Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series

Background: Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1-2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second-line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. Methods: Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6-week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. Results: We identified 9 paediatric/young adult patients (aged 11-21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to > 73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. Conclusion: The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment

Dovitinib in patients with gastrointestinal stromal tumour refractory and/or intolerant to imatinib

Background: This multicentre phase II trial (DOVIGIST) evaluated the antitumour activity of dovitinib as second-line treatment of patients with gastrointestinal stromal tumour (GIST) refractory to imatinib or who do not tolerate imatinib. Methods: Patients received oral dovitinib 500 mg day(-1), 5 days on/2 days off, until GIST progression or unacceptable toxicity, with an objective to evaluate efficacy, assessed as the disease control rate (DCR) at 12 weeks. Tumour assessment and response to dovitinib therapy were evaluated by Response Evaluation Criteria In Solid Tumours (RECIST v1.1) and the Choi criteria. Secondary objectives included assessment of progression-free survival (PFS), safety and tolerability, and DCR at the end of treatment. Results: Thirty-eight of the 39 patients enrolled had histologically confirmed GIST. The DCR at 12 weeks was 52.6% (90% confidence interval (CI), 38.2-66.7%) meeting the preset efficacy criterion for the primary end point. The objective response rate (complete response+partial response) was 2.6% (1 of 38; 90% CI, 0.1-11.9%), and 5.3% (n = 2; 90% CI, 0.9-15.7%) at the end of the study. The median PFS was 4.6 months (90% CI, 2.8-7.4 months). Dose interruption was required in 26 patients (66.7%), of which 18 (69.2%) were due to adverse events. The most frequently observed grade 3 adverse events included hypertension (n = 7), fatigue (n = 5), vomiting (n = 4), hypertriglyceridaemia (n = 4), and gamma-glutamyltransferase increase (n = 4). Conclusions: Dovitinib is an active treatment for patients with GIST who are intolerant to imatinib or whose GIST progresses on imatinib.Peer reviewe

Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial

BACKGROUND: This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer. METHODS: Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more. RESULTS: In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%). CONCLUSION: Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted