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)

Abstract

Background: Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. Patients and methods: Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m 2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m 2 i.v., days 1e4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m 2 to 80 mg/m 2. Results: The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06e2.98; P ¼ 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79 e1.75; P ¼ 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. Conclusion: EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. Trial registration: ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: Why clinical trials have failed and how they could succeed

“…However, clinical results of EGFR monoclonal antibodies both as monotherapy and in combination with PBC in ESCC have been similar to those demonstrated with EGFR TKis (10, 18, 20-23, 27, 28, 35). In addition, in line with our conclusions, the POWER phase III RCT in advanced ESCC did not demonstrate any bene t of the addition of the humanised monoclonal anti-EGFR antibody panitumumab to cisplatin plus uoropyrimidine chemotherapy (28). POWER enrolled molecularly unselected ESCC patients, but, a retrospective analysis demonstrated that EGFR IHC did not correlate signi cantly with overall survival, and EGFR copy number was not investigated.…”

“…Several clinical trials have investigated the combination of EGFR inhibitors with cytotoxic chemotherapy or concurrent chemoradiotherapy (27)(28)(29)(30)35). In the palliative setting, in both ESCC and GOA the addition of EGFR inhibitors to platinum plus uoropyrimidine chemotherapy has not improved overall survival (28)(29)(30). Similarly, in the radical treatment setting, the addition of EGFR inhibitors to concurrent chemoradiotherapy, with a platinum and uoropyrimidine chemotherapy backbone has not improved overall survival (27).…”

“…Clinical trials combining EGFR inhibitors and platinum/ uoropyrimidine chemotherapy in the advanced stage setting or with platinum uoropyrimidine-based concurrent chemoradiotherapy in the curative treatment setting, have not shown an incremental bene t (27). In the largest randomised trial in ESCC, in molecularly unselected patients with advanced stage disease, the addition of the EGFR monoclonal antibody pantitumumab to cisplatin and 5FU chemotherapy did not improve overall survival (28). Similarly, in unselected advanced stage gastroesophageal adenocarcinoma (GOA) patients a negative impact on overall survival was observed with addition of panitumumab to epirubicin, oxaliplatin and capecitabine (29,30).…”

Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed

“…Several clinical trials have investigated the combination of EGFR inhibitors with cytotoxic chemotherapy or concurrent chemoradiotherapy [17][18][19][20]24]. In the palliative setting, in both ESCC and GOA, the addition of EGFR inhibitors to platinum plus fluoropyrimidine chemotherapy has not improved overall survival [18][19][20]. Similarly, in the radical treatment setting, the addition of EGFR inhibitors to concurrent chemoradiotherapy, with a platinum and fluoropyrimidine chemotherapy backbone has not improved overall survival [17].…”

“…Clinical trials combining EGFR inhibitors and platinum/fluoropyrimidine chemotherapy in the advanced stage setting or with platinum fluoropyrimidine-based concurrent chemoradiotherapy in the curative treatment setting, have not shown an incremental benefit [17]. In the largest randomised trial in ESCC, in molecularly unselected patients with advanced stage disease, the addition of the anti-EGFR monoclonal antibody pantitumumab to cisplatin and 5FU chemotherapy did not improve overall survival [18]. Similarly, in unselected advanced stage gastroesophageal adenocarcinoma (GOA) patients, a negative impact on overall survival was observed with addition of panitumumab to epirubicin, oxaliplatin and capecitabine [19,20].…”