Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC): Preliminary results from a phase 1b/2 study.

person Keun Wook Lee Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea info_outline Keun Wook Lee, Li-Yuan Bai, Minkyu Jung, Jieer Ying, Young Hyuck Im, Do-Youn Oh, Jae Yong Cho, Sang Cheul Oh, Yee Chao, Huiyan Li, Ping Zhou, Yuanyuan Bao, Yoon-Koo Kang

Authors person Keun Wook Lee Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea info_outline Keun Wook Lee, Li-Yuan Bai, Minkyu Jung, Jieer Ying, Young Hyuck Im, Do-Youn Oh, Jae Yong Cho, Sang Cheul Oh, Yee Chao, Huiyan Li, Ping Zhou, Yuanyuan Bao, Yoon-Koo Kang Organizations Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea, Division of Hematology and Oncology, China Medical University Hospital, and China Medical University, Taichung, Taiwan, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, Department of Oncology, Zhejiang Cancer Hospital, Hangzhou, China, Department of Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea, Department of Oncology, Gangnam Severance Hospital, Yonsei University Health System, Seoul, South Korea, Department of Oncology, Korea University Guro Hospital, Seoul, South Korea, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, BeiGene Co., Ltd., Shanghai, China, Asan Medical Center, University of Ulsan, Seoul, South Korea Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that targets two distinct extracellular domains of HER2. Zani has shown preliminary antitumor activity and tolerability in pts with HER2+ gastroesophageal adenocarcinoma as monotherapy/with chemo in Phase 1/2 studies (NCT02892123, NCT03929666). TIS, an anti-PD-1 antibody, has demonstrated antitumor activity in pts with advanced solid tumors. Combining anti-HER2 therapy with anti-PD-1 therapy and chemo increased tumor response in G/GEJC in a Phase 3 clinical trial. Methods: Cohort 2 of this ongoing open-label, Phase 1b/2 study was in pts with untreated locally advanced/metastatic HER2+ G/GEJC (NCT04276493). Cohort A received zani 30 mg/kg IV, Cohort B received zani 1800 mg IV (weight < 70 kg) or 2400 mg IV (weight ≥ 70 kg), both with TIS 200 mg IV and capecitabine/oxaliplatin (CAPOX) Q3W. Primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results: As of Nov 26, 2021, 33 pts with a median age of 64.0 years (range: 29.0–80.0) were assigned to Cohort A (n=19) or B (n=14). Median study follow-up was 7.7 months (range: 2.1–19.0) and the median number of treatment cycles was 10 (range: 1–28), 20 (60.6%) pts remained on treatment. All pts were efficacy evaluable ([EE], n=33), confirmed ORR was 72.7% (95% CI: 54.5, 86.7). Median PFS was 10.9 months (95% CI: 6.9, NE). Efficacy data are summarized in the Table. All pts experienced ≥ 1 treatment emergent adverse event (TEAE), and 24 (72.7%) pts experienced ≥ Grade 3 TEAEs. All pts experienced treatment related TEAEs (trTEAEs), 20 (60.6%) pts experienced ≥ Grade 3 trTEAEs and trTEAEs leading to death occurred in two (6.1%) pts. Immune-mediated AEs (imAEs) occurred in nine (27.3%) pts, of which seven (21.2%) pts experienced ≥ Grade 3 imAEs. Conclusions: Zani, TIS and CAPOX combination demonstrated a manageable safety profile and antitumor activity as 1L therapy for pts with HER2+ G/GEJC. Clinical trial information: NCT04276493. Summary of efficacy results (EE analysis set). Cohort A (n=19) Cohort B (n=14) Total (n=33) Confirmed best overall response, n (%) Complete response 1 (5.3) 0 (0) 1 (3.0) Partial response 13 (68.4) 10 (71.4) 23 (69.7) Stable disease* 5 (26.3) 4 (28.6) 9 (27.3) Progressive disease 0 (0) 0 (0) 0 (0) Confirmed ORR, n (%) 95% CI 14 (73.7) 48.8, 90.9 10 (71.4) 41.9, 91.6 24 (72.7) 54.5, 86.7 Confirmed DCR, n (%) 95% CI 19 (100.0) 82.4, 100.0 14 (100.0) 76.8, 100.0 33 (100.0) 89.4, 100.0 Confirmed DoR, range 2.4–15.3 2.8–7.2 2.4–15.3 *One pt’s partial response is to be confirmed.Data cut off: Nov 26, 2021.