Zolbetuximab benefits subset of patients with gastric, gastroesophageal junction cancer
Click Here to Manage Email Alerts
First-line treatment with zolbetuximab added to chemotherapy significantly extended OS and PFS among adults with certain forms of claudin-18.2-positive/HER2-negative gastric adenocarcinoma, results of the phase 3 SPOTLIGHT trial showed.
Study participants, who had locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, demonstrated a 25% reduction in risk for disease progression or death with zolbetuximab (Astellas Pharma) and a modified FOLFOX6 chemotherapy regimen (mFOLFOX6) compared with placebo and mFOLFOX6, according to a primary analysis of the study presented at ASCO Gastrointestinal Cancers Symposium.
“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 SPOTLIGHT is very encouraging given the limited treatment options available,” Kohei Shitara, MD, chief of the department of gastrointestinal oncology at National Cancer Hospital East in Kashiwa, Japan, and primary investigator for the SPOTLIGHT trial, told Healio.
Background
Patients with gastric or gastroesophageal junction adenocarcinoma — especially those with locally advanced or unresectable disease — had median OS of approximately 1 year in global studies, according to Shitara.
“Early-stage gastric cancer symptoms frequently overlap with more common stomach-related conditions, which means gastric cancer is often diagnosed in the advanced or metastatic stage,” he told Healio. “In fact, the 5-year relative survival rate for patients with gastric cancer at the metastatic stage is approximately 6%.”
Targeted therapy combined with chemotherapy has prolonged survival in a limited number of patients, Shitara said during a presentation at the symposium.
“There is a need to identify additional subsets of patients with gastroesophageal junction adenocarcinoma who can be therapeutically targeted for benefit,” he added.
Claudin 18.2 — a protein normally expressed in gastric mucosa cells — can be expressed on the surface of gastric or gastroesophageal junction adenocarcinoma cells, making it a promising therapeutic target, Shitara noted.
Zolbetuximab is an investigational immunoglobulin-1 monoclonal antibody that targets claudin 18.2.
Methodology
The SPOTLIGHT trial included 565 patients with previously untreated claudin-18.2-positive/HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma randomly assigned in a 1:1 ratio to receive either IV zolbetuximab dosed at 800 mg/m2 (cycle 1, day 1) followed by 600 mg/m2 (cycle 1, day 22, and every 3 weeks in later cycles) plus IV mFOLFOX6 (days 1, 15 and 29) for four 42-day cycles (n = 283; median age, 62 years; range, 27-83; 62% men; 31.1% Asian) or placebo plus mFOLFOX6 (n = 282; median age, 60 years; range, 20-86; 62% men; 31.6% Asian).
PFS according to RECIST version 1.1 as determined by an independent review committee served as the study’s primary endpoint. Secondary endpoints included OS, objective response rate and safety.
Sept. 9 served as the data cutoff date for the primary PFS and interim OS analyses.
Key findings
This study met its primary endpoint, with the addition of zolbetuximab to mFOLFOX6 significantly prolonging median PFS (10.61 months vs. 8.67 months; HR = 0.75; 95% CI, 0.58-0.94).
The zolbetuximab regimen also significantly increased median OS compared with the placebo regimen (18.23 months vs. 15.54 months; HR = 0.75; 95% CI, 0.6-0.93).
Researchers reported similar ORRs between the groups: 60.7% (95% CI, 53.72-67.3) in the zolbetuximab group and 62.1% (95% CI, 55.17-68.66) in the placebo group.
Safety results showed similar rates of overall and grade 3 or higher treatment-related adverse events between the treatment groups. Five treatment-related deaths occurred in the zolbetuximab group compared with four in the placebo group.
Nausea was the most common treatment-related adverse event in each treatment arm, followed by vomiting and decreased appetite.
Clinical implications
The fact that SPOTLIGHT had already met its primary endpoint by the interim analysis suggests that zolbetuximab may provide durable benefit as a first-line treatment option in this subgroup of patients with gastric or gastroesophageal junction adenocarcinoma, Shitara said.
“Notably, SPOTLIGHT has achieved one of the longest median OS in patients with locally advanced unresectable or metastatic gastric or [gastroesophageal junction] adenocarcinoma in phase 3 trials,” he added.
“SPOTLIGHT showed approximately 38% of patients with gastric and gastroesophageal junction adenocarcinoma screened have [claudin-18.2]-positive tumors, supporting the potential of zolbetuximab as a precision therapy for this subset of [patients],” Shitara said.
Perspective
Back to Top
Suneel Kamath, MD
The SPOTLIGHT trial is exciting because, for the first time in many years, it gives us a novel target and drug with a significant survival benefit that is specific to gastric and gastroesophageal junction adenocarcinoma.Claudin 18.2 is an attractive target for several reasons. It is relatively specific to gastric mucosal cells, which limits toxicities to other tissues. It is present in 35% to 40% of gastric and gastroesophageal junction adenocarcinomas, so it is not a rare target. Additionally, claudin 18.2 expression is detected by immunohistochemistry, which is inexpensive, fast and easier to adopt worldwide.
Shitara and colleagues showed the addition of zolbetuximab to mFOLFOX6 significantly prolonged median PFS by nearly 2 months and increased median OS by nearly 3 months. These are clinically meaningful improvements in this disease. The combination was well- tolerated, with modest increases in rates of nausea and vomiting.
SPOTLIGHT clearly will be practice-changing, and hopefully will lead to FDA approval for zolbetuximab and its companion diagnostic later this year. The question is, how does zolbetuximab fit into the current landscape of chemotherapy-immunotherapy combinations? The zolbetuximab-chemotherapy combination likely makes the most sense for those with claudin 18.2-positive tumors and PD-L1 combined positive scores (CPS) less than 5%. However, 14% of patients screened in the SPOTLIGHT trial had both claudin 18.2 expression and PD-L1 CPS of 5% or higher. There is no clear right answer, but I might favor chemoimmunotherapy given the possibility of more durable responses or remission in a small percentage of patients treated with immunotherapy.
Fortunately, trials like the ILUSTRO study that combine chemotherapy, immunotherapy and zolbetuximab are ongoing. The CLAUDIO-01 trial evaluating the claudin 18.2-targeted antibody drug conjugate SOT102 (SOTIO Biotech) in combination with mFOLFOX6 and nivolumab (Opdivo, Bristol Myers Squibb) may provide further evidence for the triple-targeted approach.
Collapse
Shitara K, et al. Abstract LBA292. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco.
Click Here to Manage Email Alerts