FDA approval may be looming for the combination of zolbetuximab and capecitabine/oxaliplatin after primary phase 3 results were presented during the March ASCO Virtual Plenary.
The anti-claudin 18.2 (CLDN18.2) monoclonal antibody zolbetuximab administered in combination with capecitabine and oxaliplatin (CAPOX) showed a statistically significant and clinically meaningful progression-free survival (PFS) and overall survival (OS) prolongation in patients with unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.1
Findings come from the primary analysis of the GLOW study (NCT03653507), which had a data cutoff date of October 7, 2022. The results were presented by Manish Shah, MD, PhD, at the 2023 March ASCO Plenary Series. A total of 507 patients were included, and of those 254 were treated with the combination of zolbetuximab and CAPOX while the other 253 received the comparator combination of placebo and CAPOX.
At a median follow-up of 12.62 months in the experimental arm vs 12.09 months in the comparator arm, the median PFS was 8.21 months (95% CI, 7.46-8.84 months) compared with 6.80 months (95% CI, 6.14-8.08 months), respectively (HR, 0.687; 95% CI, 0.544-0.866; P =.0007). The 12-month PFS rate with zolbetuximab/CAPOX was 35% vs 19% with placebo/CAPOX, and the 24-month PFS rate was 14% vs 7%, respectively.2
The median OS was 14.39 months (95% CI, 12.29-16.49 months) with the experimental combination vs 12.16 months (95% CI, 10.28-13.67 months) with the comparator (HR, 0.771; 95% CI, 0.615-0.965; P = .0118). At 12 months, the OS rate was 58% with zolbetuximab/CAPOX compared with 51% in the placebo/CAPOX arm. The 24-month OS was 29% in the experimental arm vs 17% in the comparator arm.
The survival benefit of the experimental combination was also shown across various unresectable or metastatic gastric/GEJ adenocarcinoma subgroups included in the study.
“Our study showed, zolbetuximab, an investigational first-in-class CLDN18.2 targeted monoclonal antibody, plus CAPOX demonstrated statistically significant improvements in progression-free survival and overall survival compared to placebo plus CAPOX. For patients with gastric cancer whose disease is locally advanced but inoperable or metastatic, to see a positive progression-free and overall survival response in GLOW is very encouraging,” Rui-Hua Xu, MD, PhD, professor in the Department of Medical Oncology, Sun Yat-Sen University Cancer Center, and lead investigator of GLOW told Targeted Oncology™.
GLOW results also revealed zolbetuximab plus CAPOX can improve responses in patients with CLDN18.2-positive/HER2-negative, unresectable, or metastatic gastric or GEJ cancer. The objective response rate (ORR) observed with the zolbetuximab/CAPOX arm was 53.5% (95%, 46.58%-60.99%) compared with 48.4% (95% CI, 41.76%-55.84%) in the comparator arm. The median duration of response (DOR) was similar in both arms at 6.28 (95% CI, 5.39-8.28 months) with zolbetuximab and CAPOX vs 6.18 (95% CI, 4.53-6.41 months) with placebo and CAPOX.
Regarding safety, the zolbetuximab/CAPOX combination was tolerable and manageable. Treatment-emergent adverse events (TEAEs) occurred in 98.8% of the experimental arm vs 98.0% of the comparator arm, and TEAEs were grade or higher in 72.8% vs 69.6% of patients, respectively.Serious TEAEs occurred in 47.2% of the zolbetuximab/CAPOX arm vs 49.8% of those treated with placebo and CAPOX. Percentages of patients needing to discontinue any study drug due to treatment-related AEs (TRAES) were similar in both arms. TRAEs leading to discontinuation of zolbetuximab or placebo occurred in 7.1% of the experimental arm vs 4.4% of the comparator arm.
The most common TEAEs in experimental vs comparator the study were nausea (8.7% vs 2.4%) and vomiting (12.2% vs 3.6%). During the presentation, Shah noted that these were predominantly grade-1 events that were resolved after the first or second treatment cycle.
GLOW is global, multicenter, double-blind, randomized study. The study has met its target enrollment of 507 patients.
In the experimental arm, zolbetuximab is administered at a loading dose at cycle 1, day 1 followed by a lower dose during subsequent cycles, every 3 weeks. Patients in the experimental arm will also receive CAPOX until confirmed disease progression or completion of 8 treatments. For the CAPOX regimen, oxaliplatin is administered on day 1 of each cycle and capecitabine is administered on days 1 through 14. Chemotherapy is continued at the investigator’s discretion or until the patient meets the discontinuation criteria. Patients in the comparator arm are administered matching placebo and CAPOX.
PFS is the primary study end point. The key secondary end points of the study are OS, time to confirmed deterioration in global health status or quality-of-life (QOL), ORR, DOR, and safety/tolerability. The study is also investigating the number of patients with laboratory abnormalities, vital sign abnormalities, electrocardiogram abnormalities, and ECOG status abnormalities, as well as health-related QOL, pharmacokinetics, and the number of anti-drug antibody-positive patients.
Patients are required to have histologically confirmed diagnosis of gastric of GEJ adenocarcinoma, radiographically confirmed locally advanced unresectable or metastatic disease within 28 days prior to randomization, CLDN18.2 in expression in ≥ 75% of tumor cells, negative HER2 tumor expression, and an ECOG performance score of 0 or 1.
According to Xu, these data have high significance for the future of the field.
“The global 5-year relative survival rate for patients at the metastatic stage is approximately 6 percent. While the treatment landscape is continuing to evolve, patients at this stage of the disease are in need of options; the results of this study are statistically significant and add to the growing clinical profile of zolbetuximab. The GLOW results along with the positive results from the SPOTLIGHT trial, mark progress in Astellas’ gastric cancer development program,” Xu stated.
“We are committed to the ongoing clinical development of zolbetuximab and to bringing new therapeutic options for patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma,” said Ahsan Arozullah, MD, MPH, senior vice president and head of Development Therapeutic Areas, Astellas, in a press release. “These two statistically significant phase 3 trials, GLOW and SPOTLIGHT, will serve as the basis for global regulatory submissions, marking remarkable progress in our gastric cancer development program.”