Zolbetuximab Plus Chemo Extends PFS and OS in CLDN18.2+ Metastatic Gastric Cancer


Zolbetuximab demonstrated a survival benefit and a tolerable safety profile when combined with mFOLFOX6 vs mFOLFOX6 plus placebo in patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, according to primary results from the phase 3 SPOTLIGHT trial.

Kohei Shitara, MD

Kohei Shitara, MD

Zolbetuximab demonstrated a survival benefit and a tolerable safety profile when combined with mFOLFOX6 vs mFOLFOX6 plus placebo in patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, according to primary results from the phase 3 SPOTLIGHT trial (NCT03504397). The results were presented by Kohei Shitara, MD, at the 2023 Gastrointestinal Cancers Symposium.

Previously, zolbetuximab, a monoclonal antibody (mAb) targeting CLDN18.2, was studied in the phase 2b FAST trial (NCT01630083). In FAST, zolbetuximab plus epirubicin, oxaliplatin, and capecitabine (EOX) prolonged progression-free survival (PFS) and overall survival (OS) vs EOX alone in patients with CLDN18.2 expression in at least 70% of tumor cells.1 In SPOTLIGHT, zolbetuximab plus chemotherapy led to a median PFS of 10.61 months and a median OS of 18.23 months.2

“I’m happy to share these positive results with the gastric cancer field because after HER2-targeted therapy with trastuzumab [Herceptin] in the front line and outside of checkpoint inhibitors, we didn’t have success with other targeted agents,” Shitara said in an interview with OncLive®.

In the interview, Shitara discussed the unique mechanism of action of zolbetuximab, how unmet needs in gastric cancer informed this research, and key efficacy and safety data from SPOTLIGHT.

Shitara is a gastrointestinal (GI) medical oncologist in the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa City, Chiba, Japan.

OncLive®: What is the current standard of care (SOC) for patients with gastric cancer?

Shitara: [The SPOTLIGHT trial included patients with] gastric cancer with unresectable or metastatic disease. The SOC in that population is systemic chemotherapy. Treatment is based on [a patient’s] biomarker status. Patients with HER2-positive disease are usually treated with chemotherapy plus trastuzumab.

For HER2-negative disease, patients receive chemotherapy plus immunotherapy like nivolumab [Opdivo], especially patients with a PD-L1 combined positive score [CPS] of 5 or higher. For other patients, chemotherapy alone or in combination with nivolumab could be [an option]. Those are the SOC regimens, especially in the first line.

What unmet needs exist in gastric cancer?

We have treatment options like up-front chemotherapy, but the efficacy is still not [great]. A proportion of patients has good tumor shrinkage, but eventually, most of them progress. These patients may receive subsequent chemotherapy but eventually pass away, most of them from disease progression. We need additional therapies to improve outcomes for our patients.

What does CLDN18.2 positivity mean for patient prognosis?

CLDN18.2 is a tight junction protein mainly expressed in normal gastric mucosa cells. It is positive in some patients with gastric cancer. CLDN18.2 is exposed on the tumor cell surface, and it becomes an attractive target in patients with positive expression. In our trial, CLDN18.2 positivity was defined as [disease where] at least 75% of the tumor cells had moderate to strong CLDN18.2 expression.

There are no specific characteristics of this population’s prognosis. In our retrospective analysis, having CLDN18.2-positive or CLDN18.2-negative disease had no prognostic effect. No specific patient background [is more likely] to have high CLDN18.2 expression. Any patient could have positive CLDN18.2 expression.

What is the mechanism of action of zolbetuximab?

Zolbetuximab is a first-in-class IgG1 mAb targeted against CLDN18.2. It can induce ADCC [antibody-dependent cell-mediated cytotoxicity] and CDC [complement dependent cytotoxicity]. However, since CLDN18.2 is a protein without a specific signal like HER2 or PD-L1, there is no biological effect for targeting this pathway and purely inducing ADCC and CDC.

[Eliciting] ADCC or CDC [is] a unique mode of action and target. A previous trial suggested some single-agent activity with low response rates. Tumor shrinkage by this agent [alone] is not common, but around half of patients achieved disease control, which is still clinically meaningful.

What inspired the SPOTLIGHT trial?

The target is unique. About 30% to 40% of patients with gastric cancer have CLDN18.2 expression, so there’s enough of a population to test. Zolbetuximab is a first-in-class agent with single-agent activity. Importantly, the previous, relatively small FAST trial showed a significant improvement in overall survival in patients with CLDN18.2-high disease [who received] chemotherapy plus zolbetuximab.

Could you describe the rationale for pairing first-line zolbetuximab with mFOLFOX6 in this population?

