In the first-line setting, the monoclonal antibody zolbetuximab in combination with chemotherapy extended overall survival in patients with claudin-18.2 (CLDN18.2)-positive, HER2-negative, locally advanced or metastatic gastric adenocarcinoma. This regimen is now positioned as a new standard of care in a subset of patients, according to the results of the global phase III GLOW trial, presented in the March 2023 session of the ASCO Plenary Series by Manish A. Shah, MD, Director of the Gastrointestinal Oncology Program at Weill Cornell Medicine, Chief of the Solid Tumor Oncology Service, and Co-Director of the Center for Advanced Digestive Care at NewYork-Presbyterian Hospital. Dr. Shah presented the findings in a virtual session, and the study’s first author is Rui-hua Xu, MD, PhD, of Sun Yat-sen University Cancer Center, Guangzhou, China.1
Manish A. Shah, MD
Rui-hua Xu, MD, PhD
Median progression-free survival was 8.2 months with zolbetuximab compared with 6.8 months in the placebo group (hazard ratio [HR] = 0.687; P = .0007), and median overall survival was 14.4 vs 12.2 months (HR = 0.771; P = .0118), respectively, according to Dr. Shah. “The progression-free and overall survival benefits were sustained at 24 months, and the benefits were observed across most subgroups,” he reported. “Zolbetuximab successfully targets CLDN18.2 and [satisfies] a high unmet medical need in the treatment of metastatic gastric and gastroesophageal adenocarcinoma. GLOW confirmed that zolbetuximab plus chemotherapy is a new standard-of-care treatment for patients with CLDN18.2-positive, HER2-negative, locally advanced disease,” he said.
Findings Validate SPOTLIGHT Trial Findings
The results validate the findings from the global phase III -SPOTLIGHT trial, which were presented at the 2023 ASCO Gastrointestinal Cancers Symposium.2 Patients treated with the combination of zolbetuximab and modified leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) had a 25% reduction in the risk of disease progression or death (P = .0066) as well as a 25% reduction in mortality (P = .0053). The median overall survival of 18.2 months (vs 15.5 months in the control arm) was the longest overall survival seen in this patient population, according to SPOTLIGHT’s presenting author Kohei Shitara, MD, of the National Cancer Center Hospital East, Kashiwa City, Chiba, Japan.
Kohei Shitara, MD
Pamela L. Kunz, MD
Reflecting on the two zolbetuximab trials in tandem, Dr. Shah commented: “Remarkably, SPOTLIGHT and GLOW had very similar overall survival hazard ratios (0.75 and 0.77, respectively), which validate CLDN18.2 as a target in gastric and gastroesophageal junction adenocarcinoma and show that the monoclonal antibody, zolbetuximab, finds that target and activates the immune response against the tumors when combined with chemotherapy. The progression-free survival was perhaps a little better with GLOW than with SPOTLIGHT, but both were significantly positive,” he said. The drug’s relative efficacy for the two studies probably reflects differences in their patient populations that may affect outcomes, he added.
ASCO expert in gastrointestinal cancers, Pamela L. Kunz, MD, Director of the Center for -Gastrointestinal -Cancers and Chief of GI Medical Oncology at Smilow Cancer Hospital and Yale Cancer Center, commented on these findings: “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 or gastroesophageal junction cancer.” Since the standard first-line treatment of this malignancy, however, is currently platinum/fluoropyrimidine plus nivolumab, Dr. Kunz said the next question will be “how zolbetuximab will compare to or combine with checkpoint inhibitors.”
Mechanism of Action
Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a tight junction protein normally expressed in gastric mucosa cells and retained in gastric and gastroesophageal adenocarcinomas. As gastric tumors develop, CLDN18.2 may become more exposed on the surface of the cancer cells, thus making it a promising target for drugs such as zolbetuximab. Zolbetuximab induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
GLOW Details
The global phase III GLOW trial enrolled 507 patients with previously untreated, unresectable, locally advanced or metastatic gastric (86%) or gastroesophageal junction (14%) adenocarcinoma. All patients had HER2-negative and CLDN18.2-positive disease, as defined by at least 75% of tumor cells with moderate-to-strong membranous staining.
