Gastroenterology, Oncology

Advancing a Promising New Targeted Treatment for Metastatic Gastric Cancer

    For Manish Shah, MD, a medical oncologist at NewYork-Presbyterian/Weill Cornell Medicine, finding new and better treatments for gastric and gastroesophageal cancers is a top priority. Gastric cancer is the fifth most diagnosed cancer globally, and although its incidence has decreased markedly in the last few decades, it remains an important malignancy both in the United States and globally. About two-thirds of the patients with gastric cancer that Dr. Shah sees have metastatic cancer, and treatment options are limited. According to the National Cancer Institute, the five-year survival rate for patients with metastatic disease is about 7 percent.

    “Gastric cancer is a pretty significant global problem,” says Dr. Shah, who is the Director of the Gastrointestinal Oncology Program, Chief of the Solid Tumor Oncology Service, and Co-Director of the Center for Advanced Digestive Disease at NewYork-Presbyterian/Weill Cornell Medicine. “[For patients with metastatic cancer,] unfortunately only about 20% live more than two years. There are some patients that have more of an extended survival, but it is a tough disease with a grim prognosis.”

    Gastric cancer is a pretty significant global problem. [For patients with metastatic cancer,] unfortunately only about 20% live more than two years. There are some patients that have more of an extended survival, but it is a tough disease with a grim prognosis.

    — Dr. Manish Shah

    These historical outcomes have been the catalyst for Dr. Shah’s involvement in the GLOW Study, an international, double-blind phase 3 clinical trial, done in participation with NewYork-Presbyterian/Weill Cornell Medicine, which has demonstrated promising results. Recent findings uncovered that a new targeted treatment called zolbetuximab, when given in combination with standard chemotherapy consisting of capecitabine and oxaliplatin (CAPOX), extended survival for patients with metastatic gastric or gastroesophageal junction cancer that is human epidermal growth factor receptor 2 (HER2)-negative and overexpresses the protein claudin-18 isoform 2 (CLDN 18.2). Dr. Shah was the lead author and co-primary investigator of the GLOW Study, and the results were published in Nature Medicine on July 31.

    If approved, zolbetuximab will be the first targeted therapy in the U.S. for patients with previously untreated advanced gastric or gastroesophageal junction cancer that is HER2-negative and overexpresses CLDN 18.2. The U.S. Food and Drug Administration has granted priority review to the manufacturer’s biologic license application for zolbetuximab and set January 12, 2024, as the target decision date.

    Targeting CLDN 18.2 to Treat Gastric and Gastroesophageal Junction Cancers

    Gastric cancers tend to have higher levels of CLDN 18.2, which is normally found in gastric mucosa cells and becomes more exposed as gastric cancer develops. Zolbetuximab is a monoclonal antibody, administered intravenously, that binds to CLDN18.2, killing the dividing cancer cells directly and also alerting the immune system to respond. “The goal of the GLOW Study was to identify patients who have a high expression of CLDN 18.2 that might benefit from attacking it with the antibody that binds to it,” says Dr. Shah. “The primary endpoint of the study was to improve progression free survival, and then we looked at other endpoints, like overall survival and toxicity.”

    digital illustration of gastric cancer

    The GLOW study was conducted between November 2018 and February 2022 at 166 sites, including NewYork-Presbyterian/Weill Cornell Medicine, across 18 countries. A total of 507 patients with previously untreated HER2-negative locally advanced or metastatic gastric or gastroesophageal junction cancer expressing CLDN18.2 were randomized to receive zolbetuximab in combination with CAPOX or a placebo plus CAPOX.

    Zolbetuximab plus CAPOX significantly increased progression-free survival compared with placebo plus CAPOX. Specifically, zolbetuximab plus CAPOX lowered the risk of disease progression or death by 31 percent compared with placebo plus CAPOX. The median progression-free survival was 8.21 months for patients in the zolbetuximab group compared with 6.8 months for those in the placebo group. Furthermore, the addition of zolbetuximab doubled the chance of not having disease progression at 2 years (from 7 percent with placebo versus 14 percent with zolbetuximab).

    Results also demonstrated that zolbetuximab plus CAPOX significantly lengthened overall survival and reduced the risk of death by 23 percent. The median overall survival was 14.4 months for patients in the zolbetuximab plus CAPOX group versus 12.2 months for those in the placebo plus CAPOX group. Long term survival similarly increased significantly with the addition of zolbetuximab – 29 percent survival at 2 years with zolbetuximab versus 17 percent with placebo.

    Treatment-related adverse events were similar between groups, with nausea, vomiting and decreased appetite reported most frequently. “Because this protein is normally expressed on the gastric mucosa, we see patients having more nausea, vomiting, and upper GI symptoms likely because of zolbetuximab binding to the CLDN18.2 on the normal gastric mucosa, almost like an on-target effect,” says Dr. Shah. “Despite its mechanism of action, it was good to see zolbetuximab did not add significant toxicity.”

    Dr. Shah has been involved in zolbetuximab research for over five years, beginning with the ILLUSTRO Study – the phase 1 and phase 2 trials assessing the efficacy and safety of zolbetuximab combinations. The results from ILLUSTRO led to the GLOW Study and a similar phase 3 study, SPOTLIGHT, which evaluated zolbetuximab in combination with a different chemotherapy regimen consisting of modified folinic acid or levofolinate, fluorouracil and oxaliplatin (mFOLFOX). The results from the global, randomized, placebo-controlled, double-blind SPOTLIGHT trial were published in The Lancet May 20, 2023 and also reported strong survival outcomes among those enrolled. Dr. Shah was a member of the SPOTLIGHT steering committee, co-author of The Lancet paper and involved in designing both the GLOW and SPOTLIGHT trials, which were sponsored by Astellas Pharma, the maker of zolbetuximab.

    We now have evidence from two large trials showing that the addition of zolbetuximab provides a meaningful survival benefit for patients with CLDN 18.2-positive gastric cancers. If zolbetuximab is approved, patients will be able to decide with their physicians whether zolbetuximab plus CAPOX or mFOLFOX is the right regimen for them.

    — Dr. Manish Shah

    “We now have evidence from two large trials showing that the addition of zolbetuximab provides a meaningful survival benefit for patients with CLDN 18.2-positive gastric cancers,” he said. “If zolbetuximab is approved, patients will be able to decide with their physicians whether zolbetuximab plus CAPOX or mFOLFOX is the right regimen for them.”

    Implications for the Future

    Zolbetuximab isn’t the only treatment being studied targeting CLDN18.2. Other drugs currently being studied include monoclonal antibodies ASKB589 and osemitamab; bispecific antibodies PT886 and TJ-CD4B; an antibody drug conjugate CMG901; and a CAR-T cell therapy CT 041. These drugs are being investigated for use in untreated locally advanced, inoperable, or metastatic gastric, gastroesophageal junction, esophageal, or pancreatic cancer.

    In addition to CLDN18.2, there are several types of claudins that are dysregulated in other cancers such as breast cancer, melanoma, oral squamous cell carcinoma, thyroid cancer, ovarian cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, among others.

    The CLDN18.2 studies further validate the potential for other claudins to be future targets for other novel therapeutics. “Zolbetuximab is already being tested in other cancers that overexpressed CLDN18.2 and actually it's opened up a whole field in drug development activity,” says Dr. Shah. “There are several companies and new drugs that are targeting CLDN18.2, empowered by the positive data from these trials that demonstrates that targeting CLDN18.2 is a viable way to treat cancer. It’s spurned a lot of research to try to improve survival by better targeting this protein.”

    Dr. Shah and the gastrointestinal oncology team at NewYork-Presbyterian/Weill Cornell Medicine will continue to search for other treatments for these cancers. “We have an active gastric cancer clinical and research program,” he says. “We have trials in patients focused across the spectrum of disease, from patients with localized disease to patients with metastatic disease. We also have trials trying to overcome resistance to immunotherapy. For example, in one study, we are injecting an oncolytic virus into the tumor to try to engender an immune response against the cancer as well. We have a diverse portfolio of clinical trials to address all the needs of patients with gastric cancers.”

    Dr. Shah is a national and international thought leader in drug development and the treatment of gastrointestinal malignancies. In addition to researching treatments, he has helped author gastric and esophageal cancer treatment guidelines for the American Society of Clinical Oncology, and he uses his practice at NewYork-Presbyterian/Weill Cornell Medicine to ensure that these guidelines offer patients the most comprehensive and highest quality of care. “We truly have a multidisciplinary approach to the disease,” he says. “We have an active clinical team that involves surgeons, gastroenterologists, radiologists, radiation oncologists, and others. It really does take a team to provide the best care for patients with upper GI cancers.”

      Learn More

      A New Targeted Treatment Shows Promise for Select Patients with Stomach Cancer (Weill Cornell Medicine Newsroom)

      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. Nature Medicine. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7

      Kohei Shitara, Florian Lordick, 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. The Lancet. Published online April 1, 2023. doi:10.1016/s0140-6736(23)00620-7

      Klempner SJ, Lee KW, Kohei Shitara, et al. ILUSTRO: Phase II Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2–Positive Gastric or Gastroesophageal Junction Adenocarcinoma. Clinical Cancer Research. Published online August 22, 2023:OF1-OF10. doi:10.1158/1078-0432.ccr-23-0204

      For more information

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      Dr. Manish Shah
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