Findings from the phase 2 ILUSTRO trial (NCT03505320) confirmed that first-line zolbetuximab-clzb (Vyloy), mFOLFOX6 (modified leucovorin, 5-fluorouracil [5-FU], and oxaliplatin), and nivolumab (Opdivo) could be a rational, effective frontline strategy for patients with Claudin 18.2 (CLDN18.2)–positive, HER2-negative, unresectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, affirming the importance of biomarker-based treatment selection, according to Raji Shameem, MD.1
In ILUSTRO, the combination improved PFS and yielded durable responses across patient subgroups, although this benefit was particularly pronounced among those with high CLDN18.2 expression. 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%. These data were shared during the 2026 Gastrointestinal Cancers Symposium (ASCO GI).
“We hope that in the near future, we will be able to offer our patients the option of a triplet-based regimen in the frontline setting,” Shameem, a medical oncologist and hematologist at Orlando Health Cancer Institute, shared in an interview with OncLive®.
In the interview, Shameem expanded on efficacy and safety data from cohort 4B of the ILUSTRO trial, detailed planned avenues of investigation supported by this trial, and highlighted the importance of biomarker testing for patients with metastatic gastric and GEJ adenocarcinoma.
Topline Findings From ILUSTRO at ASCO GI
- In cohort 4B, zolbetuximab, mFOLFOX6, and nivolumab generated a median PFS of 14.8 months (95% CI, 8.3-NE) and an estimated 12-month PFS rate of 59.1%.
- In patients with CLDN18.2-high tumors, the median PFS was 18.0 months (95% CI, 11.1-NE); the median PFS was 6.7 months (95% CI, 3.0-NE) among those with CLDN18.2-intermediate tumors.
- The triplet’s safety profile was acceptable and consistent with findings from prior studies, although 98.7% of patients experienced zolbetuximab-related adverse effects.
OncLive: What was the rationale for investigating zolbetuximab plus mFOLFOX6 and nivolumab in gastric/GEJ cancer?
Shameem: Currently, when I see a patient, there are cases where they express PD-L1 with a combined positive score [CPS] of 1 or greater and have high expression of CLDN18.2. The question that arises is: What is the best frontline option? Zolbetuximab is FDA approved in combination with chemotherapy for patients who have high [CLDN18.2] expression—defined as 75% or greater per immunohistochemistry—but it is not approved for use [in combination with] immunotherapy.2 For patients with a CPS of 1 or greater, another regimen we can give is chemotherapy plus immunotherapy. This led to the big question addressed by ILUSTRO: What if we study triplet-based therapy by giving immunotherapy with a chemotherapy backbone to target CLDN18.2?
What was the design of ILUSTRO?
The ILUSTRO study is a global trial where most patients were from Asia, and most of the cancers were gastric cancer, though it also included GEJ adenocarcinoma. The investigators wanted to study the combination of zolbetuximab—a monoclonal antibody targeting CLDN18.2, plus mFOLFOX6 and the immunotherapy agent nivolumab.
The trial included patients who had either intermediate (50% to 74%) or high (75% or greater) CLDN18.2 expression.1 It should be noted that the current FDA approval for [zolbetuximab] in combination with chemotherapy is specifically for those [with high CLDN18.2 expression]. [ILUSTRO] also included patients regardless of whether they expressed PD-L1, though 65.3% of patients had a PD-L1 CPS of 1 or greater.
What efficacy data were reported from cohort 4B of the ILUSTRO trial?
Although the trial had different cohorts, the treatment efficacy data for cohort 4B were presented at ASCO GI. The results from the standard dosing of nivolumab, chemotherapy, and zolbetuximab were impressive. For all-comers, the median PFS was 14.8 months. If broken down specifically for patients with [high CLDN18.2 expression], the median PFS was even higher at 18.0 months [95% CI, 11.1-NE].
A post hoc analysis evaluated patients with high CLDN18.2 expression who also had a PD-L1 CPS of 1 or greater, and the median PFS in that group was 23.6 months. Although this is a phase 2 trial limited by sample size, and further confirmatory studies are needed, it is intriguing to see that this combination could have improved efficacy.
What should be known about the safety profile of the ILUSTRO regimen?
Regarding safety, there were no new safety signals. The toxicities observed were expected for chemotherapy and immunotherapy, as well as what is typically seen with zolbetuximab in the clinic. It is important to highlight the gastrointestinal toxicity associated with zolbetuximab; patients should be counseled about the incidence of nausea and potential for decreased appetite. In the ILUSTRO trial, most of these adverse effects were low-grade, but early recognition and appropriate evaluation are needed to prevent high-grade toxicity.
How do the IUSTRO trial findings inform future research and clinical practice?
[These data have] set the stage for the [phase 3] LUCERNA study [NCT06901531], an ongoing study investigating the combination of chemotherapy, pembrolizumab [Keytruda], and zolbetuximab in patients with high CLDN18.2 and PD-L1 expression.3 It will be interesting to see those efficacy results in comparison with the control arm of chemotherapy plus zolbetuximab.
These types of abstracts highlight the paramount importance of biomarker testing. In my practice, it is typical to perform expanded tumor next-generation sequencing [NGS] and liquid NGS testing for patients with metastatic gastric or GEJ adenocarcinoma. To make an informed frontline treatment choice, we need to know the status of microsatellite instability, HER2 expression, PD-L1 expression, and CLDN18.2. Because many of our patients do not receive second-line therapy, the first-line treatment choice is vital to ensure we find the best treatment for the patient. We consider all these biomarkers to make our treatment decisions.
References
- 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
- FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed January 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma
