Regorafenib Shows Refractory Gastric Cancer PFS Potential

Phase II trial results support further investigation into regorafenib for patients with advanced gastric adenocarcinoma

medwireNews: The multikinase inhibitor regorafenib may prolong progression-free survival (PFS) in patients with advanced, treatment-refractory gastric adenocarcinoma, INTEGRATE trial findings indicate.

PFS was a median of 2.6 months for the 97 patients randomly assigned to receive best supportive care plus regorafenib 160 mg on days 1 to 21 of a 28-day cycle until progression or intolerable side effects versus 0.9 months for the 50 patients given placebo plus best supportive care, giving a significant hazard ratio of 0.40.

The absolute difference in median PFS with regorafenib is comparable to that achieved by other agents in this patient population, such as apatinib and ramucirumab, the authors comment in the Journal of Clinical Oncology.

Nick Pavlakis, from Royal North Shore Hospital in Sydney, New South Wales, Australia, and co-authors note that PFS was significantly longer in patients from South Korea than their counterparts in Australia, New Zealand and Canada (HR=0.12 versus 0.61).

Noting that this appears to “contradict” the finding of a reduced survival benefit in Asian patients using bevacizumab in the AVAGAST trial, the authors suggest the difference might be explained by genetic polymorphisms affecting drug response or molecular phenotype differences that alter sensitivity or prognosis.

Nevertheless, the PFS benefit was “consistent” across patient subgroups stratified by age, neutrophil-to-lymphocyte ratio, receipt of one versus two prior lines of chemotherapy, the presence or absence of peritoneal metastases, number of sites of metastases and plasma vascular endothelial growth factor (VEGF) A level.

And there was a trend towards improved overall survival with regorafenib compared with placebo, at 5.8 versus 4.5 months and a HR of 0.74.

Regorafenib toxicity profile was also consistent with previous reports, with at least one serious event experienced by 32% of patients given the multikinase inhibitor versus 18% of those given placebo. Gastrointestinal disorders (11 vs 0%), infections (6 vs 2%) and metabolic or nutritional disorders (4 vs 2%) were the most common grade 3 to 5 adverse effects.

“No participant in INTEGRATE had received any prior anti-VEGF treatment”, observe Nick Pavlakis et al.

“Modern practice today would likely include second-line chemotherapy with ramucirumab in fit patients, thus leaving the refractory setting as an ongoing area of clinical need.”

They conclude: “A multinational phase III trial in refractory GC (INTEGRATE II) is commencing in 2016, and studies evaluating regorafenib with chemotherapy in earlier settings are under way.”


Pavlakis N, Sjoquist KM, Martin AJ, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II trial. J Clin Oncol 2016; Advance online publication 20 June. doi: 10.1200/JCO.2015.65.1901

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