Patients were randomly assigned 1:1 to receive zolbetuximab at a loading dose of 800 mg/m2 intravenously on cycle 1, day 1, followed by zolbetuximab at a dose of 600 mg/m2 intravenously every 3 weeks plus capecitabine plus oxaliplatin (CAPOX) or placebo with CAPOX. After eight cycles, patients continued zolbetuximab at 600 mg/m2 every 3 weeks or placebo, plus capecitabine, until progressive disease or a treatment discontinuation criterion was met.
The authors noted that platinum/fluoropyrimidine chemotherapy is a standard first-line therapy for this patient population, but there is no consensus on the specific regimen to be used in clinical practice. Thus, they selected standard chemotherapy regimens used globally to pair with zolbetuximab—mFOLFOX6 in the SPOTLIGHT trial and CAPOX in the GLOW trial.
Other Outcomes
At a median follow-up of 12.6 months, the combination of zolbetuximab and CAPOX significantly improved progression-free and overall survival, with the curves remaining separate over time. However, the combination had a similar objective response rate compared with placebo.
For the zolbetuximab and placebo arms, respectively, progression-free survival rates were 35% vs 19% at 12 months and 14% vs 7% at 24 months (HR = 0.687; P = .0007). Similarly, overall survival rates were 58% vs 51% at 12 months and 29% vs 17% at 24 months (HR = 0.771; P = .0118). The objective response rates were similar: 53.8% in the zolbetuximab arm vs 48.8% in the placebo arm.
Zolbetuximab showed efficacy is almost all subgroups except for the gastroesophageal junction subset, for whom hazard ratios were 1.351 for progression-free survival and 1.013 for overall survival. Questioned about this notable lack of benefit, Dr. Shah said this subset comprised just 16% of the study population, although he said this is probably an unsatisfactory explanation. The relative efficacy might be explained by differences in the biology and microenvironments of the two tumor types, but at this time, the answer is unclear, he said.
Toxicity
The most common treatment-emergent adverse events with zolbetuximab plus CAPOX, vs CAPOX alone, were nausea (68.5% vs 50.2%), vomiting (66.1% vs 30.9%), and decreased appetite (41.3% vs 33.7%). Serious treatment-emergent adverse events (47.2% vs 49.8%), grade ≥ 3 events (72.8% vs 69.9%), and drug-related events leading to death (2.4% vs 2.8%) were similar between the arms.
“Nausea and vomiting were the most frequent treatment-emergent adverse events, and their initial onset was mostly in the first and second zolbetuximab cycles,” Dr. Shah said.
Interest is now focused on identifying which patients might benefit from this novel therapy, should it become approved. It is generally accepted that zolbetuximab’s utility will be in patients with CLDN18.2-expressing tumors—though this is currently difficult to accomplish without an approved companion diagnostic or readily available assay.
DISCLOSURE: Dr. Shah has received institutional research funding from Bristol Myers Squibb, Merck, and Oncolys BioPharma. Dr. Xu has served as a consultant or advisor to Astellas, AstraZeneca, BeiGene, Bristol Myers Squibb, HenRui, Junshi Biosciences, KYM Biosciences, Merck Serono, and Roche. Dr. Shitara has received honoraria from Bristol Myers Squibb, Janssen, and Takeda; has served as a consultant or advisor to AbbVie, Amgen, Astellas Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda; and has received institutional research funding from Amgen, Astellas Pharma, Chugai Pharma, Daiichi Sankyo, Eisai, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical. Dr. Kunz has served as a consultant or advisor to Ipsen, Novartis, Advanced Accelerator Applications, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich SE.
REFERENCES
1. Xu RH, Shitara K, Ajani JA, et al: Zolbetuximab + CAPOX in 1L claudin-18.2+/HER2− locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: Primary phase 3 results from GLOW. 2023 March ASCO Plenary Series. Abstract 405736. Presented March 22, 2023.
2. Shitara K, Lordick F, Bang YJ, et al: Zolbetuximab + mFOLFOX6 as first-line treatment for patients with claudin-18.2+/HER2− locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. 2023 ASCO Gastrointestinal Cancers Symposium. Abstract LBA292. Presented January 19, 2023.
