Zolbetuximab Approval Paves Way for Precision Medicine in Gastric and GEJ Adenocarcinoma

The success of novel biomarker-driven therapies such as zolbetuximab-clzb (Vyloy) reflects an increasing shift toward precision medicine in gastric or gastroesophageal junction (GEJ) adenocarcinoma and opens new avenues for managing this notoriously difficult-to-treat cancer, according to Cindy M. Pabon, MD, who adds that the agent’s FDA approval is a significant step forward for patients and encourages further exploration of Claudin 18.2 (CLDN 18.2)–targeted agents.

On October 18, 2024, the FDA approved zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced, unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN 18.2–positive.¹ Findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials supported this regulatory decision, showing that the addition of zolbetuximab to standard chemotherapy improved survival vs chemotherapy alone.

“Being able to find [novel] targets these days in cancer treatment is really the foundation to improving outcomes in these hard-to-treat tumors, because we're seeing that we need something more specific beyond traditional chemotherapy.” said Pabon, an assistant professor at Sylvester Cancer Center, University of Miami, and assistant lead of GI Cancer Clinical Research in the Department of Gastrointestinal Medical Oncology at the University of Miami Health Systems, in Florida. “Across the country and the world, there are ongoing studies aiming to develop novel ways of targeting CLDN 18.2 now that we have these studies showing that it is an effective target in these tumors.”

In an interview with OncLive® regarding her presentation at the 2024 Sylvester Cancer Survivorship Symposium, Pabon discussed the significance of CLDN 18.2 as a target for gastric/GEJ cancer, the impact of the FDA approval of zolbetuximab in combination with chemotherapy, and the need for timely biomarker testing to inform more effective treatment strategies in the metastatic setting.

OncLive: What developments in gastric cancer treatment are generating the most optimism, particularly for improving outcomes among disproportionately affected populations?

Pabon: Gastric cancer is a bit of a challenging cancer to treat, because even when we catch it early on, it tends to come back. The 5-year overall survival rate is approximately 32% for this kind of cancer. It's very important that we not only catch it early, but that we continue to work towards developing better treatment options for these patients.

In Florida and Miami Dade County, especially, this is very relevant, because Hispanics are disproportionately affected by this kind of cancer. There's a great need for us to improve our efforts in gastric cancer, and [the field] hasn't had a lot of very robust updates until this past year, where we started identifying a new target that we could treat, [CLDN 18.2]. There was a lot of excitement [upon this discovery] and it reignited [efforts] to improve outcomes in this tumor type. That was one of the main reasons why we were all really looking forward to an update in this field.

What is the mechanism by which zolbetuximab targets CLDN 18.2 in gastric cancer?

Zolbetuximab is targeting a new biomarker called CLDN 18.2. This is a specific biomarker that we think is important in gastric cancer, because it's a protein that plays a role in making those stomach cells joined together. Sometimes, when it's abnormally expressed, we could see abnormal growth of cancer cells. The thought that by targeting [CLDN 18.2], we could then block some of that tumor growth and more easily target the cancer. Zolbetuximab is an antibody that targets that CLDN 18.2 protein and causes different mechanisms of cancer cell death. Through that, theoretically, we would imagine better outcomes.

How has the FDA approval of this combination revitalized efforts to target CLDN18.2 in gastric cancer?

There have been 2 main studies in the last couple years evaluating zolbetuximab in stage IV metastatic gastric cancer: the SPOTLIGHT and GLOW trials. They were looking at whether adding zolbetuximab to the chemotherapy we already use, mFOLFOX6 [5-fluorouracil, leucovorin, and oxaliplatin], would improve outcomes for these patients.

The 2 trials were able to confirm that [adding zolbetuximab to mFOLFOX] improved outcomes and [produced a] survival benefit [vs standard chemotherapy alone]. In October 2024, we got the approval from the FDA to go ahead and treat patients with the combination, which is wonderful for our patients who have very limited treatment options. What is even more exciting is that this [approval] opened the door to us targeting a new protein.

What role does biomarker testing play in shaping treatment strategies for gastric cancer, and how might emerging biomarkers like CLDN 18.2 influence patient outcomes?

Gastric cancer continues to be tricky to treat. If it's locally advanced, the key is to have multidisciplinary discussions and work together from a surgical, medical oncology and sometimes radiation perspective, to make sure you're doing everything possible to improve chance of cure. When it comes to the metastatic setting, biomarker testing is key. If possible, getting molecular profiling as soon as [the patient is] diagnosed with gastric cancer would be helpful, because knowing the biomarker landscape is what's going to help drive the treatment options for these patients. Chemotherapy tends to still be the backbone of treatment, but there's so much more we can help patients with if we are able to know about their combined positive score [CPS], their CLDN 18.2 status, or their HER2 status. Being able to obtain [this information] in a timely manner is helpful for these patients.

I have a lot of hope that emerging markers like CLDN 18.2 may [help patients obtain] longer responses than what we have seen before with CPS-positive patients. This is not a tumor that seems to be very hot or responsive to immunotherapy. Instead, the key will be to target specific overexpressed proteins or mutations. I am hopeful that taking this route with CLDN 18.2 as well as improving our HER2-directed therapies will lead to better outcomes for these patients.

What were your key takeaways from the meeting as a whole?

There's so much evolving in medical oncology that it's important to be able to gather as a group and not only review the updates but have these open discussions with each other about what is realistic in the community setting and in the academic setting. [We need to ask]: how are patients experiencing these treatments? Toxicity from treatment, whether it's financial or physical, is very real and so is quality of life. As much as we want to improve the treatment landscape, it's important that we continue to get together in these meetings to just reevaluate if we are doing good for our patients. Are we keeping their overall wellbeing in mind? Financial [toxicities], goals of care, and adverse effects or symptom profiles are things that we need to reflect on. This [meeting] is a great opportunity to go through all of that together and find out what is practical and helpful for our patients going forward.

Reference

FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed November 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma