Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma

Abstract

Zolbetuximab is a chimeric monoclonal antibody that targets claudin‐18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin‐18.2–positive locally advanced/metastatic gastric/gastroesophageal cancer in two parts: Safety (Arms A and B, n = 3 each) and Expansion (n = 12). Patients received intravenous zolbetuximab 800 mg/m2 on cycle 1, day 1 followed by 600 mg/m2 every 3 weeks (Q3W; Safety Part Arm A and Expansion) or 1000 mg/m2 Q3W (Safety Part Arm B). For the Safety Part, the primary endpoint was safety (i.e., dose‐limiting toxicities [DLTs]) and a secondary endpoint was objective response rate (ORR) by investigator. For the Expansion Part, the primary endpoint was ORR by investigator and secondary endpoints included ORR by central review and safety. Additional secondary endpoints for both the Safety and Expansion Parts were disease control rate (DCR), overall survival (OS), progression‐free survival (PFS), duration of response, pharmacokinetics, and immunogenicity. In 18 patients, no DLTs (Safety Part) or drug‐related treatment‐emergent adverse events (TEAEs) grade ≥3 were observed. Most TEAEs were gastrointestinal. In 17 patients with measurable lesions, best overall response was stable disease (64.7%) or progressive disease (35.3%). The DCR was 64.7% (95% confidence interval 38.3–85.8). In Arm A and Expansion combined (n = 15), median OS was 4.4 months (2.6–11.4) and median PFS was 2.6 months (0.9–2.8). In Arm B (n = 3), median OS was 6.4 months (2.9–6.8) and median PFS was 1.7 months (1.2–2.1). Zolbetuximab exhibited no new safety signals with limited single‐agent activity in Japanese patients.

Zolbetuximab: An Investigational First-Line Treatment for CLDN18.2-positive, HER2-negative Gastric and Gastro-oesophageal Junction Cancer

“…In the phase I trials, zolbetuximab was well tolerated across the entire dose range (33-1,000 mg/m 2 ), and treatment-related AEs mostly were of grades 1-3. 15,35,36 A similar safety profile was observed in the phase II MONO and FAST trials. 27,31 In the MONO study, the most common AEs were nausea, vomiting and fatigue, and 20% of patients (n=11) discontinued treatment due to treatment-emergent AEs (TEAEs).…”

“…gov identifier: NCT00909025). 35 Patients received 800 mg/ m 2 intravenous zolbetuximab on cycle 1, day 1, followed by 600 mg/m 2 or 1,000 mg/m 2 every 3 weeks. Similarly to the previous phase I study, this trial did not identify any dose-limiting toxicities.…”

“…Various modalities were employed to reduce gastric toxicity, including infusion time lengthening, antiemetics administration and infusion interruptions. 31,33,35 In the FAST trial, patients received proton pump inhibitors for gastric mucosal protection. 27 In addition, premedication with antiemetics was recommended for the first 3 days of each cycle.…”

Efficacy and safety of zolbetuximab for first-line treatment of advanced Claudin 18. 2-positive gastric or gastro-esophageal junction adenocarcinoma: a systematic review and meta-analysis of randomized controlled trials

“…A phase I study in Japan evaluating zolbetuximab monotherapy in previously treated Japanese patients with CLDN 18.2-positive locally advanced G/GEJ adenocarcinoma showed that 11 of 17 patients achieved stable disease ( 30 ). MONO, a phase II study, showed that zolbetuximab monotherapy in recurrent/refractory CLDN 18.2-positive gastric cancer had an ORR of 9% and a clinical benefit rate of 23% ( 31 ).…”

Antibody-mediated targeting of Claudins in cancer

“…In terms of patient reported outcomes, maintenance therapy with zolbetuximab lowered symptom burden and increased quality of life compared to EOX alone (95). Given that GC is very prevalent amongst Asian populations (96), a phase I trial (NCT03528629) of zolbetuximab in CLDN18.2-positive locally advanced/metastatic GC/ GEJ patients from Japan was conducted, which yielded no new safety concerns (88). ILUSTRO Trial (NCT03505320): A phase II clinical trial was conducted to assess safety and efficacy of zolbetuximab alone (cohort 1, n=30), zolbetuximab in combination with mFOLFOX6 (cohort 2, n=21) or zolbetuximab plus pembrolizumab (cohort 3, n=3) in advanced GC/GEJ adenocarcinoma with moderate (≥50% but <75%) to high (≥75%) CLDN18.2+ staining.…”