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Summary Background To date, only two agents, imatinib and sunitinib, have shown clinical benefit in patients with gastrointestinal stromal tumours (GISTs), but almost all metastatic GISTs eventually develop resistance to these agents, resulting in fatal disease progression. This phase 3 trial assessed efficacy and safety of regorafenib in patients with metastatic and/or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods Patients were randomised 2:1 to receive either regorafenib 160 mg orally daily or placebo, plus best supportive care in both arms, for the first 3 weeks of each 4-week cycle. The primary endpoint was progression-free survival (PFS). Upon disease progression, patients on placebo could cross over to regorafenib. Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR: rate of durable stable disease lasting for ≥12 weeks plus complete or partial responses), and safety. This trial is registered at ClinicalTrials.gov (NCT01271712). Results From January to August 2011, 240 patients were screened at 57 centres in 17 countries, and 199 patients were randomised to receive regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central review was 4·8 months and 0·9 months, respectively (hazard ratio [HR] 0·27, 95% confidence interval [CI] 0·19–0·39; p<0·0001). Following progression, 56/66 patients (84·8%) on placebo crossed over to regorafenib, resulting in no significant difference in OS between study arms (HR 0·77, 95% CI 0·42–1·41; p=0·199). A best response of partial response or stable disease was observed in 101/133 patients (75·9%) on regorafenib and 23/66 patients (34·8%) on placebo. DCR was 52·6% (70/133 patients) and 9·1% (6/66 patients), respectively. Drug-related adverse events were reported in 130 (98·5%) of 132 regorafenib patients and 45 (68·2%) of 66 placebo patients. The most common grade ≥3 regorafenib-related adverse events were hypertension (31/132, 23·5%), hand–foot skin reaction (26/132, 19·7%), and diarrhoea (7/132, 5·3%). Interpretation Regorafenib significantly improved PFS and DCR, compared with placebo, in patients with advanced GIST progressing after failure of at least imatinib and sunitinib.

Soft tissue sarcomas (STSs) gather over 80 histological entities, with even more molecular subsets, characterised by a low to very low incidence in all populations. The majority of sarcomas arise from the soft tissue (close to 75%), with 15% gastrointestinal stromal tumours (GISTs) and 10% bone sarcomas. These ESMO-EURACAN (European Society for Medical Oncology-European Reference Network for rare adult solid cancers) Clinical Practice Guidelines cover STSs, while GISTs are covered by dedicated ESMO-EURACAN Clinical Practice Guidelines [1]. Kaposi's sarcoma is not considered in the present document. Extraskeletal Ewing and Ewing-like sarcoma is covered by ESMO Clinical Practice Guidelines on bone sarcomas [2]. In general, the

ASTROINTESTINAL STROMAL tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Gastrointestinal stromal tumors are usually found in the stomach or the small intestine but can occur at any site along the gastrointestinal tract and rarely elsewhere within the abdominal cavity. 1 The median age at presentation is 60 to 65 years, and the annual incidence approximately 10 cases per million. 2-4 Most GISTs (75% to 80%) harbor an activating mutation in the KIT oncogene and 5% to 10% in platelet-derived growth factor receptor-␣ (PDGFRA), which are important for tumor molecular pathogenesis. 5 The ma-For editorial comment see p 1312.