Phase 1b/2 Study of Zanidatamab in Combination with Tislelizumab and Chemotherapy in First-Line HER2-Positive Gastric/Gastroesophageal Junction Adenocarcinoma

Abstract Purpose: This phase 1b/2 trial (NCT04276493) assessed the antitumor activity, safety and pharmacokinetics (PK) of zanidatamab in combination with tislelizumab and chemotherapy in patients with advanced HER2-positive (HER2+) gastric/gastroesophageal junction cancer (GC/GEJC). Patients and Methods: Adult patients with previously untreated, unresectable, locally advanced/metastatic HER2+ GC/GEJC received zanidatamab 30 mg/kg intravenously (IV) (cohort A) or zanidatamab 1800 mg IV (weight 70 kg)/2400 mg IV (weight ≥70 kg) (cohort B) once every 3 weeks (Q3W). Both cohorts received tislelizumab 200 mg IV Q3W and standard chemotherapy (capecitabine and oxaliplatin CAPOX) Q3W. Primary endpoints were investigator-assessed confirmed objective response rate (cORR) per RECIST v1.1, in addition to frequency and severity of adverse events (AEs) and serious AEs. Secondary endpoints included investigator-assessed progression-free survival (PFS), duration of response (DoR), overall survival (OS), PK, and immunogenicity of zanidatamab. Results: As of December 7, 2023, 33 patients (cohort A, n=19; cohort B, n=14) received treatment. cORR was 75.8%; median DoR, PFS, and OS were 23.3, 16.7, and 32.4 months, respectively. The most common treatment-related AEs (TRAEs) were diarrhea (100%), nausea (63.6%), and decreased appetite (48.5%). TRAEs of grade ≥3 were reported in 22 (66.7%) patients; diarrhea was the most common (27.3%). Conclusions: Zanidatamab, in combination with tislelizumab and CAPOX, demonstrated clinically meaningful antitumor activity with a manageable safety profile as first-line therapy for patients with HER2+ GC/GEJC. These results support further development of zanidatamab and tislelizumab with chemotherapy in this patient population in the ongoing phase 3 HERIZON-GEA-01 trial (NCT05152147).