Other tyrosine kinase inhibitor treatments have been reported useful even in cases where there was progression under imatinib 800mg/day and sunitinib. Molecules are being tested in advanced GISTs, and early results of phase I and phase II trials were reported at the ASCO meeting. These include PTK787/ZK222584 (PTK/ZK) – Novartis AG, Basel, Switzerland and Schering AG, Berlin, Germany – for which results of a phase II trial in patients with imatinib-resistant GISTs was reported at the 2006 ASCO meeting.¹³ In this study, PTK/ZK was given orally and the reported clinical benefit rate – defined here as complete response+partial response+stable disease (CR+PR+SD) for more than three months – was 67% (10 out of 15 patients).

AMG 706 is another broad spectrum tyrosine kinase inhibitor that was shown to inhibit KIT protein phophorylation in vitro.¹⁴ Preliminary results of a phase II trial showing activity in patients with GIST were recently reported at the meeting of the Connective Tissue Oncology Society in November 2006.

Protein kinase C412 (PKC412) is a broad spectrum protein kinase inhibitor, initially developed to target the members of the protein kinase C family, but which was shown to exert inhibitory activity against the kinases of c-KIT, VEGFR and PDGFRs, as well as FLT3. In pre-clinical models, PKC412 was shown to be active against several c-KIT and PDGFR? mutations that are known to be resistant to imatinib. A phase I/II trial of PKC412 in imatinib-resistant GIST was reported at the 2005 ASCO meeting, showing interesting, though very limited, data.¹⁵

This study also showed pharmacological interaction between PKC412 and imatinib, requiring the dose of imatinib to be increased from 600 to 1,000mg/day. Nilotinib (formerly ANM 107; Novartis, Basel, Switzerland), which was developed as a second-line therapy for imatinib-resistant chronic myeloid leukemia (CML), seems to show a high efficiency in GISTs where imatinib therapy fails, and combines with a favourable toxicity profile.¹⁶ A phase II trial of nilotinib in imatinibresistant GISTs has recently finished accrual, and a phase III trial should soon be launched.

Conclusion
The management of advanced GIST patients has evolved considerably over the last three years. Second-, third- or even fourth-line tyrosine kinase inhibitor treatments are now being explored. Surgery in advanced phases remains experimental in cases of focal progression that is amenable to complete surgical removal. These patients should be managed in specialised multidisciplinary centres.