ILUSTRO: Phase II Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2–Positive Gastric or Gastroesophageal Junction Adenocarcinoma

Abstract

Background: Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive human epidermal growth factor receptor 2–negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Patients and methods: This phase 2 study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n=30), with mFOLFOX6 in first-line (Cohort 2, n=21), or with pembrolizumab in third/later-line (Cohort 3A, n=3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts). Results: ORR was 0% in Cohorts 1A and 3A, and 71.4% (95% CI, 47.82–88.72) in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31–2.56) in Cohort 1A, 2.96 months (95% CI, 1.48–4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05–25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27–11.53). Gastrointestinal adverse events occurred across cohorts (nausea, 63%–90% [grade ≥3, 4.8%–6.7%] and vomiting, 33%–67% [grade ≥3, 6.7%–9.5%]). Conclusions: Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2 positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.

Claudin 18.2 as a New Biomarker in Gastric Cancer—What Should We Know?

“…In line with the FAST trial outcomes, a recent phase II study also demonstrated interesting ORR and PFS results for the combination of zolbetuximab and chemotherapy in CLDN18.2-positive gastric or gastroesophageal adenocarcinoma [64]. The ILUSTRO phase II multicohort trial had three main study arms: zolbetuximab monotherapy in the third/later-line setting (Cohort 1A, n = 30); zolbetuximab with FOLFOX in the first-line setting (Cohort 2, n = 21); and zolbetuximab with pembrolizumab in the third/later-line setting (Cohort 3A, n = 3).…”

“…The authors explained that the elevation of the previous cut-off from the FAST study from 70% to 75% of tumor cells was due to the use of this new automated IHC kit. The results of these studies also favored the combination of chemotherapy with zolbetuximab compared to chemotherapy alone in gastroesophageal cancer [13,14,64].…”

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

“…These results suggest that zolbetuximab combined with chemotherapy may have superior efficacy. Additionally, the ILUSTRO trial showed that zolbetuximab plus mFOLFOX6 for first-line treatment showed positive results ( 32 ). These data support further development of zolbetuximab as a first-line treatment.…”

Claudin18.2 in Advanced Gastric Cancer

“…The ILUSTRO trial is phase II non-randomized study assessing zolbetuximab efficacy (800 mg/m 2 loading dose and then at 600 mg/m 2 every 3 weeks thereafter) in patients with advanced/metastatic G/GEJ adenocarcinoma whose tumors have high (≥75% of tumor cells) or intermediate (≥50% but <75% expression of tumor cells) CLDN18.2 expression [46]. This trial comprised four cohorts.…”