INTEGRATE: A randomized, phase II, double-blind, placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC): A study by the Australasian Gastrointestinal Trials Group (AGITG)—Final overall and subgroup results.

Abstract

4003 Background: REG is an oral multi-kinase inhibitor warranting evaluation in AOGC following failure of 1st or 2nd line chemotherapy (CT) where few options exist. Methods: International (Australia & New Zealand (ANZ), Korea, Canada (NCIC CTG)) phase II RCT with 2:1 randomization to 160 mg REG or matched Placebo (PBO) on days (D) 1-21 each 28 D cycle until disease progression (PD) or prohibitive adverse events. Primary endpoint: progression free survival (PFS). Final analysis used data to December 31, 2014. Results: 152 patients (pts) enrolled (November 2012 to February 2014) yielding 147 pts evaluable for analysis (97 REG and 50 PBO). M:F (118:29); primary site: OGJ (56), stomach (85); lines of prior CT: 1 (62), 2 (85); ECOG PS 0 (62): 1 (85). Median (med.) treatment wks: 8 (REG) v 4 (PBO). Med. REG dose intensity: 150 mg (130 mg Korea and 160mg ANZ/Can). 27 PBO pts received REG following PD. REG Med. PFS 11.1 wks (95% CI: 7.7 – 13.3) v PBO 3.9 wks (3.7 - 4.0), HR 0.40, p < 0.0001. Med. REG OS 25 wks (95% CI: 18.9-29.6) v PBO 19.4 wks (95% CI: 14.9 – 22.7), HR 0.74, p = 0.11. Pre-specified analyses found REG effect greater in Korea than ANZ/Can (HR 0.12 v 0.61, p = 0.0009) but consistent across age, NLR, primary site, lines of CT, peritoneal metastases (mets) presence, number of met. sites, and VEGF-A (Table). Results comparable for ITT population (n = 152). REG was well tolerated, with expected spectrum of toxicities. Conclusions: REG was highly effective in prolonging PFS across a broad range of pts, with a non-significant positive OS trend. Regional differences were found in the magnitude of effect but REG was effective in all regions and subgroups. A phase III trial is merited. Clinical trial information: 12612000239864. Key sub-groups PFS HR (95% CI) P value Interaction p Value Korea (n = 54) ANZ/Canada (n = 93) 0.12 (0.06 – 0.27) 0.61 (0.39 – 0.97) < 0.0001 0.03 0.0009 Lines of prior therapy 1 (n = 62) 2 (n = 85) 0.49 (0.28 – 0.86) 0.32 (0.19 – 0.55) 0.01 < 0.001 0.50 Neutrophil-lymphocyte ratio (NLR) <3 (n = 71) ≥ 3 (n = 76) 0.41 (0.23 – 0.70) 0.37 (0.22 – 0.64) 0.0007 0.0001 0.72 Plasma VEGF-A (pg/ml) Low (≤ 0.14), (n = 82) High (> 0.14), (n = 62) 0.39 (0.24 – 0.65) 0.42 (0.23 – 0.78) 0.0001 0.003 0.72