Claudin 18.2—a FAST-moving target in gastric cancer?

Abstract

When combined, cancers of the oesophagus, oesophago-gastric junction (OGJ) and stomach represent the second leading cause of cancer-related mortality globally, with over 1.3 million deaths in 2020 (13% of all cancer deaths).1Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; https://doi.org/10.3322/caac.21660Crossref PubMed Scopus (7909) Google Scholar Cytotoxic chemotherapy remains the mainstay of treatment in the first-line setting for advanced disease. Adding trastuzumab to chemotherapy2Bang Y.-J. Van Cutsem E. Feyereislova A. et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet (Lond, Engl). 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (4762) Google Scholar and, more recently, trastuzumab deruxetecan,3Shitara K. Bang Y.-J. Iwasa S. et al.Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer.N Engl J Med. 2020; 382: 2419-2430Crossref PubMed Scopus (219) Google Scholar are the only approved biomarker-targeted agents in HER2-positive advanced gastric cancer. Recent data on checkpoint inhibition in combination with first-line oxaliplatin-based chemotherapy will likely transform oncological practice in gastric cancers,4Moehler M. Shitara K. Garrido M. et al.LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study.Ann Oncol. 2020; 31: S1191Abstract Full Text Full Text PDF Google Scholar especially those with PD-L1 expression combined positive score ≥5. The family of claudin proteins were first described in 1998 as important components of tight junction integral membrane proteins.5Furuse M. Fujita K. Hiiragi T. et al.Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin.J Cell Biol. 1998; 141: 1539-1550Crossref PubMed Scopus (1628) Google Scholar Claudin 18.2 (CLDN18.2) is exclusively present in gastric mucosa and is retained on malignant transformation, making it an ideal candidate for monoclonal antibody binding with the capability of reduced off-target effects. The Cancer Genome Atlas (TCGA) identified the presence of CLDN18 aberrations enriched in the genomically stable (GS) subgroup of gastric cancer,6Bass A.J. Thorsson V. Shmulevich I. et al.Comprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (3438) Google Scholar suggesting a potential role in invasive phenotype of diffuse tumours. However, it has subsequently been demonstrated that CLDN18.2 expression is frequently detected in both diffuse and intestinal gastric cancer7Hong J.Y. An J.Y. Lee J. et al.Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer.Transl Cancer Res. 2020; 9Crossref Scopus (4) Google Scholar as well as oesophageal cancer.8Moentenich V. Gebauer F. Comut E. et al.Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies.Oncol Lett. 2020; 19: 3665-3670PubMed Google Scholar Zolbetuximab (previously IMAB362) is a novel chimeric monoclonal IgG1 antibody highly specific for CLDN18.2. Investigated as monotherapy in second- and subsequent-line therapy in the MONO study,9Türeci O. Sahin U. Schulze-Bergkamen H. et al.A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.Ann Oncol. 2019; 30: 1487-1495Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar zolbetuximab treatment resulted in an objective response rate of 9% in gastric cancer. In the FAST study10Sahin 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 gastrooesophageal adenocarcinoma.Ann Oncol. 2021; 32: 609-619Abstract Full Text Full Text PDF Scopus (32) Google Scholar published in this issue of the Annals of Oncology, the addition of zolbetuximab to EOX (epirubicin, oxaliplatin and capecitabine) significantly improved progression-free survival (PFS; primary study endpoint) and overall survival (OS). The magnitude of survival benefit observed was even greater in patients with high CLDN18.2 expression (≥70% tumour cells). This enhanced efficacy from zolbetuximab was also seen in the MONO study.9Türeci O. Sahin U. Schulze-Bergkamen H. et al.A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.Ann Oncol. 2019; 30: 1487-1495Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar These encouraging results have led to two phase III trials, SPOTLIGHT11Yamaguchi K. Shitara K. Al-Batran S.-E. et al.198TiP – SPOTLIGHT: comparison of zolbetuximab or placebo + mFOLFOX6 as first-line treatment in patients with claudin18.2+/HER2– locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ): a randomized phase III.Ann Oncol. 2019; 30: ix66-ix67Abstract Full Text PDF Google Scholar and GLOW,12Shah M. Ajani J.A. Al-Batran S.-E. et al.836TiP - GLOW: randomized phase III study of zolbetuximab + CAPOX compared with placebo + CAPOX as first-line treatment of patients with CLD18.2+/HER2− locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.Ann Oncol. 2019; 30: v322Abstract Full Text PDF Google Scholar which are currently recruiting. However, several points are worth considering in regard to the FAST study results. Firstly, the control arm of the study, EOX, was likely chosen based on the REAL-2 study,13Cunningham D. Starling N. Rao S. et al.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med. 2008; 358: 36-46Crossref PubMed Scopus (1756) Google Scholar but this arm performed poorly in comparison with previous studies (median survival 8.3 months in FAST versus 11.2 months in REAL-213Cunningham D. Starling N. Rao S. et al.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med. 2008; 358: 36-46Crossref PubMed Scopus (1756) Google Scholar versus 11.3 months in REAL-314Waddell T. Chau I. Cunningham D. et al.Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.Lancet Oncol. 2013; 14: 481-489Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar). Whereas the authors attribute this poor performance to a high proportion of patients with metastatic disease in the FAST study (95.2%), 91% of patients in REAL-3 treated with EOX also had metastatic disease.14Waddell T. Chau I. Cunningham D. et al.Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.Lancet Oncol. 2013; 14: 481-489Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar Patients with histologically diffuse subtype gastric cancer have poorer prognosis and the association of the GS subtype in TCGA with CLDN18 aberrations and diffuse histology might explain the poorer prognosis seen in the control arm in FAST. Nevertheless, at least 32% of patients had intestinal histology in the FAST study and 37% in MONO.9Türeci O. Sahin U. Schulze-Bergkamen H. et al.A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.Ann Oncol. 2019; 30: 1487-1495Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Furthermore, CLDN18.2 expression has not been shown to be of poor prognosis, at least in oesophageal cancer.8Moentenich V. Gebauer F. Comut E. et al.Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies.Oncol Lett. 2020; 19: 3665-3670PubMed Google Scholar Perhaps the lack of further lines of systemic therapy was the main driver for poor outcome in FAST. In total 60% of patients did not receive further systemic therapy in FAST, although 86% of patients in the REAL-2 study did not receive second-line therapy either.13Cunningham D. Starling N. Rao S. et al.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med. 2008; 358: 36-46Crossref PubMed Scopus (1756) Google Scholar The reasons why these factors are of importance is that the survival benefit might be much less pronounced in the current phase III trials if control arms have better survival. FOLFOX/CAPOX are being used as chemotherapy backbones in the SPOTLIGHT and GLOW studies and no data exists on whether epirubicin has synergistic effects with zolbetuximab, thereby potentially resulting in the promising results seen in FAST. Secondly, the survival benefit seen in the FAST study was primarily driven by the subgroup of patients with moderate to strong expression of CLDN18.2 in a high proportion of tumour cells (≥70%). This particular subgroup achieved a median PFS of 9.0 months and OS of 16.5 months with a more pronounced survival benefit in the hazard ratios compared with the intention-to-treat population. In contrast, those with 40%-69% CLDN18.2 positive tumour cells had overlapping survival curves for both PFS and OS with EOX ± zolbetuximab. When one inspects the CONSORT diagram, 334/730 patients were CLDN18.2 positive. If 72% of patients had CLDN18.2 in ≥70% of tumour cells, that would translate into approximately one-third of all-comers in this molecular subgroup. FAST recruited predominantly gastric cancers; therefore there are currently insufficient data to differentiate the proportion of CLDN18.2 positivity within gastric versus OGJ versus oesophageal adenocarcinoma, although rates are likely to be similar.7Hong J.Y. An J.Y. Lee J. et al.Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer.Transl Cancer Res. 2020; 9Crossref Scopus (4) Google Scholar,8Moentenich V. Gebauer F. Comut E. et al.Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies.Oncol Lett. 2020; 19: 3665-3670PubMed Google Scholar There could be a preponderance of strong CLDN18.2 expression in gastric primaries compared with oesophageal and OGJ primaries, hence forming the dominant group in the FAST patient population. With the ongoing phase III SPOTLIGHT and GLOW studies, a cut-off of 75% tumour cell CLDN18.2 expression is being taken forward for patient eligibility. This slight difference in cut-off between FAST and SPOTLIGHT/GLOW is likely to be due to optimisation of the immunohistochemistry (IHC) assay. Lastly, a cautionary note needs to be made; when promising survival benefits seen in phase II studies, they do not always translate into positive outcomes in subsequent phase III testing, especially when a subgroup population is taken forward. A prime example is rilotumumab in advanced untreated MET-positive gastric and OGJ adenocarcinoma where, indeed, a detrimental survival was observed in the phase III RILOMET-1 study.15Iveson T. Donehower R.C. Davidenko I. et al.Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study.Lancet Oncol. 2014; 15: 1007-1018Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar,16Catenacci D.V.T. Tebbutt N.C. Davidenko I. et al.Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1467-1482Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar The underlying molecular heterogeneity of gastric cancer, together with complex signalling pathway crosstalk, inadequate patient enrichment and inherent limitation of IHC for patient selection may hinder single biomarker-targeted drug development and positive late-phase clinical testing. Therefore, we eagerly await the completion of recruitment and results from the ongoing SPOTLIGHT/GLOW trials to fully elucidate the true benefit of zolbetuximab. However, with the recent reporting of survival benefit with upfront nivolumab with oxaliplatin-based chemotherapy4Moehler M. Shitara K. Garrido M. et al.LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study.Ann Oncol. 2020; 31: S1191Abstract Full Text Full Text PDF Google Scholar and the likelihood that standard of care in advanced gastric cancer will shift in the near future, how would one choose between checkpoint versus CLDN18.2 blockade? In the FAST study, recruitment was completed in June 2014 and the first results were reported in 2016, unlike the lead authors' other innovation of the BNT162b2 mRNA COVID-19 vaccine17Polack F.P. Thomas S.J. Kitchin N. et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (4260) Google Scholar with this significant time lapse, is the development of zolbetuximab in gastric cancer FAST enough in 2021? All authors acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.