Can zolbetuximab be used in 2L/3L for G/GEJ adenocarcinoma?

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Available studies suggest limited efficacy of zolbetuximab monotherapy in 2L/3L and zolbetuximab + pembrolizumab in 3L for advanced G/GEJ adenocarcinoma

In Cohort 1A of the Phase 2 ILUSTRO trial (n= 30):¹

ORR by independent review committee was 0% (n = 27) with zolbetuximab monotherapy in ≥ 3L metastatic or unresectable G/GEJ adenocarcinoma with ≥ 75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining.
DCR by independent review committee was 44.4% (95% CI 25.48, 64.67).

In Cohort 3A of the Phase 2 ILUSTRO trial (n = 3):¹

ORR by independent review committee was 0% with zolbetuximab + pembrolizumab in ≥ 3L metastatic or unresectable G/GEJ adenocarcinoma with ≥ 50% of tumor cells demonstrating moderate to strong membranous CLDN18 staining.
DCR by independent review was 66.7% (95% CI, 9.43, 99.16).

In the Phase 2 MONO trial (n = 54):²

ORR was 14% (n = 4) with zolbetuximab monotherapy in ≥ 2L recurrent or refractory advanced gastric or esophageal adenocarcinoma among patients with CLDN18.2 expression in ≥ 70% of tumor cells (n = 29).

In the Phase 2 FAST trial and the Phase 3 SPOTLIGHT and GLOW trials, patients who received previous chemotherapy for advanced G/GEJ adenocarcinoma were excluded.^3–5 However, patients may have received previous perioperative chemotherapy as long as it was completed at least 6 months prior to randomization.

In FAST, 52.5% of patients on zolbetuximab + EOX had surgical cancer therapy and less than 10% received prior chemotherapy.⁶
In SPOTLIGHT, 66 out of 283 (23.3%) patients on zolbetuximab + mFOLFOX6 had received prior chemotherapy.⁶
In GLOW, 50 out of 254 (19.7%) patients on zolbetuximab + CAPOX received prior chemotherapy.⁶
No subanalysis of efficacy or safety was conducted in patients who received prior surgery or perioperative chemotherapy in the FAST, SPOTLIGHT or GLOW trials.^4–6

Table 1. Phase 2 clinical trials evaluating zolbetuximab as ≥ 2L treatment of advanced or metastatic G/GEJ adenocarcinoma

Abbreviations. 2L: second-line; 3L: third-line; AE: adverse event; CAPOX: capecitabine and oxaliplatin chemotherapy; CBR: clinical benefit rate; CI: confidence interval; CLDN18: claudin 18; CLDN18.2: claudin 18 isoform 2; CR: complete response; DCR: disease control rate; DOR: duration of response; EOX: epirubicin, oxaliplatin, capecitabine; FAS: full analysis set; G/GEJ: gastric/gastroesophageal junction; IRC: independent review committee; mFOLFOX6: modified folinic acid (or levofolinate), fluorouracil, and oxaliplatin; ORR: objective response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response; SD: stable disease; TEAE: treatment emergent AE; TRAE: treatment-related AE.

Ongoing clinical trials

ZELDA (jRCTs071250038) is a Phase 2 trial evaluating the efficacy and safety of zolbetuximab in the 2L for CLDN18.2 positive advanced G/GEJ cancer patients previously treated with zolbetuximab and platinum-based chemotherapy.^8,9

This randomized, multicenter, open-label trial will initially enroll six patients in a safety lead-in Phase to assess the tolerability of zolbetuximab + nab-paclitaxel + ramucirumab. Once safety is confirmed, 210 patients will be randomized in the Phase 2 portion to evaluate OS with zolbetuximab + nab-paclitaxel + ramucirumab versus nab-paclitaxel + ramucirumab alone.
No efficacy and safety results have been published.

RAINSPOT (NCT06962137) is a Phase 2 trial evaluating whether adding zolbetuximab to paclitaxel + ramucirumab can improve patients' survival in the 2L for CLDN18.2 positive gastroesophageal cancer.¹⁰

This trial is divided into a prospective open label cohort (zolbetuximab + paclitaxel + ramucirumab) and a retrospective cohort (patients treated with paclitaxel-ramucirumab between JAN-2021 until DEC-2023). Patients who received zolbetuximab or other anti-CLDN18.2 direct therapy in 1L were excluded.

References

1. Klempner SJ, Lee KW, Shitara K, et al. ILUSTRO: Phase 2 Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma. Clin. Cancer Res. 2023;29(19):3882-3891. Available at: https://doi.org/10.1158/1078-0432.ccr-23-0204.

2. Türeci O, Sahin U, Schulze-Bergkamen H, et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann. Oncol. 2019;30(9):1487-1495. Available at: https://doi.org/10.1093/annonc/mdz199.

3. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann. Oncol. 2021;32(5):609-619. Available at: https://doi.org/10.1016/j.annonc.2021.02.005.

4. Shitara K, Lordick F, Bang YJ, et al. Supplement to: Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-1668. Available at: https://doi.org/10.1016/s0140-6736(23)00620-7.

5. Shah MA, Shitara K, Ajani JA, et al. Supplement to: Zolbetuximab plus CAPOX in CLDN18.2- positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat. Med. 2023;29(8):2133-2141. Available at: https://doi.org/10.1038/s41591-023-02465-7.

6. Data on file.

7. Electronic Citation. NIH. Clinicaltrials.gov NCT03505320. ILUSTRO. Available at: https://clinicaltrials.gov/study/NCT03505320/. Accessed 27-MAR-2026.

8. Electronic Citation. jRCT. jRCTs071250038. ZELDA. Available at: https://jrct.mhlw.go.jp/en-latest-detail/jRCTs071250038/. Accessed 27-MAR-2026.

9. Ando K, Inagaki C, Narita Y, et al. Randomized phase II trial evaluating the efficacy of zolbetuximab in the second-line for claudin18.2 positive advanced gastric/EGJ cancer patients previously treated with zolbetuximab and platinum-based chemotherapy (ZELDA trial) [oral slide presentation]. American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium 2026; January 8-10, 2026. San Francisco, CA. Abstract TPS470.

10. Electronic Citation. NIH. Clinicaltrials.gov NCT06962137. RAINSPOT. Available at: https://clinicaltrials.gov/study/NCT06962137/. Accessed 27-MAR-2026.

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