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Clin Cancer Res. 2019 Aug 30. pii: clincanres.2150.2019. doi: 10.1158/1078-0432.CCR-19-2150. [Epub ahead of print]

Phase I study of rapid alternation of sunitinib and regorafenib for the treatment of tyrosine-kinase inhibitor refractory gastrointestinal stromal tumors.

Author information

1
Medical Oncology, Hospital Universitario Vall d'Hebron cserrano@vhio.net.
2
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine.
3
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute.
4
Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute.
6
Oncology, Johns Hopkins University School of Medicine.
7
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School.
8
Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute.
9
Department of Medical Oncology, Dana-Farber Cancer Institute.
10
Medical Oncology, Dana-Farber Cancer Institute.

Abstract

PURPOSE:

Polyclonal emergence of KIT secondary mutations is a main mechanism of imatinib progression in gastrointestinal stromal tumor (GIST). Approved KIT inhibitors sunitinib and regorafenib have complementary activity against KIT resistance mutations. Preclinical evidence suggests that rapid alternation of sunitinib and regorafenib broadens the spectrum of imatinib-resistant subclones targeted.

EXPERIMENTAL DESIGN:

Phase Ib study investigating continuous treatment with cycles of sunitinib (three days) followed by regorafenib (four days) in tyrosine-kinase inhibitor (TKI)-refractory GIST patients. A 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Plasma samples were analyzed for pharmacokinetics and circulating tumor DNA (ctDNA) studies using targeted error correction sequencing (TEC-seq) and ddPCR.

RESULTS:

Of the fourteen patients enrolled, two experienced dose-limiting toxicities at dose level 2 (asymptomatic grade 3 hypophosphatemia). Sunitinib 37.5mg/d and regorafenib 120mg/d was the RP2D. Treatment was well tolerated and no unexpected toxicities resulted from the combination. Stable disease was the best response in four patients, and median progression free survival was 1.9 months. Combined assessment of ctDNA with TEC-seq and ddPCR detected plasma mutations in 11/12 patients (92%). ctDNA studies showed that KIT secondary mutations remain the main mechanism of resistance in TKI-refractory GIST, revealing effective suppression of KIT-mutant subpopulations in patients benefiting from the combination.

CONCLUSIONS:

Sunitinib and regorafenib combination is feasible and tolerable. Rapid alternation of TKIs with complementary activity might be effective when combining drugs with favorable pharmacokinetics, potentially allowing active doses while minimizing adverse events. Serial monitoring with ctDNA may guide treatment in GIST patients.

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