Zongertinib (BI 1810631) for HER2-positive Solid Tumors with Brain Metastases: Subanalysis of the Beamion LUNG-1 Trial

Introduction: Brain metastases (BM) are present in up to 30% of patients (pts) with HER2 mutation-pos (m+) NSCLC at diagnosis and are particularly common in pts with the HER2 ex20ins YVMA. Zongertinib, a novel HER2-specific TKI, binds selectively and covalently to the HER2 TKD while sparing WT EGFR. Beamion LUNG-1, a Ph Ia/Ib, first-in-human, open-label trial, is evaluating the safety and efficacy of zongertinib in pts with HER2 aberration-pos (abr+) solid tumors (Ph Ia) and HER2m+NSCLC (Ph Ib). Here, we present data from Ph Ia, incl. pts with BM at baseline (BL).

Methods: Ph Ia enrolled pts with confirmed HER2abr+(mutations, rearrangements, amplification, overexpression) adv./unresect./met. solid tumors, refractory to/unsuitable for standard treatment. Pts with asympt. BM were eligible. Pts received escalating doses of oral zongertinib≥15 mg BID or≥60 mg QD. Brain lesion OR (acc. to RANO-BM) and OR in other lesions (acc. to RECIST v1.1) was assessed.

Results: At DCO (Jan 29, 2024), 83 pts in Ph Ia have received zongertinib, incl. 19 pts with BM at BL. In all treated pts, the mDoT was 4.2 mos (range 0–24); treatment was ongoing in 38 pts (46%) at DCO. TRAEs were reported in 63 pts (76%), incl. gr≥3 TRAEs in 7 pts (8%). The most common TRAEs (any/gr≥3), incl. diarrhea (42%/1%), rash (12%/0%), and decreased appetite (10%/0%). 34 pts (41%) had SAEs, incl. 2 pts (2%) with TRSAEs. In 74 evaluable pts, the confirmed ORR across all dose levels was 35%, with a DCR of 85%. The mDoR was 12.7 mos, mPFS was 8.0 and 8.3 mos with zongertinib BID and QD, resp. In 41 evaluable NSCLC pts, the ORR and DCR were 44% and 93%, resp. The mDoR was 15.8 mos, mPFS was 13.8 and 12.3 mos with zongertinib BID and QD, resp. All 19 pts with BM at BL had lung cancer (NSCLC: 16 pts; unspecified cancer of the lung: 3 pts). Of these, 15 (79%) had TRAEs, incl. 5 (26%) with gr≥3. The most common TRAEs (any/gr≥3) included diarrhea (42%/0%), increased ALT (26%/16%), and increased AST (21%/5%). SAEs were reported in 13 pts (68%), incl. 1 pt (5%) with TRSAEs (gr 3 increased ALT and AST). Of the 17 evaluable pts with BM, the ORR per RECIST v1.1 (w/o confirmation) and DCR was 53% and 94%, resp.

Conclusion: Zongertinib demonstrated manageable safety and promising efficacy in pts with HER2abr+solid tumors, incl. in those with BM at baseline. Updated data will be presented, incl. Ph Ia RANO-BM data and Ph Ib data.

Publication History

Article published online:
18 March 2025