Anti-EGFR therapy in oesophagogastric cancer: precise but not enough
Authors: M. Salati, S. Cascinu
Journal: Annals of Oncology (2018)

A recently published article in Annals of Oncology reported an umpteenth negative trial investigating anti-epidermal growth factor receptor (EGFR) treatment in oesophagogastric (OG) cancer. Indeed, although Ruhstaller et al. [1.Ruhstaller T. Thuss-Patience P. Hayoz S. et al.Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).Ann Oncol. 2018; Abstract Full Text Full Text PDF Scopus (54) Google Scholar] demonstrated a significant improvement in loco-regional control from the addition of cetuximab to multimodal treatment in resectable oesophageal cancer, the study did not meet its primary survival end points. These results are added to an ever-growing number of anti-EGFR negative trials in molecularly unselected OG, including RTOG0436 and SCOPE1 (with cetuximab) in non-metastatic oesophageal cancer, REAL-3 (with panitumumab) and EXPAND (with cetuximab) in untreated advanced gastric cancer and COG (with gefitinib) in pre-treated advanced oesophageal cancer. Based on that, it is legimate wondering whether the anti-EGFR story in OG will ever have a happy ending. EGFR overexpression and amplification occur in 27%–55% and 4%–14% of OG, respectively, and are thought to mediate a more aggressive oncogenic phenotype [2.The Cancer Genome Atlas Research Network Comprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (3947) Google Scholar, 3.The Cancer Genome Atlas Research Network Integrated genomic characterization of oesophageal carcinoma.Nature. 2017; 541: 169-175Crossref PubMed Scopus (1018) Google Scholar]. Specifically, EGFR amplification has been reported to be more common in junctional tumours and stage IV disease [4.Maron S.B. Alpert L. Kwak H.A. et al.Targeted therapies for targeted populations: anti-EGFR treatment for EGFR amplified gastroesophageal adenocarcinoma.Cancer Discov. 2018; 8: 696Crossref PubMed Scopus (84) Google Scholar]. In patient-derived xenografts of OG treated with cetuximab, all responding patients had ≥4 EGFR gene copies and those with the highest copy number displayed the highest chance of benefit [5.Zhang L. Yang J. Cai J. et al.A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy.Sci Rep. 2013; 3: 2992Crossref PubMed Scopus (74) Google Scholar]. Moving to the clinic, although the abovementioned trials failed to demonstrate an improvement in OS, patients' population were not enriched neither for positive predictive factors (e.g. EGFR) nor negative predictive factors (e.g. RAS mutation). More interestingly, post hoc analyses suggested that a small subset of OG exists that may benefit from EGFR-directed therapy. A biomarker analysis of the EXPAND study showed that higher EGFR expression assessed by immunohistochemistry correlated with improved OS, PFS and tumour response in patients receiving cetuximab. Accordingly, in a correlative molecular analysis of the COG trial, EGFR-amplified patients (7.2%) derived the greatest benefit from gefitinib (HR 0.21, P = 0.006, 4.17 versus 1.70 months). Very recent evidence prospectively supports anti-EGFR treatment in EGFR-amplified GC. Maron et al. [4.Maron S.B. Alpert L. Kwak H.A. et al.Targeted therapies for targeted populations: anti-EGFR treatment for EGFR amplified gastroesophageal adenocarcinoma.Cancer Discov. 2018; 8: 696Crossref PubMed Scopus (84) Google Scholar] showed an overall response rate of 57%, a disease control rate of 100% and a median PFS of 10 months for a subgroup of 7 EGFR-amplified (≥8 copies) patients, identified after screening 140 stage IV OG cases over a 27-month period. Bearing in mind all the caveats related to the tiny sample size and heterogeneous treatment modalities, this study offers a promising proof of concept regarding the selection and the targeting of EGFR-driven OG. Despite negative results so far attained, it seems that a subgroup of molecularly highly selected OG could benefit from anti-EGFR therapy. Notably, in view of the worldwide burden of OG and the rising incidence of junctional OG, these numbers are not negligible. Following previous success in other cancer types, such ALK in lung cancer, it is desirable that collaborative efforts would be set up to ascertain the real value of a 'targeted agent in a targeted population'. Next-generation clinical trials using expansion platform design provide a proper tool to address the issue of low-incidence druggable genomic aberrations. This appears as the most reasonable road to get closer to the goal of precision and personalized medicine in OG. This work was supported in part by LILT Modena Onlus (no grant numbers apply).