Molecular circulating tumor DNA (ctDNA) profiling from patients (pts) treated with zanidatamab + chemotherapy (CT) in first-line (1L) HER2-positive (HER2+) advanced or metastatic gastroesophageal adenocarcinoma (mGEA).

4050 Background: Zanidatamab is a dual HER2-targeted bispecific antibody that binds to HER2 extracellular domains 2 and 4. In the phase 3 HERIZON-GEA-01 trial, 1L zanidatamab ± tislelizumab + CT significantly prolonged progression-free survival (PFS) and, with tislelizumab, yielded significant overall survival benefits versus trastuzumab + CT in HER2+ mGEA. Consistent results were previously reported in a phase 2 trial of zanidatamab + CT. ctDNA profiling provides a noninvasive approach to identify pts who could benefit from HER2-targeted therapies, and on-treatment ctDNA reductions may be associated with response. Here we report ctDNA profiling from the phase 2 trial. Methods: The phase 2 trial (NCT03929666) evaluated zanidatamab + CT (mFOLFOX6, CAPOX, or 5-FU/cisplatin FP) in 1L mGEA. Pts in part 1 had HER2-expressing (IHC 3+ or 2+) mGEA. Pts in part 2 had HER2+ (IHC 3+ or IHC 2+/FISH+) mGEA by central assessment (ccHER2+). Primary endpoint was confirmed objective response rate (cORR). PFS was a secondary endpoint. Plasma ctDNA samples were collected prior to cycle 1 of zanidatamab (baseline BL) and on treatment (cycle 2 day 15 for zanidatamab + CAPOX or FP; cycle 3 day 1 for zanidatamab + mFOLFOX6) for NGS by Guardant360 and/or Guardant Infinity. Results: 46 pts were enrolled (zanidatamab + mFOLFOX6 n = 24, CAPOX n = 20, FP n = 2). Most (41 89%) pts had ccHER2+ mGEA. cORR was 76.2% (95% CI 60.5, 87.9) and median PFS was 12.5 (95% CI 8.2, 21.8) mo. BL ctDNA was available from 39 pts; 29 had on-treatment samples, and 16 had matched BL and on-treatment samples. The concordance was 94% (34/36) between centrally assessed ERBB2 amplification by FISH in tissue and ERBB2 amplification in plasma ctDNA by NGS. Among 34 pts with detectable ERBB2 amplification at BL, median PFS was 18.6 (95% CI 12.0, NE) mo. All pts with available samples and confirmed complete (CR) or partial (PR) response or stable disease (SD) had undetectable on-treatment ERBB2 amplification in ctDNA. Most pts with ERBB2 indel, fusion, or SNV (79% 15/19) or with PIK3CA amplification or SNV (86% 12/14) at BL had CR or PR. Nearly all (94% 15/16) pts with available matched samples had a > 80% decrease in ctDNA from BL to on-treatment assessment on the Guardant Infinity panel. On-treatment ctDNA samples from pts with progressive disease or SD showed recurrence/persistence of ERBB2 alterations and co-alterations across PI3K/AKT and RAS/MAPK pathways. Additional data will be presented. Conclusions: Molecular ctDNA profiling showed that 1L zanidatamab + CT in HER2+ mGEA could markedly reduce total ctDNA levels and ERBB2 amplification detection early in treatment. Antitumor activity was observed among pts whose tumors harbored ERRB2 and PIK3CA mutations, both of which are associated with resistance to standard HER2-targeted therapies. Clinical trial information: NCT03929666 .