Zolbetuximab regimen extends survival in gastric, gastroesophageal junction cancer subset
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Key takeaways:
- The group that received the claudin-18.2-targeted antibody plus chemotherapy had a 23% improvement in OS vs. the placebo-chemotherapy group.
- Claudin 18.2 is an important biomarker in gastric cancer.
The addition of zolbetuximab to capecitabine and oxaliplatin significantly extended PFS and OS for patients with claudin-18.2-positive/HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer.
The results of the phase 3 GLOW study, presented during an ASCO Plenary Series session, align with those of the phase 3 SPOTLIGHT trial, which evaluated the investigational treatment in the same population but with modified FOLFOX6 (mFOLFOX6) as the chemotherapy regimen.
“GLOW confirmed zolbetuximab plus chemotherapy is a new standard-of-care treatment for patients with claudin-18.2-positive/HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction [GEJ] adenocarcinoma,” Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine and chief of the solid tumor service and co-director of Center for Advanced Digestive Disease at NewYork-Presbyterian, said during a presentation.
Rationale
An unmet need exists for treatments that improve outcomes in HER2-negative, locally advanced unresectable or metastatic gastric/GEJ cancer, Shah said, noting that targeted therapies in combination with chemotherapy have prolonged survival for a limited number of patients. For others, survival with standard platinum-fluoropyrimidine chemotherapy is approximately 12 months, he said.
Zolbetuximab (Astellas Pharma) is a first-in-class immunoglobulin-1 monoclonal antibody that targets claudin 18.2 and induces antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
Results of the SPOTLIGHT study, which included patients with claudin-18.2-positive disease, showed median PFS of 10.61 months with zolbetuximab plus mFOLFOX6 vs. 8.67 months with mFOLFOX6 alone (HR = 0.75) and median OS of 18.23 months vs. 15.54 months (HR = 0.75).
Methodology
The global, randomized, double-blinded GLOW trial enrolled 507 patients who had moderate to strong membranous claudin-18 staining in 75% or greater tumor cells. Researchers randomly assigned patients 1:1 to receive either IV zolbetuximab dosed at 800 mg/m2 (cycle 1, day 1) followed by 600 mg/m2 (day 1 in later cycles) or placebo, each in combination with the CAPOX regimen of oral capecitabine dosed at 1,000 mg/m2 twice daily on day 1 to 14 of each cycle and IV oxaliplatin dosed at 130 mg/m2 on day 1 of each cycle, for eight 21-day cycles. Patients remained on zolbetuximab or placebo, in addition to capecitabine, beyond eight cycles until disease progression or if they met a discontinuation criterium.
The zolbetuximab and placebo groups had similar baseline characteristics, including median age (61 years vs. 59 years) and percentages of patients with prior gastrectomy (29.5% vs. 29.6%), three or more organs with metastases (25.6% vs. 25.7%) and stomach as the primary site (86.2% vs. 82.6%).
PFS by independent committee review per RECIST version 1.1 served as the primary endpoint, with OS as a key secondary endpoint. Other secondary endpoints included objective response rate and safety.
Oct. 7 served as the data cutoff date for the PFS and interim OS analysis.
Results
The study met its primary endpoint, with significantly longer PFS in the zolbetuximab vs. placebo group (median, 8.21 months vs. 6.8 months; HR = 0.68; 95% CI, 0.54-0.86). Shah reported PFS rates of 35% vs. 19% at 12 months and 14% vs. 7% at 24 months.
Results also showed significantly longer median OS with zolbetuximab (14.39 months vs. 12.16 months; HR = 0.77; 95% CI, 0.61-0.96) and higher OS rates at 12 months (58% vs. 51%) and 24 months (29% vs. 17%).
“The curves split early and they stayed split,” Shah said.
Researchers observed the PFS and OS benefit with zolbetuximab across patient subgroups.
The zolbetuximab group had a higher ORR (53.8% vs. 48.8%).
The groups had similar rates of treatment-emergent adverse events, including all-grade (98.8% zolbetuximab vs. 98% placebo), grade 3 or higher (72.8% vs. 69.9%) and serious (47.2% vs. 49.8%) events. The most common all-grade treatment-emergent adverse events included nausea (68.5% vs. 50.2%) and vomiting (66.1% vs. 30.9%), most of which occurred during cycle 1, Shah noted.
Implications
In her discussion of the abstract, Yelena Y. Janjigian, MD, medical oncologist and chief of the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center, considered how the GLOW and SPOTLIGHT trials fit into the first-line gastric cancer treatment landscape.
“GLOW and SPOTLIGHT are important studies,” she said. “They show us that the [claudin-18.2] biomarker is critical, but what we really need is a glowing spotlight in a disease that needs a flame. Even for other biomarker-selected populations such as PD-1 and so forth, we need more responses, more survivors [and] more cures.”
Janjigian and Shah agreed that biomarker testing is key.
“We do HER2 immunohistochemistry testing, we do MMR testing and PD-L1 CPS testing, and I think we’ll have to do claudin-18.2 testing, as well,” he said.
Collapse
Xu R, et al. Abstract 405736. Presented at: ASCO Plenary Series: March 2023 Session; March 22, 2023.
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