Spotlighting Zolbetuximab for Gastric/Gastroesophageal Junction Adenocarcinoma with Kohei Shitara, MD

In this interview from the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Kohei Shitara, a Medical Oncologist at the National Cancer Center Hospital East in Japan, discusses his two abstracts investigating the efficacy of zolbetuximab in gastric cancers.  

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we’re at the ASCO Annual Meeting, and I’m joined by Dr. Kohei Shitara. Thanks so much for coming on today.

Dr. Shitara: My pleasure.

Oncology Data Advisor: Would you like to introduce yourself and share what your work focuses on?

Dr. Shitara: At this ASCO, I’m presenting two posters. One is the prevalence data of claudin 18.2 (CLDN18.2) in gastric cancer patients during two phase 3 trials, and the second is a trial in progress, a phase 2 study to evaluate the zolbetuximab combination.

Oncology Data Advisor: For this first study, why was CLDN18.2 chosen as a drug target? And what is its prevalence in this disease?

Dr. Shitara: Yes, it’s very important question. CLDN is one of the tight junction proteins, which are usually expressed in normal gastric mucosa cells, but during transformation to gastric cancer, this target is exposed on tumor cell surface, and it looks almost like a visible and targetable molecule. Previous literature has suggested that 40% of patients show a high expression, and already one very new agent, zolbetuximab, which is a monoclonal antibody, has shown a preliminary efficacy signal in previous phase 1 or phase 2 trials. That’s why the phase 3 trials were conducted.

Oncology Data Advisor: What have the phase 3 trials demonstrated so far?

Dr. Shitara: There were two phase 3 trials, and one is named the SPOTLIGHT trial. It is a global study to compare FOLFOX (leucovorin/fluorouracil/oxaliplatin) plus zolbetuximab and standard FOLFOX plus placebo. The primary end point is progression-free survival, and the secondary end point is overall survival, and it showed a significant improvement in both end points. It shows us some notable toxicity with nausea and vomiting, which present usually at a very early phase of treatment and usually feasible to manage.

Another phase 3 trial is the GLOW study. This is also a global study, and it is studying CAPOX (capecitabine/oxaliplatin) plus zolbetuximab. CAPOX is an oral drug regimen. The treatment cycle is every three weeks, so a little bit different from FOLFOX. Both the SPOTLIGHT and the GLOW study show a progression-free survival and overall survival improvement with zolbetuximab. These two studies may suggest chemotherapy plus zolbetuximab as a new treatment option for patients.

Oncology Data Advisor: Great, that’s very exciting. What were the most common adverse events, and how were they managed?

Dr. Shitara: As mentioned, nausea and vomiting as a CLDN18.2-related toxicity is very commonly observed. But usually, this occurs at the first or second cycle and is usually managed by dose interruptions during infusion, as well as antiemetics for prophylaxis. After the first cycle, usually this nausea and vomiting rarely happens. It’s usually feasible to manage, at least in the overall patient population in my experience. Around 10% of patients discounting zolbetuximab due to toxicities, but again, dosing management is usually feasible.

Oncology Data Advisor: That’s good to know. So, do you think that all patients with gastric or gastroesophageal junction cancer should be screened for CLDN18.2?

Dr. Shitara: Exactly. Eventually, maybe we’ll have an approval of zolbetuximab based on these two trial2 in future. Then this treatment should become the standard treatment option. So, testing for CLDN18.2 should be one of the standard types testing for gastric cancer. Surely, we already have our other important biomarkers, like HER2, MSI, TGM1, and TPS. But now we need to test for CLDN18.2 if this treatment is available.

Oncology Data Advisor: That’s great to know. Is this treatment combination being investigated in other settings, such as the adjuvant settings?

Dr. Shitara: This is planned, especially as a neoadjuvant treatment, but the trial has not yet been started.

Oncology Data Advisor: Are there any other future directions or anything else you would like to mention?

Dr. Shitara: Yes, as I mentioned before, at this ASCO, we presented a trial in progress to introduce the ILUSTRO study. This is a multicohort study. Recently, we included a new cohort to evaluate FOLFOX plus zolbetuximab in combination with nivolumab. This is an additional combination with nivolumab, which is already established, with FOLFOX plus zolbetuximab. There is ample preclinical data to suggest the combination may work. Also, we’ve now established a standard FOLFOX/nivolumab and FOLFOX/rituximab, so to combine these is very reasonable. There is usually some debate of which combination should be used for patients who are programmed death-ligand 1 (PD-L1) TPS-high, as well as CLDN18.2. So, to answer this clinical question, we are now evaluating the combination, and enrollment is ongoing.

Oncology Data Advisor: That’ll be really exciting to see the results as everything progresses. Thanks so much for stopping by to talk about this today.

Dr. Shitara: Thank you very much.

About Dr. Shitara

Kohei Shitara, MD, is a Medical Oncologist at the National Cancer Center Hospital East in Japan. His research focuses on the development of novel therapies for gastrointestinal cancers, including gastric, gastroesophageal junction, and colorectal cancers.

For More Information

Shitara K, Yamaguchi K, Shoji H, et al (2023). Phase 2 trial of zolbetuximab in combination with mFOLFOX6 and nivolumab in patients with advanced or metastatic claudin 18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas. J Clin Oncol (ASCO Annual Meeting Abstracts), 41(suppl_16). Abstract TPS4173. DOI:10.1200/JCO.2023.41.16_suppl.TPS4173

Shitara K, Xu RH, Moran DM, et al (2023). Global prevalence of CLDN18.2 in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Biomarker analysis of two zolbetuximab phase 3 studies (SPOTLIGHT and GLOW). J Clin Oncol (ASCO Annual Meeting Abstracts), 41(suppl_16). Abstract 4035. DOI:10.1200/JCO.2023.41.16_suppl.4035

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 

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