GLEAM is a Phase II randomized trial testing zolbetuximab, an anti-CLDN18.2 antibody, added to gemcitabine/nab-paclitaxel in CLDN18.2-positive metastatic pancreatic cancer. The trial did not meet its primary endpoint — no overall survival benefit (mOS 13.7 vs 13.6 months). Zolbetuximab (Vyloy) remains FDA-approved only in first-line gastric/GEJ cancer; Astellas has discontinued pancreatic development.
Phase IICLDN18.2+ mPDACAstellasNCT03816163Negative Trial (OS)Vyloy Approved — Gastric/GEJ Only
SAME DRUG · DIFFERENT INDICATIONZolbetuximab is FDA-approved in gastric cancer — this pancreatic cancer trial was negative
Zolbetuximab (Vyloy™, Astellas) is FDA-approved (October 18, 2024) for first-line HER2-negative, CLDN18.2-positive locally advanced/metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, based on the Phase 3 SPOTLIGHT and GLOW trials. GLEAM tested the same drug added to gemcitabine/nab-paclitaxel in a different tumor type — CLDN18.2-positive metastatic pancreatic adenocarcinoma — and did not meet its primary endpoint. Zolbetuximab remains investigational and unapproved in pancreatic cancer; Astellas has discontinued the pancreatic development program.
Design: Phase II randomized (2:1), open-label GLEAM trial (NCT03816163, n=393, 136 sites) of zolbetuximab + gemcitabine/nab-paclitaxel (GN) vs GN alone in CLDN18.2-positive (≥75% membranous IHC) metastatic pancreatic adenocarcinoma. Primary endpoint (OS): NOT MET — mOS 13.7 vs 13.6 months (Astellas press release, final analysis, Oct 14 2025; also ESMO GI 2026 congress recap). HR ≈ 0.99–1.00, P ≈ 0.499–0.50 per two independent KOL live-tweets from the ESMO GI 2026 oral session (abstract 342O) — not yet in an official publication. PFS: no benefit. ORR/DoR: numerically higher with zolbetuximab (one KOL reported ORR 45% vs 37.4%), not confirmatory. Exploratory: an IL-18-high subgroup showed a possible OS signal — hypothesis-generating only. Regulatory: zolbetuximab (Vyloy) is FDA-approved ONLY for first-line HER2-negative, CLDN18.2+ gastric/GEJ adenocarcinoma (Oct 18, 2024); NOT approved in pancreatic cancer — Astellas has discontinued the pancreatic program. Sponsor/drug: Astellas Pharma; zolbetuximab (anti-CLDN18.2 monoclonal antibody).
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[Slide 1 - Study design]
Study design: GLEAM (NCT03816163) - Design of the phase 2, open-label, randomized study
Individuals with mPAC identified for screening N=2529. Key inclusion criteria: Adults with chemotherapy-naive mPAC; Measurable disease per RECIST; Moderate-to-strong membranous CLDN18 staining in >=75% of tumor cells by IHC; ECOG PS 0-1; Predicted life expectancy >=12 weeks. N=393 randomized 2:1 (n=2133 failed screening).
Arm 1: Zolbetuximab 1000 mg/m2 C1D1 IV then 600 mg/m2 Q2W IV + GN (1000 mg/m2 Gem and 125 mg/m2 Nab-P IV on days 1, 8, 15 of every 28-day cycle), n=262.
Arm 2: GN alone (same regimen), n=131.
Primary endpoints: Safety/tolerability; Confirm RP2D; OS.
Secondary endpoints: PFS, ORR, DOR, DCR (RECIST v1.1), PK, Immunogenicity, Serum CA19-9 response, EORTC QLQ-C30, EORTC QLQ-PAN26, PGIS and PGIC, EQ-5D-5L.
Exploratory endpoints: Genomic and/or other biomarkers correlated with zolbetuximab treatment outcomes.
Presenter: Wungki Park, MD, MS.
[Slide 2 - Safety]
Zolbetuximab had no new safety signals in patients with CLDN18.2+ mPAC.
