Zolbetuximab/mFOLFOX6/Nivolumab Confers Efficacy in Metastatic Gastric/GEJ Cancer

First-line zolbetuximab (Vyloy), mFOLFOX6 (modified leucovorin, 5-fluorouracil [5-FU], and oxaliplatin), and nivolumab (Opdivo) led to meaningful progression-free survival (PFS) outcomes and durable responses in patients with unresectable gastric/gastroesophageal junction (GEJ) adenocarcinoma across biomarker-defined subgroups, although efficacy findings favored those with high Claudin 18.2 (CLDN18.2) expression, according to findings from cohort 4 of the phase 2 ILUSTRO trial (NCT03505320). ¹

Results presented at the 2026 Gastrointestinal Cancers Symposium showed that, at a median follow-up of 11.5 months (95% CI, 10.9-15.6), the median PFS in cohort 4B (n = 71) was 14.8 months (95% CI, 8.3-not estimable [NE]), and the estimated 12-month PFS rate was 59.1%.

At a median follow-up of 11.5 months (95% CI, 9.4-15.6), in patients with CLDN18.2-high tumors (n = 59) from cohort 4B, the median PFS was 18.0 months (95% CI, 11.1-NE), and the estimated 12-month PFS rate was 64.2%. The median PFS was 6.7 months (95% CI, 3.0-NE) among those with CLDN18.2-intermediate tumors. At a median follow-up of 11.4 months (95% CI, 3.9-NE), the estimated 12-month PFS rate was 36.8%.

At a median follow-up of 23.6 months (95% CI, 12.9-NE), patients with CLDN18.2-high tumors who also had a PD-L1 combined positive score (CPS) of at least 1 (n = 36) achieved a median PFS of 23.6 months; the estimated 12-month PFS rate was 69.4%. Among patients with CLDN18.2-high tumors who had a PD-L1 CPS of less than (n = 21), at a median follow-up of 12.1 months (95% CI, 7.2-NE), the median PFS was 12.1 months, and the estimated 12-month PFS rate was 59.5%.

“[Zolbetuximab plus mFOLFOX6 and nivolumab] demonstrated encouraging PFS and antitumor activity, particularly in patients with high CLDN18.2 expression and a PD-1 CPS of 1 of greater,” lead study author Kohei Shitara, MD, said in a presentation of the data.

Shitara is the director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan.

What was the rationale for investigating zolbetuximab plus mFOLFOX6 and nivolumab in gastric/GEJ cancer?

A pooled analysis of the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies showed that zolbetuximab in combination with chemotherapy (n = 537) led to a median PFS of 9.2 months (95% CI, 8.4-10.4) vs 8.2 months (95% CI, 7.6-8.4) with chemotherapy alone (n = 535; HR, 0.71; 95% CI, 0.61-0.83).² Furthermore, the median overall survival (OS) was 16.4 months (95% CI, 15.0-17.9) with the zolbetuximab-based regimens vs 13.7 months (95% CI, 12.3-15.3) with chemotherapy alone (HR, 0.77; 95% CI, 0.67-0.89).

Additionally, Shitara noted that preclinical models and on-treatment immune profiling have shown that zolbetuximab plus chemotherapy has synergistic activity with PD-1 inhibition.¹ Based on these findings, the ILUSTRO study evaluated the efficacy and safety of zolbetuximab alone or in addition to chemotherapy and/or a PD-1 inhibitor.

What was the design of the ILUSTRO study?

Cohort 4 of the ILUSTRO study enrolled patients with previously untreated, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma. Patients needed to have CLDN18.2-positive disease with intermediate-to-high expression, as well as HER2-negative disease and an ECOG performance score of 0 or 1.

In cohort 4A, the safety lead-in phase, patients received zolbetuximab at 600 mg/m² or 800 mg/^m2 on cycle 1 day 1, followed by subsequent doses at 400 mg/m² through cycle 4, in combination with nivolumab at 240 mg plus mFOLFOX6 every 2 weeks; in cycles 5 and beyond, patients received zolbetuximab at 400 mg/m² plus nivolumab at 240 mg and 5-FU plus fluorouracil every 2 weeks.

In cohort 4B, the expansion phase, patients received zolbetuximab at 800 mg/m² on cycle 1 day 1, followed by subsequent doses at 400 mg/m² through cycle 4, in combination with nivolumab at 240 mg plus mFOLFOX6 every 2 weeks; in cycles 5 and beyond, patients received the same dosing regimen as patients received during these cycles in cohort 4A.

Key end points included PFS, overall response rate (ORR), disease control rate, duration of response (DOR), OS, safety, and tolerability. Preplanned CLDN18.2 and PD-L1 CPS analyses were also conducted.

Cohort 4A enrolled 12 patients, all of whom were treated with zolbetuximab. Of these patients, 6 received zolbetuximab at the 800/400 mg/m² dose, which was deemed tolerable and confirmed for further assessment in cohort 4B. Cohort 4B enrolled 71 patients, all of whom were treated at the target dose. At the data cutoff date, 50 patients had discontinued treatment due to disease progression (n = 39), physician decision (n = 5), adverse effects (AEs; n = 3), death (n = 1), and other reasons (n = 2).

“These patient characteristics were representative of the usual first-line population,” Shitara reported. Notably, most patients were Asian (79.1%), had primary tumors in the stomach (86.5%), had high CLDN18.2 expression (85.5%), and had a PD-L1 CPS of 1 or greater (65.3%).

