Combination of PKC412 and sirolimus in a metastatic patient with PDGFRA-D842V gastrointestinal stromal tumor (GIST)

Abstract

21515 Background: The exon 18 PDGFRA-D842V mutation is the most common PDGFRA mutation in GIST. This mutation appears to be resistant to imatinib, but preclinical data have reported its sensitivity to PKC412, a multitarget protein kinase inhibitor. The combination of mammalian target of rapamycin (mTOR) inhibitor and imatinib has been previously explored in imatinib-resistant GIST, based on the involvement of AKT/mTOR pathway in GIST oncogenic signalling mechanisms. We report on the use of PKC412 and sirolimus, an mTOR inhibitor, in a patient with a PDGFRA-D842V metastatic GIST, progressing on PKC412 as a single agent. Methods: In January 2002, a 54 year-old woman with a PDGFRA-D842V GIST arising from the omentum was treated with surgery. In April 2007, following multifocal peritoneal recurrence, imatinib 400 mg/day was started. After 3 months, it was interrupted due to progressive disease, with hemoperitoneum. In July 2007, PKC412 100 mg/day was started, on a named individual basis. After 6 weeks, CT scan showed progressive disease according to Choi's criteria. In August 2007, sirolimus 2 mg/day was added to PKC412. Results: After 4 weeks of combined treatment, a stable disease according to Choi's and RECIST criteria was observed. It was maintained at 11 weeks. Plasma concentrations of sirolimus have been monitored (range 9–15 ng/mL). Treatment is ongoing, in the lack of severe or unexpected toxicities. Conclusions: In this patient, progressing on PKC412, a stable disease was obtained by adding sirolimus to the latter. Nevertheless, potential drug-drug interaction of this formerly unexplored combination, through CYP3A4 common metabolic pathway, would require for any future cases formal DLT and reciprocal drug level assessment within a proper clinical trial setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis