Phase I study of rapid alternation of sunitinib and regorafenib for the treatment of tyrosine-kinase inhibitor refractory gastrointestinal stromal tumors
Mené sur 14 patients atteints d'une tumeur stromale gastro-intestinale réfractaire aux inhibiteurs de tyrosine kinase, cet essai de phase IB évalue la dose maximale tolérée d'un traitement à base de sunitinib dispensé pendant 3 jours puis de régorafénib dispensé pendant 4 jours, et analyse les caractéristiques pharmacocinétiques de cette combinaison
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.