What additional efficacy findings were reported in the ILUSTRO study?

The OS data for cohort 4B were not mature at the data cutoff date; however, OS outcomes with the triplet were favorable the CLDN18.2-high population. At a median follow-up of 13.0 months (95% CI, 8.7-16.3) in this population, the median OS was NE (95% CI, 13.7 months-NE), and the estimated 12-month OS rate was 76.2%. In the CLDN18.2-intermediate population, at a median follow-up of 16.8 months (95% CI, 6.6-NE), the median OS was 9.6 months (95% CI, 5.4-NE), and the estimated 12-month OS rate was 49.9%.

The ORR among all patients in cohort 4B was 62.1% (95% CI, 48.4%-74.5%). ORR rates were 68.1% (95% CI, 52.9%-80.9%) in the CLDN18.2-high population and 40.0% (95% CI, 12.2%-73.8%) in the CLDN18.2-intermediate population.

Antitumor responses in cohort 4B were generally durable. The median DOR in the overall population was 19.1 months (95% CI, 10.8-NE). In the CLDN18.2-high and -intermediate populations, the median DORs were NE (95% CI, 10.8 months-NE) and 19.1 months (95% CI, 3.5-NE), respectively.

What is the safety profile of zolbetuximab plus mFOLFOX6 and nivolumab?

The safety and tolerability of the triplet were consistent with reports from prior studies of mFOLFOX6 in combination with zolbetuximab or nivolumab. Among patients evaluable for safety (n = 77), treatment-emergent AEs (TEAEs) led to:

• Discontinuation of any study drug (49.4%)
• Discontinuation of zolbetuximab (5.2%)
• Discontinuation of nivolumab (7.8%)
• Discontinuation of an mFOLFOX6 component:
  • Oxaliplatin (35.1%)
  • Fluorouracil bolus (26.0%)
  • Fluorouracil infusion (2.6%)
• Dose adjustment of zolbetuximab (3.9%)
• Dose adjustment of an mFOLFOX6 component:
  • Oxaliplatin (55.8%)
  • Fluorouracil bolus (37.7%)
  • Fluorouracil infusion (46.8%)

Notably, no patients experienced TEAEs leading to nivolumab dose adjustments.

The median duration of zolbetuximab treatment was 288.5 days (range, 1-1271); this value was 226.0 days (range, 1-872) for nivolumab. The mean relative dose intensity was 97.1% (standard deviation [SD], 11.6) for zolbetuximab and 97.0% (SD, 7.1) for nivolumab.

Overall, any-grade TEAEs occurred in 98.7% of patients, all of which were deemed related to any study drug. Grade 3 or higher TEAEs were reported in 37.7% of patients, and 23.4% of patients had grade 3 or higher TEAEs that were attributed to any study drug.

The most common TEAEs included nausea (any-grade, 80.5%; grade ≥ 3, 0%), decreased appetite (72.7%; 7.8%), decreased neutrophil counts (45.5%; 32.5%), peripheral sensory neuropathy (45.5%; 2.6%), vomiting (37.7%; 3.9%), diarrhea (36.4%; 1.3%), pyrexia (31.2%; 0%), anemia (24.7%; 2.6%), and constipation (22.1%; 0%).

What are the next steps for evaluating zolbetuximab-based combinations in gastric/GEJ cancer?

“These results support this combination as a promising treatment and provide a strong rationale for the ongoing phase 3 LUCERNA study [NCT06901531],” Shitara concluded.

LUCERNA is investigating zolbetuximab plus pembrolizumab (Keytruda) and chemotherapy in the first-line setting for the treatment of patients with CLDN18.2-positive, HER2-negative, PD-L1–positive locally advanced or metastatic gastric/GEJ adenocarcinoma.

Disclosures: Shitara reported receiving honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, and Ono Pharmaceutical; performing consulting or advisory roles with AbbVie, ALX Oncology, Amgen, Arcus Biosciences Inc., Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CMIC Co., Ltd., Daiichi Sankyo, eChainaHealth,Inc., Elevation Oncology, Gilead Sciences, GlaxoSmithKline K.K., Guardant Health, Healios, Janssen, Leap Therapeutics, Levolution Medicines,Inc., Moderna, Inc, MSD, Novartis, Oncolys BioPharma, Ono Pharmaceutical, Phanes Therapeutics, Sanofi, Scandion Oncology, Suzuhou Liangyihui Network Technology Co., Takeda, and Zymeworks; and receiving institutional research funding from Amgen, Astellas Pharma, AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Insyte Biosciences G.K., Medpace Japan K.K., MSD, Ono Pharmaceutical, PPD-SNBL, PRA Health Sciences, Syneos Health, Taiho Pharmaceutical, and Toray Industries.

References

1. Shitara K, Shoji H, Fazio N, et al. Phase 2 ILUSTRO trial of 1L zolbetuximab plus mFOLFOX6 and nivolumab in patients with CLDN18.2+ locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. J Clin Oncol. 2026,44(suppl 4):LBA284.doi:10.1200/JCO.2026.44.2_suppl.LBA284
2. Kang Y-K, Shah MA, Shitara K, et al. 1438P First-line (1L) zolbetuximab + chemotherapy in patients (pts) with claudin 18.2 (CLDN18.2) +, HER2-, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: a pooled final analysis of SPOTLIGHT + GLOW. Ann Oncol. 2024;35(suppl 2):S895. doi:10.1016/j.annonc.2024.08.1504