Another Win for Zolbetuximab in Advanced Gastric/GEJ Cancer

Zolbetuximab plus capecitabine and oxaliplatin (CAPOX) improved survival outcomes in patients with Claudin (CLDN)18.2-positive, HER2-negative, locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinomas compared with placebo plus CAPOX, the randomized phase III GLOW trial showed.

At a median follow-up of 12.6 months, patients receiving first-line zolbetuximab plus CAPOX had a median progression-free survival (PFS) of 8.2 months compared with 6.8 months among patients receiving placebo plus CAPOX (HR 0.687, 95% CI 0.544-0.866, P=0.0007), reported Manish A. Shah, MD, of Weill Cornell Medicine and NewYork-Presbyterian Hospital in New York City, during an American Society of Clinical Oncology (ASCO) virtual plenary.

The median overall survival (OS) was 14.39 months with the combination versus 12.16 months in the placebo group (HR 0.771, 95% CI 0.615-0.965, P=0.0118).

Those PFS and OS benefits were sustained up to 24 months, with a 24-month PFS rate of 14% with the combination compared with 7% with placebo and CAPOX, and a 24-month OS rate of 29% versus 17%, respectively.

Objective response rates were 53.8% in the zolbetuximab group compared with 48.8% in the placebo group.

These efficacy results were observed across most prespecified subgroups, Shah said.

"Zolbetuximab successfully targets CLDN18.2 and meets a truly unmet medical need in the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma," Shah said. "GLOW confirmed that zolbetuximab plus chemotherapy is a new standard-of-care treatment for CLDN18.2-positive, HER2-negative, locally advanced, unresectable, or metastatic gastric or gastroesophageal junction adenocarcinoma."

While combining chemotherapy with targeted therapies such as trastuzumab (Herceptin) for HER2-positive disease, and nivolumab (Opdivo) for patients with a PD-L1 combined positive score (CPS) ≥5, has improved survival in some patients, there is a need to identify additional groups of patients who will benefit from targeted therapy.

"There are many patients who have tumors that are HER2-negative or have a PD-L1 less than 5," Shah said. "And for these patients when treated with standard platinum-fluoropyrimidine chemotherapy, their median survival is around 12 months."

CLDN18.2 is a protein expressed in normal and malignant gastric mucosa cells, Shah explained. "During malignant transformation, the malignant cells lose their polarity. This allows the CLDN18.2 receptor to be exposed on the surface of the gastric/gastroesophageal junction adenocarcinoma cells, making it a promising target."

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, and it induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.

Shah noted that the results from GLOW were consistent with those seen in the SPOTLIGHT trial, which evaluated zolbetuximab plus modified FOLFOX chemotherapy in the same patient population.

In SPOTLIGHT, median PFS increased from 8.67 months with modified FOLFOX alone to 10.61 months with the zolbetuximab-based combination, while median OS improved from 15.54 to 18.23 months.

The GLOW and SPOTLIGHT trials are "practice changing," said ASCO discussant Yelena Janjigian, MD, of Memorial Sloan Kettering Cancer Center in New York City, noting that these trials were the first to validate CLDN18.2 as a clinically validated target.

However, "we need to wait for FDA-approved IHC [immunohistochemistry] tests before clinical testing begins in the clinic," she said. "That's the number one question I get asked from patients and clinicians."

Regarding safety, Shah and colleagues observed that the incidence of serious treatment-emergent adverse events was similar between both arms (47.2% in the zolbetuximab arm vs 49.8% in the placebo arm) and consistent with SPOTLIGHT.

However, nausea (68.5% vs 50.2%), vomiting (66.1% vs 30.9%), and decreased appetite (41.3% vs 33.7%) all occurred more frequently in the zolbetuximab arm versus the placebo arm. Thus, nausea inhibition should be considered in this treatment scenario, Janjigian suggested.

For this study, Shah and team included 507 patients who were randomly assigned 1:1 to receive 8 cycles of CAPOX with zolbetuximab or placebo. Patients then continued on maintenance capecitabine, either with zolbetuximab or placebo.

Patients had a median age of 60 years, about 62% were men, and a similar percentage came from Asia. All patients had an Eastern Cooperative Oncology Group performance status score of 0-1. One-quarter of patients had metastases in three or more organs, and about 30% of patients had undergone prior gastrectomy.

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