We used mFOLFOX6 because that is 1 of the SOC regimens, a 5-fluorouracil [5-FU] and oxaliplatin–based regimen. Previously, we also tested additional cytotoxic agents like docetaxel, but that [agent did not pan out well]. The current SOC in the first-line population remains 5-FU and a fluoropyrimidine plus another combination like FOLFOX. We planned to combine [this standard] with zolbetuximab.

What outcomes from this trial were presented at the 2023 Gastrointestinal Cancers Symposium?

We screened 2,735 patients during the past 4 years for CLDN18.2. [In total], 565 patients [with CLDN18.2-positive tumors] were randomized. Centrally assessed PFS was the primary end point.

We observed a significant improvement in PFS, so [this trial] met the primary end point. The median PFS was 10.61 months with mFOLFOX6 plus zolbetuximab and 8.67 months with mFOLFOX6 plus placebo. The HR was 0.751 with a P value of .0066, which was highly statistically significant. Additionally, we observed higher 1-year and 2-year PFS rates [with zolbetuximab].

We also observed a clear improvement in OS. If the primary end point of PFS was met, we also planned to test OS from a statistical point of view. We observed a statistically significant OS improvement as a secondary end point. This was 1 of the longest durations of median OS [seen in phase 3 trials in this population]. The median OS was 18.23 months with zolbetuximab and 15.54 months with placebo. The HR was 0.750 with a Pvalue of .0053, which was lower than the predefined threshold for significance.

What safety data are important to note?

Zolbetuximab has some notable toxicities. It is a CLDN18.2-targeted therapy, and CLDN18.2 is expressed in normal gastric and mucosa cells, so some GI symptoms [can occur]. For example, [the incidence of] any-grade nausea and vomiting [was 20.2% and 30% higher, respectively], with zolbetuximab, and [the incidence of grade 3 or higher nausea and vomiting was 9.6% and 10.3% higher, respectively]. [The incidence of any-grade decreased appetite] was 13.5% more common with zolbetuximab, but there was no difference in [the incidence of] grade 3 or higher [decreased appetite between the arms].

These 3 toxicities are most important. Otherwise, there were no major differences in toxicity. These GI toxicities are in line with previous reports of zolbetuximab. Importantly, these only happened during early cycles of treatment, most commonly the first or second zolbetuximab infusion. We can manage these well with infusional adjustment. The incidence [of these AEs] decreased in subsequent cycles. Transient nausea and vomiting are notable toxicities, but otherwise, this is a feasible combination.

What would be the implications of the potential future approval of zolbetuximab?

If approved, zolbetuximab plus mFOLFOX6 could be a treatment option, especially for patients with CLDN18.2-positive tumors. In this population, this combination could [become] a SOC.

[Some common questions remain unanswered]. For example, in patients with PD-L1–positive and CLDN18.2-positive disease, should we use zolbetuximab or chemotherapy plus nivolumab? Which is better? At this time [we cannot answer that].

However, our exploratory analysis had a small proportion of patients with a PD-L CPS of 5 or higher. This was evaluated in 311 patients with a tumor sample. Only 13.2% of patients had a PD-L CPS of 5 or higher. Most patients had a CPS of less than 5, so the benefit of chemotherapy plus nivolumab may not be highly anticipated. For that population, chemotherapy plus zolbetuximab should be the SOC.

For the future, maybe we can combine chemotherapy, zolbetuximab, and immunotherapy. This has already been tested in clinical trials. 

What would you like your colleagues to take away from this research?

Now, we have another treatment option with chemotherapy plus zolbetuximab, which can target a specific population defined by CLDN18.2 expression. In the future, we need to test several biomarkers, including HER2, PD-L1 CPS, and CLDN18.2, so patients have treatment options based on their molecular profile.

What other therapeutic approaches are on the horizon in gastric cancer?

SPOTLIGHT established CLDN18.2 as a viable target for gastric cancer. Additional targeted agents for CLDN18.2 are already under assessment in several clinical trials, including modified antibodies, bispecific antibody T-cell engagers, antibody-drug conjugates, and CAR T-cell therapies. This is an attractive field, [and CLDN18.2 is] an attractive target in development.

Editor’s Note: Dr Shitara has received honoraria from Bristol-Myers Squibb, Janssen, and Takeda; consulting or advisory roles with Abbvie, Amgen, Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda; and research funding from Amgen (Inst), Astellas Pharma (Inst), Chugai Pharma (Inst), Daiichi Sankyo (Inst), Eisai (Inst), MSD (Inst), Ono Pharmaceutical (Inst), and Taiho Pharmaceutical (Inst).


  1. 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. doi:10.1016/j.annonc.2021.02.005
  2. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT trial. J Clin Oncol. 2023;41(suppl 4):LBA292. doi:10.1200/JCO.2023.41.3_suppl.LBA292
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