Cisplatin/5-fluorouracil +/- panitumumab for patients with non-resectable, advanced or metastatic esophageal squamous cell cancer: A randomized phase III AIO/EORTC trial with an extensive biomarker program

Abstract

Introduction: Most esophageal squamous cell cancer (ESCC) patients (pts) have advanced disease at time of diagnosis. Chemotherapy (CTX) improved overall survival (OS), but still with limited impact. Prior studies suggested increased efficacy of EGFR antibodies (AB) combined with cisplatin (C) / 5‐fluorouracil (F). Methods: This open‐label, randomized (1:1), multinational phase III trial included ECOG 0‐1 pts with non‐resectable, advanced or metastatic ESCC (RECIST1.1), not eligible for radiochemotherapy (RCTX). Previous CTX in metastatic setting, concurrent RCTX and previous exposure to EGFR‐AB were excluded. To test for overall survival (OS) superiority of CFP vs CTX alone, pts received CF (C 100 mg/m2 d1+ F 1000 mg/ m2/d, d1‐4)+panitumumab (P) (9 mg/kg d1) or CF alone (each q3 weeks) until disease progression. To define prognostic and predictive markers, EGFR and MET expression status were determined by immunohistochemistry. Serum samples were collected before first CTX cycle for enzyme‐linked immunosorbent assay (ELISA) analyses. Results: Between 6.2012‐5.2015, the ITT population consisted of randomized 146 patients with 73 in each treatment arm, 71 of each group received at least one dose of study medication. The per‐protocol set (PPS) contained 101 patients. Due to more Gr3‐4 SAEs in the first 60 pts with CFP, C was reduced to 80mg/m2d1. Recruitment and trial was terminated prematurely after a scheduled safety interim analysis and an unscheduled efficacy interim analysis. Median progression‐free survival was similar in both groups: 5.8 months with CF vs. 5.3 months in CFP (HR 1.21, 95% CI 0.85‐1.73, p=0.29). Median OS in CF (10.3 months) was similar to CFP (9.6 months, HR 1.17, 95% CI 0.79‐1.75, p=0.43). After C was reduced in 85 pts, OS favored CFP vs CF, with 9.8 vs. 8.3 mo (HR 0.84, 95%CI 0.49‐1.43; P=0.51). Safety: 60 (83%) of CFP and 55 (79%) of CF pts had any AE, mostly diarrhoea, hypokalaemia, hypomagnesaemia, rash, or hand‐foot syndrome. Main Gr‐3 AEs were balanced with low neutrophils (21/ 24%) and anaemia (13/16%) for CFP vs CF, respectively. Gr 3‐4 skin reactions and rash were higher in CFP (10%) vs CF (0%). Overall, 51/72 (71%) of CFP and 36/70 (51%) of CF had an SAE. Main SAEs were dysphagia, acute kidney injury, diarrhoea, fevers and febrile neutropenia. EGFR and MET expression showed no correlation to any clinical or pathological parameters. Low sEGFR serum levels were linked to better PFS (p=0.014) in all patients, especially in the CF arm (p=0.039). Moreover, sEGFR levels increased during CF‐P therapy but not with CF. Conclusion: To our knowledge, this has been the largest European first‐line palliative phase III trial of chemotherapy +/‐ EGFR targeting agent in ESCC patients only. Addition of Panitumumab to CF provided no benefit to first‐line CTX alone. A low sEGFR level was associated with better PFS and increased under CF+ Panitumumab. Further results of second line therapies and further biomarker analysis will be presented at the meeting.