remained on treatment. Treatment-related AEs (TRAEs, any grade/grade ≥3) were reported in 70%/5% of pts. The most common TRAEs were diarrhea (9 pts 45%, all grade 1), rash (3 pts 15%, all grade 1), anemia (2 pts 10%, all grade 2), and increased AST (2 pts 10%, all grade 2). Only one pt had a grade ≥3 TRAE (grade 3 increased lipase). No grade 4 or 5 AEs were reported. Conclusions: Pooled analysis of HER2-positive CRC pts from two clinical trials indicates that zongertinib monotherapy has encouraging clinical activity and manageable safety in pts with advanced, HER2-positive CRC, supported by PDX models. Based on these findings, zongertinib continues to be developed in CRC, with Beamion PANTUMOR-1 actively enrolling. An additional Phase Ib/II trial (Beamion BCGC-1, NCT06324357) is also underway. Clinical trial information: NCT04886804 , NCT06581432 .