M Eriksson1, P Reichardt2, H Joensuu3, A Krarup-Hansen4, O Hagberg5, P Hohenberger6, H Hagberg7, L Hansson8, T Foukakis9, K Pulkkanen10, S Bauer11, D Goplen12, P Blach Rossen13, K Sundby Hall14. 1. Department of Oncology, Skane University Hospital and Lund University, Lund, Sweden. Electronic address: mikael.eriksson@med.lu.se. 2. Sarcoma Center Berlin-Brandenburg and Helios Clinic Berlin-Buch, Berlin, Germany. 3. Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. 4. Department of Oncology, Herlev Hospital, Copenhagen, Denmark. 5. Institution of Translation Medicine, Lund University, Malmö, Sweden. 6. Division of Surgical Oncology and Thoracic Surgery, Mannheim University Medical Center, Mannheim, Germany. 7. Department of Oncology, Uppsala Academic Hospital, Uppsala, Sweden. 8. Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden. 9. Breast Cancer, Endocrine Tumours and Sarcoma Section, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden. 10. Department of Oncology, Kuopio University Hospital, Kuopio, Finland. 11. Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University of Duisburg-Essen, Essen, Germany. 12. Department of Oncology, Haukeland University Hospital, Bergen, Norway. 13. Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. 14. Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Abstract
BACKGROUND:Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. PATIENTS AND METHODS: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. RESULTS:Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. CONCLUSION:Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.
RCT Entities:
BACKGROUND:Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. PATIENTS AND METHODS: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. RESULTS: Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. CONCLUSION:Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.