Zolbetuximab + CAPOX Improves Survival in Advanced Gastric/GEJ Cancer

Gastric Cancer: Gastric CancerZolbetuximab plus chemotherapy has the potential to be an innovative therapeutic option and a potential new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. At a median follow-up of 12.6 months, patients receiving first-line zolbetuximab plus capecitabine plus oxaliplatin (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). The median overall survival (OS) was 14.39 months in the combination group versus 12.16 months in the placebo group (HR: 0.771). CLDN18.2 is a protein found on cells in the stomach and the gastroesophageal junction. Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets CLDN18.2, causing cancer cell death. CLDN18.2 status is not routinely evaluated in patients with locally advanced resectable or metastatic gastric/GEJ adenocarcinoma, and there is currently no approved therapy for these patients. “There is a clear high, ongoing unmet medical need for patients with advanced gastric and G-junction adenocarcinoma,” said Manish Shah, MD, Director of the Gastrointestinal Oncology Program at Weill Cornell Medicine, presenting at the March 2023 session of the American Society of Clinical Oncology (ASCO) Plenary Series. Several targeted therapies are now used for treatment of gastric or G-junction cancer in combination with chemotherapy. “Trastuzumab is beneficial for the approximate 15 percent of patients who are HER2-positive,” Shah noted. “Similarly, nivolumab has been approved in combination with chemotherapy for gastric and G-junction adenocarcinoma, but the benefit mainly is in patients who are PD-L1 CPS 5 or higher. There are many patients who have tumors that are HER2-negative or who have a PD-L1 CPS score of less than 5. For these patients, when treated with standard platinum-fluoropyrimidine chemotherapy, their median survival is around 12 months,” Shah noted. He presented results from the global, randomized, double-blind, placebo-controlled, Phase III GLOW study of 507 patients who received either zolbetuximab plus CAPOX or placebo with CAPOX. After 8 cycles, patients continued with zolbetuximab or placebo, plus capecitabine, until disease progression or discontinuation criteria was met. Study Details Patients had a median age of 60 years, about two-thirds were men, and 40 percent of patients came from outside of 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 percent of patients had undergone prior gastrectomy. The benefit in PFS and OS with zolbetuximab increased with time. “At 1 year, the PFS rate went from 19 percent with placebo to 35 percent with the addition of zolbetuximab,” Shah noted. At 2 years, the PFS rate doubled from 7 percent with placebo to 14 percent with zolbetuximab. “The 12-month overall survival rate was 58 percent with the addition of zolbetuximab. And at 2 years, it was almost 30 percent (versus 17% for placebo),” he said. Most prespecified subgroups showed similar survival results. Objective response rates were 53.8 percent with zolbetuximab versus 48.8 percent with placebo. Shah said these results were consistent with those from the Phase III SPOTLIGHT trial, presented at the 2023 ASCO Gastrointestinal Cancers Symposium. SPOTLIGHT examined zolbetuximab plus folinic acid, 5-FU, and oxaliplatin (modified FOLFOX6) in patients with CLDN18.2-positive, HER2-negative, locally advanced, or metastatic gastric/GEJ adenocarcinoma. Those treated with zolbetuximab plus modified FOLFOX6 had better PFS and OS compared to those treated with placebo and mFOLFOX6. Median PFS increased from 8.67 months with modified FOLFOX alone to 10.61 months with the zolbetuximab combination, and median OS improved from 15.54 to 18.23 months. In the GLOW study, zolbetuximab plus CAPOX was tolerable and demonstrated a manageable safety profile, Shah noted. Treatment-emergent adverse events (TEAE) were about equal in the two arms (about 48%), with all TEAEs about 99 percent in both groups and about 70 percent in Grade 3 TEAEs. Some TEAEs occurred more frequently in the zolbetuximab arm versus the placebo arm, including nausea (68.5% vs. 50.2%), vomiting (66.1% vs. 30.9%), and decreased appetite (41.3% vs. 33.7%). In summary, Shah said: “Zolbetuximab plus CAPOX showed a statistically significant and clinically meaningful improvement in survival. The median PFS improved by over 1.5 months, with about a 31 percent improvement in PFS over placebo. OS improved from about 12 months to 14.4 months, and that translates to a 23 percent improvement.” Patients will continue on treatment and be followed for survival. “GLOW confirmed that zolbetuximab plus chemotherapy is a new standard-of-care treatment for patients with CLDN18.2-positive, HER2-negative, locally advanced, unresectable or metastatic gastric and G-junction adenocarcinoma,” Shah noted. Pamela L. Kunz, MD, ASCO Expert in Gastrointestinal Cancers and Director of Gastrointestinal Cancers Program at Smilow Cancer Hospital and Yale Cancer Center, commented: “Together, the results of the GLOW and SPOTLIGHT trials are poised to change the treatment landscape for patients with CLDN18.2-positive/HER2-negative advanced gastric/GEJ cancer. In the United States, the current standard of care for first-line treatment of advanced esophagogastric adenocarcinoma is platinum/fluoropyrimidine plus nivolumab. Therefore, the biggest question this trial raises is how zolbetuximab will compare or combine with checkpoint inhibitors.” Mark L. Fuerst is a contributing writer.