Anti-EGFR plus chemotherapy in unselected advanced oesophageal squamous cell carcinoma: less POWERful than expected
Authors: C. Connell, E.C. Smyth
Journal: Annals of Oncology (2020)

Oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma are distinct in their aetiology, tissue of origin, and molecular profiles.1Kim J. Bowlby R. Mungall A.J. et al.Integrated genomic characterization of oesophageal carcinoma.Nature. 2017; 541: 169-175Crossref PubMed Scopus (1018) Google Scholar Remarkably, despite squamous tumours representing almost 90% of oesophageal cancers globally, there have been no dedicated large phase III randomised trials investigating systemic treatment of advanced OSCC. Instead, the current standard of care is guided by trials in which the majority of recruited patients had oesophageal adenocarcinoma.2Lagergren J. Smyth E. Cunningham D. et al.Oesophageal cancer.Lancet. 2017; 390: 2383-2396Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar In this issue of Annals of Oncology, Moehler and colleagues report the results of POWER, the first phase III trial dedicated to the palliative treatment of advanced OSCC patients.3Moehler M. Maderer A. Thuss-Patience P.C. et al.Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER).Ann Oncol. 2020; 31: 228-235Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar POWER patients were randomised with non-resectable, advanced, or metastatic OSCC to a standard of care chemotherapy with cisplatin and 5-fluorouracil (CF) or CF plus panitumumab, a fully humanised IgG2 anti-EGFR monoclonal (CFP). The triplet of cisplatin, 5-fluorouracil and panitumumab was associated with higher rates of early mortality and chemotherapy-associated toxicity compared with CF chemotherapy; for example, Grade 5 toxicities occurred in 3/70 patients in the CF arm and 17/72 patients in the CFP arm (4.3% versus 23.6%, respectively, P = 0.0012) although 3 events in CFP arm were due to missing grading. The high rate of early deaths triggered an ad hoc efficacy analysis and, subsequently, early termination of the trial for futility. In POWER, no survival benefit was observed from the addition of panitumumab to CF chemotherapy: median overall survival (mOS) was 10.2 and 9.4 months for CF and CFP, respectively [hazard ratio (HR 1.17, 95% confidence interval (CI) 0.79–1.75; P = 0.43], and the objective response rates were equivalent in both arms of the trial. These results highlight important considerations regarding patient selection for EGFR-targeted agents, the toxicity of EGFR-targeted agent combination therapy, and the future for systemic treatment of OSCC patients. The phase III randomised POWER trial followed the positive results of a phase II randomised study in which patients with EGFR expressing OSCC were randomised to either CF chemotherapy or CF plus the IgG1 anti-EGFR monoclonal antibody cetuximab.4Lorenzen S. Schuster T. Porschen R. et al.Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie.Ann Oncol. 2009; 20: 1667-1673Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar The previous trial showed no detriment in survival for CF-cetuximab treated patients (despite a higher cisplatin dose being utilised) and suggested that the chemotherapy/anti-EGFR combination could result in improved progression-free survival (PFS) and overall survival (OS) (in the previous trials mOS were 5.5 versus 9.5 months for CF and CF-cetuximab, respectively). First, even for metastatic OSCC, OS in the control arm of the phase II trial (5.5 months) was poor, thus increasing the risk of a false-positive result favouring combination treatment. Secondly, the prior trial was conducted in a population selected for EGFR expression, which POWER was not. Thirdly, a different anti-EGFR antibody was used in POWER (panitumumab rather than cetuximab) and the activity spectrum and toxicities of these agents may not always completely overlap; IgG1 monoclonal antibodies such as cetuximab appear to have immune-related functions that IgG2 antibodies such as panitumumab lack.5Trivedi S. Srivastava R.M. Concha-Benavente F. et al.Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck cancer patients.Clin Cancer Res. 2016; 22: 5229-5523Crossref PubMed Scopus (91) Google Scholar Interestingly, in relapsed and metastatic squamous cell carcinoma of the head and neck, which bears some biological similarity to OSCC, cetuximab, but not panitumumab improved OS in randomised clinical trials.6Vermorken J.B. Mesia R. Rivera F. et al.Platinum-based chemotherapy plus cetuximab in head and neck cancer.N Engl J Med. 2008; 359: 1116-1127Crossref PubMed Scopus (2549) Google Scholar,7Vermorken J.B. Stöhlmacher-Williams J. Davidenko I. et al.SPECTRUM investigatorsCisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.Lancet Oncol. 2013; 14: 697-710Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar These findings suggest several potential explanations for the negative results of POWER compared with the previous phase II trial. Could there be a subset of OSCC patients who might benefit from anti-EGFR therapy? Translational research from historical clinical trials suggests that patients with EGFR-amplified cancers may benefit from anti-EGFR therapy. Prespecified biomarker analysis from the phase III COG trial identified EGFR copy number gain to be associated with improved disease control and PFS and OS in gefitinib treated patients compared with a placebo in patients with either previously treated OSCC or adenocarcinoma.8Dutton S.J. Ferry D.R. Blazeby J.M. et al.Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial.Lancet Oncol. 2014; 15: 894-904Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar Importantly, similar effects in PFS and OS were not observed in those patients without EGFR copy number gain. This suggests that oncogenic addiction to EGFR signalling may be a feature of both EGFR-amplified OSCC and adenocarcinoma, a finding validated for adenocarcinoma patients in the prospective PANAGEA trial.9Maron 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: 696-713Crossref PubMed Scopus (84) Google Scholar In POWER, EGFR amplification was not assessed and EGFR expression was broadly characterised using immunohistochemistry, which showed no association between EGFR protein assessment and outcome. Nevertheless, it is possible that any positive association between a small number of EGFR-driven tumours and panitumumab would be confounded by the excess toxicity observed in the combination arm of the trial. Considering the additional toxicity of combination therapy and the positive translational results of the COG and PANAGEA trials, studies investigating anti-EGFR monotherapy in a refined but highly sensitive EGFR-dependent population are more likely to inform the true value of the targeting of this pathway in oesophageal cancer. In POWER, the investigators examined the predictive and prognostic effects of multiple serum biomarkers including EGF, sEGFR, HGF, HIF1-α, leptin, SDF1α, and VEGFA but with the exception of soluble EGFR (sEGFR) and HIF1-α, these were uninformative. Low levels of sEGFR appeared to be positively prognostic in chemotherapy-treated patients but not panitumumab-treated patients. In view of this putative positive prognostic role for low sEGFR, it is of interest that panitumumab appeared to increase levels of sEGFR in the triplet arm of the study. Translational results were available for only a subset of POWER patients, however, and due to the number of biomarkers examined, these results may be underpowered and subject to multiplicity; as a result, they should be considered hypothesis-generating. In view of the paucity of ctDNA data in OSCC patients, the POWER dataset, which contains serial plasma assessments, could represent an opportunity to explore liquid biopsy as a predictor of outcome from both chemotherapy and anti-EGFR therapy in this population. Horizon scanning for future developments in OSCC suggests that the landscape has recently shifted. With respect to chemotherapy, oxaliplatin is often used as a substitute for cisplatin in chemotherapy regimens and may be associated with fewer treatment-related deaths.10Conroy T. Galais M.P. Raoul J.L. et al.Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial.Lancet Oncol. 2014; 15: 305-314Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar,11Wagner A.D. Syn N.L. Moehler M. et al.Chemotherapy for advanced gastric cancer.Cochrane Database Syst Rev. 2017; 8: CD004064PubMed Google Scholar More crucially, in patients with previously treated advanced OSCC, immune checkpoint blockade with nivolumab and pembrolizumab has been shown to be superior to chemotherapy in Asian patients and patients with high PD-L1 expressing tumours, respectively.12Kato K. Cho B.C. Takahashi M. et al.Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2019; 20: 1506-1517Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar,13Kojima T. Muro K. Francois E. et al.Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase III KEYNOTE-181 study. ASCO GI Abstract 2.J Clin Oncol. 2019; 37: 2Crossref Google Scholar Given these paradigm-changing results, the focus of OSCC research over the short to medium term is likely to be on exploring factors associated with immune responsiveness and evasion rather than targeted therapies. In view of the immune-related cell cytotoxicity immune-priming effect of IgG1 monoclonal antibodies, however, the combination of cetuximab and nivolumab is being studied in advanced head and neck squamous cell carcinoma.14Cetuximab & nivolumab in patients with recurrent/metastatic head & neck squamous cell carcinoma. Clinicaltrials.gov identifier: NCT03370276. Accessed November 8, 2019.Google Scholar Many oesophageal squamous tumours express EGFR and because synergy between anti-EGFR and anti-PD(L)1 could occur independently of EGFR addiction, this combination could be of interest to explore in OSCC in future. In conclusion, the POWER study provides an important contribution to the treatment of advanced OSCC. It confirms recent findings that EGFR-targeted agents are not effective in unselected patients and highlights the need for careful consideration of toxicity when these are combined with chemotherapy. As the first large phase III randomised trial reported in the treatment of naive OSCC, it is hoped that this may be the start of a renewed focus on this historically underserved disease. None declared.