Zolbetuximab Plus Chemotherapy May Extend Advanced Gastro-Oesophageal Cancer Survival

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: A first-in-class monoclonal antibody directed against a gastric mucosal cell protein may improve survival when given alongside first-line chemotherapy to patients with advanced gastro-oesophageal cancer, the FAST trial indicates. 

Study investigator Salah-Eddin Al-Batran, from Krankenhaus Nordwest in Frankfurt, Germany, and team explain that zolbetuximab targets the tight junction protein claudin (CLDN)18.2, epitopes of which become exposed in malignancy. Binding to CLDN18.2 subsequently induces antibody-dependent and complement-dependent cytotoxicity processes, they say. 

The phase II study recruited 246 patients with advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma with moderate or strong CLDN18.2 expression in at least 40% of tumour cells assessed by immunohistochemistry.  

All patients were given EOX chemotherapy consisting of epirubicin 50 mg/m2 plus oxaliplatin 130 mg/m2 on day 1 of up to eight 21-day cycles plus capecitabine 625 mg/m2 twice daily. Seventy-seven of these patients were randomly assigned to also receive intravenous zolbetuximab 800 mg/m2 loading dose on day 1, followed by 600 mg/m2 on day 1 of each subsequent cycle, while an exploratory group of 85 patients received EOX plus zolbetuximab 1000 mg/m2 every 3 weeks. 

The primary endpoint of progression-free survival (PFS) was a median 7.5 months for patients given the zolbetuximab 800/600 mg/m2 regimen plus EOX versus 5.3 months with EOX alone, giving a significant hazard ratio (HR) for progression or death of 0.44 in favour of the combination arm. 

The secondary endpoint of overall survival (OS) also favoured the zolbetuximab 800/600 mg/m2 regimen plus EOX, at a median 13.0 versus 8.3 months with EOX alone and a significant HR of 0.55. 

The researchers note that the significant PFS benefit with this zolbetuximab regimen was retained when assessing a subgroup of patients with strong CLDN18.2 expression in 70% or more tumour cells, giving a HR of 0.38. 

There was also a significant improvement in PFS with the exploratory zolbetuximab 1000 mg/m2 regimen plus EOX compared with EOX alone (HR=0.58) but an OS benefit was not found. Moreover, no PFS or OS benefit with zolbetuximab was detected when only the patients with high CLDN18.2 expression were assessed. 

Safety analysis indicated that the majority of adverse events (AEs) associated with zolbetuximab plus EOX were grade 1–2, with the most common AEs at these grades being nausea (81.8%), vomiting (67.5%), anaemia (45.5%) and neutropenia (44.2%).  

There were “no substantial increases” in the rates of grade 3 or more severe AEs with the combination versus EOX alone, the researchers report, with neutropenia (32.5%), anaemia (11.7%) and vomiting (10.4%) the most frequently reported AEs of this severity. 

“These data provide compelling evidence for the role of CLDN18.2 as a potential therapeutic target”, write Salah-Eddin Al-Batran and co-workers in the Annals of Oncology.

They say that zolbetuximab is now under investigation in two phase III trials as a first-line therapy for biomarker-enriched patients, given in combination with modified FOLFOX6 for EGFR2-negative patients with unresectable or metastatic disease in the SPOTLIGHT trial, and with capecitabine plus oxaliplatin in the GLOW trial.

The authors of an accompanying editorial caution, however, that patients in the EOX-only arm of the FAST trial had poorer survival outcomes than reported for the chemotherapy combination in the earlier REAL-3 study, indicating that “the survival benefit might be much less pronounced in the current phase III trials if control arms have better survival.”

This may also be true if the benefits reported in the FAST trial occurred due to a possible synergistic effect between epirubicin and zolbetuximab, observe Ian Chau and Avani Athauda, both from the Royal Marsden Hospital in London and Surrey, UK.

And they emphasize that a recently reported survival benefit of first-line nivolumab plus oxaliplatin-based chemotherapy in this population means that “standard of care in advanced gastric cancer will [likely] shift in the near future”, thus raising the question of how physicians might choose between checkpoint inhibitors and CLDN18.2-targeted therapies. 

References 

Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol; Advance online publication 18 February 2021. DOI: 10.1016/j.annonc.2021.02.005

Athauda A, Chau I. Claudin 18.2 – a FAST-moving target in gastric cancer? Ann Oncol; Advance online publication 3 March 2021. DOI: 10.1016/j.annonc.2021.02.021