Recent research offers hope to certain patients with previously untreated advanced gastric or oesophageal junction cancer, after a phase three clinical trial collaboration suggested a targeted treatment called zolbetuximab, in combination with a standard chemotherapy, extended survival for specific patients.
Results from the GLOW study and the parallel SPOTLIGHT study – with Weill Cornell Medicine and NewYork-Presbyterian – that evaluated zolbetuximab with an alternative standard chemotherapy prompted the US Food and Drug Administration to grant priority review to the manufacturer’s biologic licence application, setting 12 January 2024 as the target decision date.
MedicalXPress reports that if approved, zolbetuximab will be the first targeted therapy in the US for patients with previously untreated advanced gastric or oesophageal junction cancer that is human epidermal growth factor receptor 2 (HER2)-negative and over-expresses the protein claudin-18 isoform 2 (CLDN 18.2).
Gastric cancer is the fifth most diagnosed cancer globally. Patients with cancer of the stomach or at the junction where the oesophagus joins the stomach – the gastro-oesophageal junction – typically have few symptoms in early disease stages, so most are diagnosed after the cancer has advanced or become metastatic.
The National Cancer Institute says the five-year survival rate for patients with metastatic disease is about 7%, as few targeted treatments are available.
Those with tumours expressing the programmed cell death ligand 1 protein can be treated with immunotherapy, and those with HER2-positive tumours can be treated with trastuzumab (trade name Herceptin).
There is another group of HER2-negative patients who fit neither category, and for whom targeted therapies aren’t generally used.
However, these gastric cancers tend to have higher levels of CLDN 18.2, which is normally found in gastric mucosa cells and becomes more exposed as gastric cancer develops.
Zolbetuximab is a monoclonal antibody, administered intravenously, that binds to CLDN18.2, killing the dividing cancer cells directly and also alerting the immune system to respond.
“Currently, standard chemotherapy regimens are the only treatment options for many patients with HER2-negative and low PD-L1 gastric and gastro-oesophageal cancer, and survival is about 12 months,” said lead study author and trial co-principal investigator Dr Manish Shah, the Bartlett Family Professor of Gastrointestinal Oncology and director of the Gastrointestinal Oncology Programme in the Division of Haematology and Medical Oncology at Weill Cornell Medicine.
“A new treatment for these patients would address a significant unmet need to extend survival.”
The GLOW study was conducted between November 2018 and February 2022 at 166 sites, including NewYork-Presbyterian/Weill Cornell Medical Centre, across 18 countries.
A total of 507 patients with previously untreated HER2-negative locally advanced or metastatic gastric or gastro-oesophageal junction cancer expressing CLDN18.2 were randomised to receive zolbetuximab in combination with capecitabine plus oxaliplatin chemotherapy (CAPOX) or a placebo plus CAPOX.
Zolbetuximab plus CAPOX significantly increased progression-free survival compared with placebo plus CAPOX. Specifically, zolbetuximab plus CAPOX lowered the risk of disease progression or death by 31% compared with placebo plus CAPOX.
The median progression-free survival was 8.21 months for patients in the zolbetuximab group, compared with 6.8 months for those in the placebo group. Furthermore, the addition of zolbetuximab doubled the chance of not having disease progression at two years (from 7% with placebo versus 14% with zolbetuximab).
Results also demonstrated that zolbetuximab plus CAPOX significantly lengthened overall survival and reduced the risk of death by 23%.
The median overall survival was 14.4 months for patients in the zolbetuximab plus CAPOX group versus 12.2 months for those in the placebo plus CAPOX group. Long terms survival similarly increased significantly with the addition of zolbetuximab: 29% survival at two years with zolbetuximab, versus 17% with placebo.
Treatment-related adverse events were similar between groups, with nausea, vomiting and decreased appetite reported most frequently.
“These side effects were as expected,” said Shah. “It was good to see zolbetuximab did not add significant toxicity.”
The paper was published in Nature Medicine.
Similarly, a study published in The Lancet earlier this year reported strong survival outcomes for the international phase three SPOTLIGHT trial that evaluated zolbetuximab in combination with a different chemotherapy regimen consisting of modified folinic acid or levofolinate, fluorouracil and oxaliplatin (mFOLFOX).
Shah was a member of the SPOTLIGHT steering committee, co-author of The Lancet paper and involved in designing both the GLOW and SPOTLIGHT trials.
“We now have evidence from two large trials showing that the addition of zolbetuximab provides a meaningful survival benefit for patients with CLDN 18.2-positive gastric cancers,” he said. “If zolbetuximab is approved, patients will be able to decide with their physicians whether zolbetuximab plus CAPOX or mFOLFOX is the right regimen for them.”
Study 1 details
Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomised, phase 3 GLOW trial
Manish Shah, Kohei Shitara, Jaffer Ajani, et al.
Published in Nature Medicine on 31 July 2023
Abstract
There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrolment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544–0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615–0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma.
Study 2 details
Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial
Kohei Shitara, Florian Lordick, Manish Shah, et al.
Published in The Lancet in April 2023
Summary
Background
Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has shown efficacy in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. We report the results of the SPOTLIGHT trial, which investigated the efficacy and safety of first-line zolbetuximab plus mFOLFOX6 (modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen) versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma.
Methods
SPOTLIGHT is a global, randomised, placebo-controlled, double-blind, phase 3 trial that enrolled patients from 215 centres in 20 countries. Eligible patients were aged 18 years or older with CLDN18.2-positive (defined as ≥75% of tumour cells showing moderate-to-strong membranous CLDN18 staining), HER2-negative (based on local or central evaluation), previously untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, with radiologically evaluable disease (measurable or non-measurable) according to Response Evaluation Criteria in Solid Tumours version 1.1; an Eastern Cooperative Oncology Group performance status score of 0 or 1; and adequate organ function. Patients were randomly assigned (1:1) via interactive response technology and stratified according to region, number of organs with metastases, and previous gastrectomy. Patients received zolbetuximab (800 mg/m2 loading dose followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 (every 2 weeks) or placebo plus mFOLFOX6. The primary endpoint was progression-free survival assessed by independent review committee in all randomly assigned patients. Safety was assessed in all treated patients.
Findings
Between June 21, 2018, and April 1, 2022, 565 patients were randomly assigned to receive either zolbetuximab plus mFOLFOX6 (283 patients; the zolbetuximab group) or placebo plus mFOLFOX6 (282 patients; the placebo group). At least one dose of treatment was administered to 279 (99%) of 283 patients in the zolbetuximab group and 278 (99%) of 282 patients in the placebo group. In the zolbetuximab group, 176 (62%) patients were male and 107 (38%) were female. In the placebo group, 175 (62%) patients were male and 107 (38%) were female. The median follow-up duration for progression-free survival was 12·94 months in the zolbetuximab group versus 12·65 months in the placebo group. Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo (hazard ratio [HR] 0·75, 95% CI 0·60–0·94; p=0·0066). The median progression-free survival was 10·61 months (95% CI 8·90–12·48) in the zolbetuximab group versus 8·67 months (8·21–10·28) in the placebo group. Zolbetuximab treatment also showed a significant reduction in the risk of death versus placebo (HR 0·75, 95% CI 0·60–0·94; p=0·0053). Treatment-emergent grade 3 or worse adverse events occurred in 242 (87%) of 279 patients in the zolbetuximab group versus 216 (78%) of 278 patients in the placebo group. The most common grade 3 or worse adverse events were nausea, vomiting, and decreased appetite. Treatment-related deaths occurred in five (2%) patients in the zolbetuximab group versus four (1%) patients in the placebo group. No new safety signals were identified.
Interpretation
Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients.
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