EGFR antibodies in resectable metastatic colorectal liver metastasis: more harm than benefit?
Authors: Sepideh Gholami, Axel Grothey
Journal: The Lancet Oncology (2020)

The current standard of care for resectable liver-limited colorectal cancer is perioperative chemotherapy followed by curative resection, based on the EORTC trial, which showed a modest improvement in 3-year progression-free survival.1Nordlinger B Sorbye H Glimelius B et al.Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.Lancet Oncol. 2013; 14: 1208-1215Summary Full Text Full Text PDF PubMed Scopus (628) Google Scholar Since the addition of a biological agent to systemic therapy leads to increased proportions of patients achieving a response in the metastatic setting, a logical subsequent trial would investigate the role of biological agents in the perioperative setting. In the New EPOC study, the results of which were published by John A Bridgewater and colleagues in The Lancet Oncology, patients with resectable KRAS exon 2 wild-type colorectal liver-limited metastases were randomly assigned to perioperative chemotherapy (oxaliplatin plus fluorouracil, oxaliplatin plus capecitabine, or irinotecan plus fluorouracil) with or without addition of the epidermal growth factor receptor (EGFR) antibody cetuximab.2Bridgewater JA Pugh SA Maishman T et al.Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.Lancet Oncol. 2020; (published online Jan 31)https://doi.org/10.1016/S1470-2045(19)30798-3Summary Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 3Primrose J Falk S Finch-Jones M et al.Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial.Lancet Oncol. 2014; 15: 601-611Summary Full Text Full Text PDF PubMed Scopus (276) Google Scholar Although the concept was rational and the trial well designed, the initially reported results were rather unexpected and controversial.3Primrose J Falk S Finch-Jones M et al.Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial.Lancet Oncol. 2014; 15: 601-611Summary Full Text Full Text PDF PubMed Scopus (276) Google Scholar Although the addition of cetuximab to chemotherapy numerically increased the proportion of patients with a response, it showed shorter progression-free survival, with a hazard ratio of 1·48 (95% CI 1·04–2·12; p=0·030) in patients given chemotherapy with cetuximab versus those who had chemotherapy alone. Overall survival was similar (HR 1·49, 95% CI 0·86–2·60; p=0·16) but was not significant, conceivably because of short follow-up. On the basis of these data, the trial was stopped early. These results led to a controversial debate reflected in an exchange of letters in a different journal.4Nordlinger B Poston GJ Goldberg RM Should the results of the new EPOC trial change practice in the management of patients with resectable metastatic colorectal cancer confined to the liver?.J Clin Oncol. 2015; 33: 241-243Crossref PubMed Scopus (24) Google Scholar In their long-term analysis, Bridgewater and colleagues now confirm the initial results, showing shorter overall survival in patients given chemotherapy plus cetuximab compared with patients given chemotherapy alone (55·4 months [95% CI 43·5–71·5] vs 81·0 months [59·6 to not reached]; HR 1·45, 95% CI 1·02–2·05; p=0·036). The detrimental effects were more pronounced in patients with more favourable clinical tumour characteristics, potentially indicating an adverse effect in a true adjuvant (micrometastatic) setting. Finally, the results were largely driven by post-recurrence survival, suggesting either the development of a more aggressive disease phenotype or imbalances in post-recurrence treatment approaches. Since the initial publication of the study, new insights into prognostic and predictive molecular signatures of metastatic colorectal cancer have emerged. In right-sided colon cancer, first-line cetuximab has shown to decrease overall survival compared with bevacizumab.5Venook AP Niedzwiecki D Lenz HJ et al.Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial.JAMA. 2017; 317: 2392-2401Crossref PubMed Scopus (385) Google Scholar Additionally, several studies suggest detrimental effects (ie, shorter survival) of anti-EGFR therapy in patients with other molecular alterations such as non-KRAS exon2 RAS mutations, BRAF mutations, HER2 amplifications, and microsatellite instability.6Løes IM Immervoll H Sorbye H et al.Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases.Int J Cancer. 2016; 139: 647-656Crossref PubMed Scopus (55) Google Scholar In New EPOC, no significant differences were observed in the distribution of RAS/RAF mutations between treatment groups, but this observation does not rule out imbalances in other molecular alterations that could have affected sensitivity to EGFR antibody therapy. Moreover, the heterogeneity of the systemic therapy in the perioperative setting could be seen as a limitation since the detrimental effect was mainly seen in patients treated with oxaliplatin plus fluorouracil plus cetuximab. Importantly, only 10% of the patients within the cetuximab group received cetuximab as part of subsequent palliative therapy upon recurrence compared with 30% of patients in the chemotherapy alone group—a factor that might have led to lower overall survival because of decreased exposure to cetuximab upon recurrence.2Bridgewater JA Pugh SA Maishman T et al.Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.Lancet Oncol. 2020; (published online Jan 31)https://doi.org/10.1016/S1470-2045(19)30798-3Summary Full Text Full Text PDF PubMed Scopus (50) Google Scholar The authors offer the expression of the microRNA miR-31–3p in primary colorectal cancer of patients with metastatic disease treated with cetuximab or panitumumab as a potential explanation for resistance to EGFR inhibition and disease progression.7Manceau G Imbeaud S Thiébaut R et al.Hsa-miR-31–3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy.Clin Cancer Res. 2014; 20: 3338-3347Crossref PubMed Scopus (77) Google Scholar Some preclinical models suggest an epithelial–mesenchymal-like transition as potential mechanism of anti-EGFR therapy.8García-Foncillas J Sunakawa Y Aderka D et al.Distinguishing features of cetuximab and panitumumab in colorectal cancer and other solid tumors.Front Oncol. 2019; 9: 849Crossref PubMed Scopus (42) Google Scholar In vitro, a correlation between E-cadherin expression and growth inhibition by EGFR inhibitors was observed in colorectal cancer cells. Several other alterations, such as presence of MET amplification have been shown to play a role in anti-EGFR resistance.8García-Foncillas J Sunakawa Y Aderka D et al.Distinguishing features of cetuximab and panitumumab in colorectal cancer and other solid tumors.Front Oncol. 2019; 9: 849Crossref PubMed Scopus (42) Google Scholar These hypotheses could point to potential biological mechanisms for cetuximab's association with poor outcomes in early-stage disease. In stage III colon cancer (according to the American Joint Committee on Cancer staging system), the addition of cetuximab to adjuvant fluorouracil plus oxaliplatin showed no difference in disease-free survival, although the hazard ratio point estimate suggested a detriment in survival, independent of RAS mutation status.9Huang J Nair SG Mahoney MR et al.Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) intergroup trial N0147.Clin Colorectal Cancer. 2014; 13: 100-109Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar Multiple preclinical studies suggest that a substantial portion of the effects attributed to EGFR antibody treatment could be based on indirect effects beyond cancer cells, including the tumour microenvironment and immune–cancer cell interactions.10Giordano G Remo A Porras A Pancione M Immune resistance and EGFR antagonists in colorectal cancer.Cancers (Basel). 2019; 11E1089Crossref PubMed Scopus (18) Google Scholar Various mechanisms of resistance to anti-EGFR therapy exist in colorectal cancer, ranging from molecular and immune alterations to histological transformations, allowing for intratumoral heterogeneity, independent of the RAS mutation status. Certainly, the study has some limitations surrounding surgical quality, including imbalances in the number of patients not undergoing surgery (21 in the chemotherapy plus cetuximab group vs 15 in the chemotherapy alone group) and the use of ablation rather than resection (11 vs 5). Despite these limitations, surgery was done in high-volume expert centres and randomisation conceivably helped to balance these factors. We commend the authors for completing a large interdisciplinary trial addressing important clinical and biological questions. Despite the limitations mentioned above, it is unlikely that the final outcomes of the study were affected by these factors. Although historically good responses have been achieved with more aggressive therapies in the advanced setting, cetuximab and cytotoxic therapy (oxaliplatin plus fluorouracil) in resectable stage IV and III colorectal cancers apparently might have a detrimental effect on survival. At this point in time, EGFR antibodies should not be used as a component of neoadjuvant or perioperative therapy in resectable stage IV colorectal cancer. Although we believe that EGFR antibodies added to chemotherapy still play a role in the preoperative conversion setting, when high anatomical response are desired, we caution against their use as postoperative therapy after resection of metastatic disease. As the field of molecular targeting treatment and understanding of resistance mechanisms continue to evolve, novel combination treatment strategies should be explored. Additional studies with predefined subgroups (eg, sidedness or different molecular and immune profiles) and novel combination treatment strategies are warranted in patients with operable colorectal liver metastases. We declare no competing interests. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trialAlthough the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. Full-Text PDF Open Access