The evidence supporting this protocol is provided by a phase III multicentre international randomised trial (GRID study) involving 199 patients comparing placebo with regorafenib alone in patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib.r
Between January 4 and August 18, 2011, 199 patients were randomised in a 2:1 ratio to receive regorafenib 160mg orally once daily (n=133) or matching placebo (n=66), for the first 3 weeks of each 4 week cycle. All patients also received best supportive care.
The primary end point was progression-free survival (PFS) and secondary end points were overall survival (OS), time to progression (TTP), objective response rate (ORR), disease control rate (defined as rate of complete response or partial response plus stable disease lasting for at least 12 weeks), safety and tolerability.
At disease progression, patients assigned placebo could crossover to receive open-label regorafenib. There was significant crossover (85%) in the placebo group.
At the time of analysis when the predetermined criteria of 144 PFS events was reached, the median PFS was 4.8 months in the regorafenib group vs 0.9 months in the placebo group (HR=0.27; CI 95% 0.19 to 0.39; p<0.0001), meeting the primary endpoint of the study.r
There was no statistically significant difference in OS between the regorafenib and placebo groups (HR 0.77, 95% CI 0.42-1.41; p=0.199), however the proportion of patients who crossed over from the placebo group may account for this.r
No patients in either group had a complete response, while 6 out of 133 patients in the regorafenib group and 1 out of 66 patients in the placebo group had a partial response, giving ORRs of 4.5% and 1.5% respectively.r
QOL data was not collected in the key evidence and has not been presented.
Kaplan-Meier curve for (A) Progression-free survival (final analysis) and (B) Overall survival (interim analysis)r
© Lancet 2013
Drug-related adverse events of any grade were reported in 130 (98%) of the regorafenib-treated patients and 45 (68%) of the placebo patients. The most common adverse event of any grade was hand-foot skin reaction, which occurred in 74 (56%) patients in the regorafenib group and 9 (14%) patients in the placebo group.r
Drug-related adverse events of grade 3 or higher were reported in 81 (61%) of the regorafenib-treated patients and 9 (14%) of the placebo patients. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (23%), hand-food skin reaction (20%) and diarrhoea (5%).r
Serious adverse events were reported in 38 (29%) patients in the regorafenib group, the most common being abdominal pain (4%), fever (2%) and dehydration (2%). Grade 5 adverse events were reported in 7 (5%) patients in the regorafenib group, two of which were deemed to be drug-related (cardiac arrest and hepatic failure). In the placebo group grade 5 adverse events occurred in 3 (4.5%) of the 66 patients, one of which was deemed to be drug-related (fatigue).
Although dose modifications were more frequent in the regorafenib group (72%) vs placebo group (26%), the occurrence of adverse events that led to permanent discontinuation of treatment was similar between the two groups.r
© Lancet 2013