1473O - Encouraging activity of novel pan-KIT and PDGFRα inhibitor DCC-2618 in patients (pts) with Gastrointestinal Stromal Tumor (GIST)

Date 09 September 2017
Event ESMO 2017 Congress
Session Sarcoma
Topics Drug Development
Cancer in Adolescents
GIST
Sarcoma
Presenter Filip Janku
Citation Annals of Oncology (2017) 28 (suppl_5): v521-v538. 10.1093/annonc/mdx387
Authors F. Janku1, A.R.A. Razak2, M.S. Gordon3, D. Flynn4, M. Kaufman4, J. Pitman5, B. Smith4, N. Somaiah6, J. Jennings7, S. Salah2, D. Westwood5, D. Greensmith5, J. Jacobson5, O. Rosen5, S. George7
  • 1Investigational Cancer Therapeutics, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 2Cancer Clinical Research Unit, Princess Margaret Cancer Centre, M5G2M9 - Toronto/CA
  • 3Medical Oncology, HonorHealth Research Institute, Scottsdale/US
  • 4Research, Deciphera Pharmaceuticals, 66044 - Lawrence/US
  • 5Clinical Research And Development, Deciphera Pharmaceuticals, 02451 - Waltham/US
  • 6Department Of Sarcoma Medical Oncology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 7Center For Sarcoma And Bone Oncology, Dana Farber Cancer Institute, 02215 - Boston/US

Abstract

Background

Approved TKIs primarily inhibit either the KIT ATP binding pocket (exon 13/14) or a subset of activation loop mutations (exon 17/18) and do not demonstrate activity across both regions known to cause imatinib resistance in GIST. This leaves significant liabilities in inhibitory coverage of known KIT resistance mutations. DCC-2618 is a potent kinase switch control inhibitor active across a broad range of mutations which emerge on treatment with approved TKIs.

Methods

This is a dose-escalation study of oral DCC-2618 (QD or BID q28 days) followed by an expansion cohort in pre-treated TKI resistant GIST. During the escalation phase, FDG-PET scans were performed at baseline and after 3 wks of therapy; CT scans every 2 cycles. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to quantify KIT, PDGFRa and other molecular alterations. Concordance of mutational status between plasma cfDNA and tumor tissue was assessed.

Results

33/42 pts enrolled had KIT (30) or PDGFRa- (3) driven GIST and received daily doses ranging from 40-400 mg. Mean prior lines of therapy was 4.8. The dose selected for expansion was 150 mg QD. Safety for all 42 pts was as follows: grade (G) 3/4 adverse effects (regardless of attribution, occurring in > 1 pt) included anemia (15), asymptomatic lipase increase () (7), hypertension (4), creatine phosphokinase (CPK) (2), lower GI hemorrhage (2). Two of the G3/4 lipase at 100 mg BID and 200 mg BID and one CPK at 150 mg QD were DLTs. Of 19 pts with KIT mutant GIST assessed by FDG PET, 15 (79%) had a partial metabolic response per EORTC criteria. 2 out of 23 evaluable patients showed RECIST partial responses (PRs) and 6 out of 11 evaluable patients at doses of ³100 mg/d had RECIST progression free survival of > 6 months (5 pts on therapy at ³Cycle 10). NGS of plasma cfDNA revealed a reduction of mutation allele frequency (MAF) in exons 9, 11, 13, 14, 17 and 18.

Conclusions

DCC-2618 showed encouraging disease control with objective responses and prolonged stable disease in heavily pre-treated GIST patients. The notable decreases in MAF of resistance mutations across all exons supports the use of DCC-2618 beyond imatinib resistance.

Clinical trial identification

NCT02571036

Legal entity responsible for the study

Deciphera

Funding

Deciphera

Disclosure

F. Janku: Research funding: Deciphera; Scientific Advisory Board: Deciphera. D. Flynn, M. Kaufman: Full-time employee of Deciphera Pharmaceuticals. J. Pitman, B. Smith: Full-time employee of Deciphera Pharmaceuticals, stock options at Decipher Pharmaceuticals. All other authors have declared no conflicts of interest.