TEAEs (Zolb+GN n=259 / GN n=114 / Overall n=373): TEAEs 259(100)/114(99.1)/373(99.7); Serious TEAEs 191(73.7)/62(53.9)/253(67.6); Drug-related serious TEAEs 127(49.0)/24(20.9)/151(40.4); TEAEs leading to death 27(10.4)/8(7.0)/35(9.4); Drug-related TEAEs leading to death 9(3.5)/1(0.9)/10(2.7); TEAEs leading to permanent discontinuation 96(37.1)/24(20.9)/120(32.1); Drug-related discontinuation 68(26.3)/14(12.2)/82(21.9).
Grade >=3 TEAEs in >=10% of patients (Zolb+GN n=259 / GN n=115 / Overall n=374): Neutrophil count decreased 67(25.9)/27(23.5)/94(25.1); Anemia 59(22.8)/29(25.2)/88(23.5); Nausea 42(16.2)/3(2.6)/45(12.0); Neutropenia 41(15.8)/19(16.5)/60(16.0); WBC count decreased 35(13.5)/17(14.8)/52(13.9); Vomiting 35(13.5)/6(5.2)/41(11.0); Asthenia 33(12.7)/5(4.3)/38(10.2); Hypoalbuminemia 31(12.0)/2(1.7)/33(8.8); Fatigue 28(10.8)/4(3.5)/32(8.6); Platelet count decreased 26(10.0)/9(7.8)/35(9.4).
Data cutoff: September 3, 2025. Safety analysis set. Presenter: Wungki Park, MD, MS.
[Slide 3 - Overall Survival]
Zolbetuximab plus GN did not improve OS compared with GN alone for patients with CLDN18.2+ mPAC.
Zolbetuximab + GN Arm 1: Events/N 193/262, Median OS 13.70 months (95% CI 11.47-16.00).
GN Arm 2: Events/N 90/131, Median OS 13.57 months (95% CI 11.76-15.67).
Primary Analysis: HR (95% CI) = 0.999 (0.776-1.286), P value = 0.4987.
Data cutoff: September 3, 2025. Full analysis set.
"The primary endpoint was not met and there was no difference in OS between zolbetuximab plus GN and GN alone." Presenter: Wungki Park, MD, MS.
[Slide 4 - ORR and DOR]
ORR and DOR were numerically higher with zolbetuximab plus GN compared with GN alone in patients with CLDN18.2+ mPAC.
Zolbetuximab+GN Arm 1 (n=262): ORR 44.7% (95% CI 38.5-50.9), DCR 70.6% (95% CI 64.7-76.1); (n=118) Median DOR 7.6 months (95% CI 5.6-9.3).
GN Arm 2 (n=131): ORR 37.4% (95% CI 29.1-46.3), DCR 71.8% (95% CI 63.2-79.3); (n=49) Median DOR 5.6 months (95% CI 3.8-7.4).
"Zolbetuximab numerically improved the ORR (delta=7.3%) and DOR (delta=2.0 months) but did not improve the DCR." Data cutoff: October 13, 2024. Full analysis set. Presenter: Wungki Park, MD, MS.
[Slide - Progression-Free Survival]
Zolbetuximab plus GN did not extend PFS compared with GN alone for patients with CLDN18.2+ mPAC.
Zolbetuximab + GN Arm 1: Events/N 199/262, Median PFS 6.57 months (95% CI 5.59-7.66).
GN Arm 2: Events/N 88/131, Median PFS 7.46 months (95% CI 5.78-9.23).
Primary Analysis: HR (95% CI) = 1.105 (0.855-1.428).
Data cutoff: September 3, 2025. Full analysis set. Presenter: Wungki Park, MD, MS.
(Note: the other 3 photos in this same tweet duplicate the study-design, OS, and ORR/DOR slides already shown above from @ArndtVogel's screenshots of the identical presentation — not re-shown here to avoid redundant content.)
