A Systematic Review and Network Meta-Analysis of Post-Imatinib Therapy in Advanced Gastrointestinal Stromal Tumour

Background: The standard first-line systemic therapy for advanced gastrointestinal stromal tumour (GIST) is imatinib. However, most GISTS develop imatinib resistance, highlighting the need for new agents in the imatinib-refractory setting. Currently, no randomized studies have directly compared the available post–first-line treatments. Methods: In a systematic review, the MEDLINE, EMBASE, and CENTRAL databases, and American Society of Clinical Oncology abstracts to July 2014 were searched to identify randomized controlled trials that included GIST patients treated with post–first-line therapies. Hazard ratios (HRS) for progression-free (PFS) and overall survival (OS) were extracted. Direct pairwise meta-analyses and indirect comparisons using the Butcher method were performed. Results: Four studies were identified for the systematic review. One study showed that sunitinib in the second-line setting (vs. placebo) was associated with improved PFS, but not improved OS. Three studies examined the third-line setting (imatinib resumption vs. placebo, regorafenib vs. placebo, nilotinib vs. best supportive care). In the third-line settings, the two placebo-controlled and the non-placebo-controlled trials showed significant heterogeneity (I² = 98%). Indirect comparisons of imatinib resumption and regorafenib suggested that the hr for PFS was 0.59 (95% confidence interval: 0.31 to 1.12; p = 0.10), trending in favour of regorafenib. Indirect comparisons found that toxicities were higher in the regorafenib group, with a risk difference of 27.8% for any-grade toxicities and 19.5% for grades 3 and 4 toxicities. Conclusions: Because a head-to-head study of imatinib resumption compared with regorafenib is unlikely ever to be conducted, our study suggests that, in terms of PFS, regorafenib might be the preferred treatment. However, given the increased toxicity observed with regorafenib, clinicians should interpret that evidence with caution at an individual patient level.