Zolbetuximab/Chemo Displays PFS, OS Benefits in Gastric Cancer Trials

Commentary
Video

Data from the SPOTLIGHT and GLOW trials reveal that zolbetuximab increased survival in patients with CLDN18.2-positive gastric or GEJ adenocarcinoma.

CancerNetwork® spoke with John L. Marshall, MD, physician executive director of the MedStar Washington DC Integrated Hematology-Oncology Division and the Otto J Ruesch Center for the Cure of GI Cancers, and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University, ahead of the FDA approval of zolbetuximab-clzb about his impression of findings from 2 clinical trials that ultimately supported the agent’s approval.1 Specifically, he discussed the phase 3 SPOTLIGHT trial (NCT03504397), which evaluated traditional chemotherapy with or without zolbetuximab, and the phase 3 GLOW trial (NCT03653507), which evaluated capecitabine (Xeloda)-based chemotherapy with or without zolbetuximab in patients with Claudin 18.2–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.2,3

Marshall began by stating that both trials measured Claudin 18.2 expression, in which about 40% of patients exhibited high enough levels to be included for evaluation. He then expressed that there was an improvement in progression-free survival (PFS) and overall survival (OS) when zolbetuximab was added to either chemotherapy regimen across both trials. He followed up by stating that the delta was small in terms of response rates before describing how the therapy may have impacted the biology of the patient population.

Marshall then discussed a quandary in treating patients with both positive Claudin 18.2 expression and PD-L1–positive disease. He posed a question as to whether immunotherapy could be used in this population before explaining that expression of PD-L1 is typically lower in patients with Claudin 18.2–positive disease. Based on these factors, he concluded by stating the biggest decision to make when treating patients with gastrointestinal cancers is which targeted therapy to use.

Transcript:

The 2 big phase 3 studies that were done that demonstrate [support for the approval] took patients with gastric and GEJ cancers [and] measured their Claudin 18.2 expression. [Approximately] 40% had high enough levels to be involved [in the studies]. It was a big chunk of the overall percentage that had the expression of this marker. One of the studies was using traditional chemotherapy, the other [used] capecitabine-based therapy; [these were] essentially the same trial, [with] 2 different backbones of the fluoropyrimidine. Both of them demonstrate an improved progression-free and overall survival [with zolbetuximab]. Based on [the findings], we are hoping to get this approval.

It is important to note that there was not a big delta in response rate, which surprised [us]; there was some delta, but not a big delta. It is doing something to the biology of this patient population. The one thing that will be confusing to us as clinicians is what to do in a patient [whose disease] is PD-L1–positive and Claudin 18.2–positive. Do you bring an immunotherapy in? Right now, the preliminary data suggest that most of the patients who [have Claudin 18.2–positive disease] also have low PD-L1 [expression]. That might help our decision-making as to what targeted therapy to bring to the table, but that will be the biggest decision tree we will have going forward.

References

  1. Astellas’ VYLOY™ (zolbetuximab-clzb) approved by U.S. FDA for treatment of advanced gastric and GEJ cancer. News release. Astellas Pharmaceuticals. October 18, 2024. Accessed October 23, 2024. https://tinyurl.com/5745k9a8
  2. Shitara K, Lordick F, Bang Y-J, 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. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29:2133-2141. doi:10.1038/s41591-023-02465-7
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