Patients with gastrointestinal stromal tumours (GIST) showed promising responses to DCC-2618, a potent pan-KIT and PDGFRα kinase switch control inhibitor that has activity across a broad range of tyrosine kinase inhibitor (TKI) treatment-emergent mutations, according to findings from a clinical trial presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
The tyrosine kinase inhibitors (TKIs) that are already approved in the treatment of GIST primarily inhibit either exons 13 and 14 of the ATP binding pocket or a subset of activation loop mutations found in exons 17 and 18 of KIT. These TKIs are not active across both of these regions, which are know to be responsible for imatinib resistance in GIST, explained Dr. Filip Janku, Associate Professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, USA. Therefore, these TKIs leave a gap in the inhibitory coverage of known KIT resistance mutations.
DCC-2618 is a potent pan-KIT and PDGFRa switch control inhibitor that has activity across a broad range of mutations that emerge on imatinib treatment.
Dr. Janku and colleagues conducted this dose-escalation study of oral DCC-2618, at doses ranging from 40 up to 400 mg per day. DCC-2618 was administered once or twice daily for 28 days in patients with pre-treated TKI resistant GIST. The dose escalation phase was followed by an extension phase. The dose selected for expansion was 150 mg per day.
FDG-PET scans were performed at baseline and after 3 weeks of treatment during the escalation phase and computed tomography (CT) scans were done every 2 treatment cycles. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to quantify KIT, PDGFRa and other molecular alterations. The investigators also determined the concordance of the mutational status between plasma cfDNA and tumour tissue.
KIT or PDGFRa-driven GIST was confirmed in 42 and four of the 56 enrolled patients, respectively. The patients had received a mean of 3.4 prior lines of therapy.
Tolerable safety profile seen with DCC-2618
The investigators pointed out that DCC-2618 was well tolerated by patients. The safety analysis consisted of a safety population of 70 patients. The following grade 3/4 events of treatment-emergent adverse effects (TEAEs) >10% of TEAE were reported more than once: anaemia in 19 patients, asymptomatic lipase increase in 13, hypertension in 6, creatinine phosphokinase in 2, and increased unconjugated bilirubin in 2 patients. Both patients with G3 bilirubin are homozygous for 28 *(TA)7/(TA)7 UGT1A1 polymorphism.
Dose limiting toxicities of grade 3/4 lipase increase occurred in 2 of the patients receiving DCC-2618 at 100 mg and 200 mg twice daily and in one patients with CPK on 150 mg per day.
The majority of patients with KIT mutations showed metabolic response
FDG PET scans showed that 22 of the 32 (69%) patients with KIT or PDGFRa-mutant GIST had a partial metabolic response according to EORTC criteria. Of the 37 evaluable patients, 5 patients achieved partial response per RECIST. Fourteen of the 24 evaluable patients receiving DCC-2618 at doses of ³100 mg/day demonstrated progression-free survival lasting more than 6 months, including 9 patients on DCC-2618 at >cycle 10.
The NGS of plasma cfDNA revealed a reduction of mutation allele frequency (MAF) in KIT exons 9, 11, 13, 14, 17, and 18.
Conclusions
DCC-2618 showed encouraging disease control in heavily pre-treated GIST patients demonstrating objective responses and achieving prolonged stable disease.
The notable decreases in MAF of resistance mutations across all exons supports the use of DCC-2618 in patients showing imatinib resistance.
Disclosure
The study was funded by Deciphera.
Reference
1473O – Janku F, et al. Encouraging activity of novel pan-KIT and PDGFRα inhibitor DCC-2618 in patients (pts) with Gastrointestinal Stromal Tumor (GIST).