GLEAM is a Phase II, randomized (2:1), open-label trial testing whether adding zolbetuximab — a first-in-class anti-CLDN18.2 monoclonal antibody — to gemcitabine plus nab-paclitaxel (GN) improves outcomes in first-line CLDN18.2-positive metastatic pancreatic adenocarcinoma. Zolbetuximab already holds FDA approval as Vyloy in a different tumor type (first-line HER2-negative gastric/GEJ cancer), so GLEAM tested whether the same target-drug pairing could translate to pancreatic cancer, where about 28% of screened tumors expressed CLDN18.2 at the qualifying threshold. Enrolling 393 patients across 136 global sites, the trial's final analysis — announced by Astellas in October 2025 and presented in full at ESMO GI 2026 (abstract 342O) — showed no overall survival benefit. Presenting and discussing KOLs framed the result as evidence that CLDN18.2 may remain a valid pancreatic cancer target even though this particular antibody-chemotherapy combination did not deliver a survival benefit.
Primary endpoint — Overall Survival (OS)
Median OS was 13.7 months with zolbetuximab + GN versus 13.6 months with GN alone (Astellas press release, final analysis, Oct 14, 2025; also reported in the ESMO GI 2026 congress recap). Two independent KOLs live-tweeting the oral presentation (abstract 342O) reported HR 1.00, P=0.499 (@dr_yakupergun) and HR 0.99, P=0.50 (@OncologyMarwarD) — these exact statistics were not found in the official press release and are sourced here from verbatim, cross-corroborated physician tweets pending formal publication.
Astellas described the safety profile of the zolbetuximab combination as "generally consistent with the known profiles of each individual therapy," though adverse events were more frequent in the zolbetuximab arm than with chemotherapy alone. KOLs (@ArndtVogel) characterized toxicity as manageable, while others (@DraMartinezLago) noted that early treatment discontinuation may have limited the drug's potential benefit.
⚠️ Investigational and now negative in pancreatic cancer: GLEAM did not support adding zolbetuximab to first-line gemcitabine/nab-paclitaxel in CLDN18.2-positive metastatic pancreatic adenocarcinoma, and Astellas has discontinued the pancreatic development program following the October 2025 final OS analysis. ✅ This does NOT affect zolbetuximab's (Vyloy) existing FDA approval, which is limited to first-line HER2-negative, CLDN18.2-positive gastric/GEJ adenocarcinoma (SPOTLIGHT/GLOW). An exploratory IL-18-high subgroup showed a possible OS signal, which several KOLs framed as reason to keep pursuing CLDN18.2 as a pancreatic cancer target — with a different drug or combination — even though this trial itself was negative.
GLEAM (NCT03816163) is a Phase II randomized trial testing zolbetuximab plus gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel alone in CLDN18.2-positive metastatic pancreatic adenocarcinoma, sponsored by Astellas Pharma.
Did GLEAM meet its primary endpoint?
No. GLEAM did not meet its primary endpoint of overall survival — median OS was 13.7 months with zolbetuximab + GN versus 13.6 months with GN alone (Astellas, final analysis, October 2025).
Is zolbetuximab (Vyloy) FDA approved?
Yes, but only for a different cancer type. Zolbetuximab (Vyloy) is FDA-approved (October 18, 2024) for first-line HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma. It is NOT approved for pancreatic cancer, and Astellas has discontinued the pancreatic development program after GLEAM's negative result.
What was the IL-18 finding in GLEAM?
An exploratory biomarker analysis found that zolbetuximab affected peripheral cytokines, and a rise in IL-18 was associated with longer survival in a small subgroup. KOLs described this as hypothesis-generating, not a confirmed benefit.
What does the GLEAM result mean for CLDN18.2 as a pancreatic cancer target?
Presenting and discussing KOLs, including Arndt Vogel, suggested the negative result may reflect the specific drug rather than the target itself ("Not the right drug, but maybe the right target"), and several called for continued investigation of CLDN18.2-directed therapy in pancreatic cancer.
Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Based on 6 KOL posts (12,007 impressions). Last updated July 5, 2026.
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