Zolbetuximab Could Alter Frontline Treatment Paradigm for CLDN18.2+ Gastric/GEJ Cancer


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Andrew Ko, MD, FASCO, highlights what the potential approval of zolbetuximab could mean for the first-line treatment paradigm for patients with CLDN18.2-positive gastric/gastroesophageal junction adenocarcinoma and detailed other ongoing research in the gastrointestinal cancer space.

Andrew Ko, MD, FASCO

Andrew Ko, MD, FASCO

The potential FDA approval of zolbetuximab (IMAB362) could represent a novel targeted therapy for the frontline treatment of select patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to Andrew Ko, MD, FASCO.

In July 2023, the FDA granted priority review to a biologics license application seeking the approval of zolbetuximab for the first-line treatment of patients with unresectable, locally advanced or metastatic, Claudin18.2 (CLDN18.2)-positive, HER2-negative, gastric or GEJ adenocarcinoma.1

The application was supported by data from the phase 3 SPOTLIGHT(NCT03504397) and GLOW (NCT03653507) trials. SPOTLIGHT evaluated zolbetuximab plus mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin), and patients in the zolbetuximab group (n = 283) experienced a median progression-free survival (PFS) of 10.61 months (95% CI, 8.90-12.48) vs 8.67 months (95% CI, 8.21-10.28) for patients treated with placebo plus mFOLFOX6 (n = 282; HR, 0.75; 95% CI, 0.60-0.94; P = .0066).2 The median overall survival (OS) was 18.23 months (95% CI, 16.43-22.90) in the zolbetuximab arm compared with 15.54 months (95% CI, 13.47-16.53) in the placebo arm (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).

Data from GLOW, which evaluated zolbetuximab and CAPOX (capecitabine [Xeloda] plus oxaliplatin), showed that patients treated in the zolbetuximab arm (n = 254) achieved a median PFS of 8.21 months (95% CI, 7.46-8.84) vs 6.80 months (95% CI, 6.14-8.08) for those treated with placebo plus CAPOX (n = 253; HR, 0.687; 95% CI, 0.544-0.866; P = .0007).3 The median OS was 14.39 months (95% CI, 12.29-16.49) vs 12.16 months (95% CI, 10.28-13.67), respectively, (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).

“I anticipate that [zolbetuximab] is going to be approved in the coming months and will represent a new option for us in select patients with [gastric/GEJ adenocarcinoma],” Ko said in an interview with OncLive® following a State of the Science Summit™ (SOSS) on gastrointestinal (GI) cancers, which he chaired.

In the interview, Ko highlighted what the potential approval of zolbetuximab could mean for the first-line treatment paradigm for patients with CLDN18.2-positive gastric/GEJ adenocarcinoma and detailed other ongoing research in the GI cancer space. Ko is a professor of clinical medicine and the associate division chief of oncology in the Division of Hematology/Oncology at University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

OncLive: Could you provide some background on zolbetuximab and the data that could support its FDA approval?

Ko: Perhaps the most exciting development I shared [during the SOSS] had to do with the anticipated [FDA] approval of a new drug: an antibody directed against the tumor antigen CLDN18.2. This drug called zolbetuximab was studied in a couple phase 3 trials, including one that our institution participated in called SPOTLIGHT. [SPOTLIGHT] demonstrated that the addition of zolbetuximab to standard chemotherapy for patients whose cancers express high levels of CLDN18.2—a protein expressed in the tight junctions of gastric mucosal cells—improved survival and clinical outcomes in the first-line setting.

This was an international trial [conducted] in the first-line setting for patients with metastatic gastric or GEJ cancers. It did require, as a preselection, patients whose tumors expressed high levels of CLDN18.2, which amounted to [38%] of patients who were screened.2 It's important to note that if and when this drug is approved, a companion diagnostic antibody will have to go along with it, because pathologists will need to [include this] as a routine part of their evaluation of gastric cancers.

The SPOTLIGHT study used a chemotherapy backbone of mFOLFOX6 together with either placebo or zolbetuximab. [Treatment with the zolbetuximab regimen led to] an OS benefit [HR, 0.75; 95% CI, 0.60-0.94; P = .0053], translating to a [2.69]-month improvement in median OS vs mFOLFOX6 plus placebo. There was a corresponding improvement in PFS, and toxicity was very manageable with some increased GI toxicity, as would be expected with this type of target.

If zolbetuximab is approved by the FDA, how could this agent fit into the treatment paradigm for patients with unresectable, locally advanced or metastatic, CLDN18.2-positive, HER2-negative, gastric or GEJ adenocarcinoma?

I believe that this treatment will become a new frontline standard [for this patient population]. The outstanding question is with the current use of chemotherapy plus immune checkpoint inhibitors. How will this fit into our current treatment paradigms? Will select patients receive zolbetuximab? Will others receive an immune checkpoint inhibitor? Is it a possibility that patients will receive both in combination with chemotherapy? These [answers] may depend on expression of CLDN18.2, expression of PD-L1, and more clinical data that continue to emerge to tease out how best to use one approach vs another.

Outside CLDN18.2, what other novel targets are being investigated in the GI cancer space?

There are other potential targets of interest in gastric cancer. There are a number of ongoing studies. One is looking to further our ability to target HER2, for example, and [another is looking] to target FGFR2. There are other potential targets that could allow us in the future to be even more precise and direct in terms of how we treat [patients with] gastric cancer, according to these different markers.

[At the SOSS], we talked about immune checkpoint inhibitors as well, which are currently being used for treatments and are being evaluated in earlier-stage, perioperative settings together with chemotherapy, although [these combinations] don’t seem to show as striking of a benefit in those earlier-stage settings.

Are there any ongoing studies you are involved in that you would like to highlight?

I'm involved in a number of studies, specifically for [patients with] pancreatic cancer and upper gastric and esophageal cancers. Obviously, for pancreatic cancer, we have a long way to go, and trying to develop some novel strategies using different immunotherapy approaches—which haven't traditionally worked in pancreatic cancer—is a big area [of interest].

We're also very interested in studying specific contexts [in pancreatic cancer], such as in the maintenance setting, where we're doing some studies. Certain molecular niches of pancreatic cancer, such as patients with BRCA[-mutated] or homologous recombination deficient–associated tumors, are a particular area of interest of mine, in addition to some novel targets in gastric cancer.


  1. Astellas announces US FDA grants priority review for zolbetuximab biologics license application. News release. Astellas. July 6, 2023. Accessed September 19, 2023. https://www.astellas.com/en/system/files/news/2023-07/81743d9407/20230706_en_1.pdf
  2. Shitara K, Lordick F, Bang YJ, et al. 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. doi:10.1016/S0140-6736(23)00620-7
  3. Xu RH, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW. J Clin Oncol. 2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736
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