DCC-2618 is an orally administered kinase switch control inhibitor for the treatment of gastrointestinal stromal tumors (GIST), advanced systemic mastocytosis (ASM), gliomas, and other solid tumors driven by KIT kinase or PDGFRα kinase. Deciphera is focusing the development of DCC-2618 in patient subgroups where significant unmet medical need exists despite currently available therapies.
While approved kinase inhibitors control certain initiating and drug resistance-causing mutations in KIT and PDGFRα, the kinases that drive disease progression in most GIST patients, these approved drugs fail to inhibit all known mutations. DCC-2618 was specifically designed to improve the treatment of GIST patients by inhibiting the full spectrum of the known mutations in KIT and PDGFRα. DCC-2618 is a KIT and PDGFRα inhibitor that blocks initiating KIT mutations in exons 9, 11, 13, 14, 17, and 18, known to be present in GIST patients, and the D816V exon 17 mutation known to be present in ASM patients. DCC-2618 inhibits PDGFRα mutations in exon 18, including the D842V mutation that drives a subset of GIST.
|Tumor Type||Target||Status||Retained Rights|
|GIST – 4th Line||KIT and PDGFRα||Phase 3 Pivotal Trial – Ongoing||Worldwide|
|GIST – 2nd Line||KIT and PDGFRα||Phase 3 Pivotal Trial – Planned||Worldwide|
|GIST, ASM, gliomas||KIT and PDGFRα||Phase 1 Expansion – Ongoing||Worldwide|
|Solid Tumors||KIT and PDGFRα||Phase 1 Expansion – Ongoing||Worldwide|
Rationale for DCC-2618 in GIST:
GISTs are the most common sarcoma of the gastrointestinal tract and present most often in the stomach or small intestine. According to the American Cancer Society, in 2015 approximately 5,000 patients were newly diagnosed with GIST in the United States. Estimates for 5-year survival range from 48% to 90% depending upon the stage of the disease at diagnosis.
Metastatic KIT-driven GIST is a disease characterized by many mutations in KIT, with over 90% of individual KIT-driven GIST patients harboring multiple mutations that drive progression of their disease. The complex heterogeneity of KIT mutations within individual tumors and individual patients is a major cause of resistance to existing therapies. DCC-2618 was designed to inhibit the full spectrum of the known KIT mutations.
In PDGFRα-driven GIST, there are no approved therapies. The primary PDGFRα mutations are mostly insensitive to imatinib and other drugs approved for GIST and clinical data regarding the emergence of secondary drug resistance mutations is limited and uncertain. DCC-2618 has been designed as a PDGFRα switch control inhibitor, which compared to a traditional kinase inhibitor, reduces the likelihood of treatment-emergent mutations.
DCC-2618 is being assessed in both a pivotal Phase 3 study for the treatment of fourth-line plus GIST patients, where there are no approved therapies, and in an ongoing Phase 1 trial in patients with advanced malignancies. In September 2017 findings from the ongoing Phase 1 trial were presented at the ESMO 2017 Congress. In 57 heavily pre-treated GIST patients shown to harbor a broad range of KIT and PDGFRα mutations, who received at least 100 mg of DCC-2618 daily, 91% of the evaluable patients (30 of 33) had a best response assessed as stable disease or a partial response. In addition, we observed control rate (DCR) of 76% at 12 weeks in 19 of 25 patients and 57% at 24 weeks in 12 of 21 patients. Disease control includes stable disease, PRs and complete responses measured by a CT or MRI scan and assessed by RECIST. Based on results presented in June at the 2017 ASCO Meeting a dose of 150 mg once daily (QD) was selected for both the Phase 3 pivotal trial and the expansion cohorts in the ongoing Phase 1 trial that are evaluating DCC-2618 in patients with different stages of GIST, as well as in patients with advanced systemic mastocytosis (ASM), gliomas, including GBM, and other solid tumors driven by KIT or PDGFRα. The DCRs described above are based on investigator assessment of tumor response in a limited number of GIST patients and may not be predictive of or consistent with the results of later trials, however they compare favorably with published results for other kinase inhibitors in less advanced GIST patients (see Figure 1 below).
(Blanke et al. 2008)
(Demetri et al. 2012)
(Demetri et al. 2013)
|Disease Control Rate||83.7%*||60.0%*||52.6%**|
|TTP Time To Progression||PFS Progression Free Survival||ORR Objective Response Rate||SD Stable Disease|
* Time point not disclosed **At 12 weeks
Based on these results and the high level of unmet need, Deciphera has initiated a Phase 3 clinical study in fourth-line GIST and plans to initiate a Phase 3 clinical trial in second-line GIST.
Rationale for DCC-2618 in Glioblastoma Multiforme (GBM):
Gliomas, including GBM, are among the most severe types of brain cancer. According to Central Brain Tumor Registry of the United States (CBTRUS), approximately 12,000 patients are projected to be diagnosed in 2016 with estimates for 1-year survival of around 40% and for 2-year survival of 15% to 20%. In approximately 15% of these patients, their disease is driven by chromosome 4 genetic amplifications that increases the activity of PDGFRα, KIT and closely related kinases.
In the dose escalation stage of the Phase 1 trial of DCC-2618, we observed a partial response in one GBM patient who had a 6-fold triple chromosome 4 amplification, and had progressed after three months of standard of care treatment. Based on this encouraging observation, Deciphera continues to evaluate the therapeutic potential of DCC-2618 in a Phase 1 expansion study that includes GBM patients.
Rationale for DCC-2618 in Advanced Systemic Mastocytosis (ASM):
Mastocytosis is a disease characterized by an abnormal accumulation of mast cells, a type of white blood cell, located in peripheral tissues and organs. Mast cells store components that mediate inflammatory and allergic responses. There are several subtypes of the disease, and outcomes can vary significantly by subtype.
Approximately 94% of SM patients are reported to have a somatic D816V mutation in KIT. This D816V mutation is a gain-of-function mutation in the KIT activation switch, which leads to unregulated KIT activation. The KIT receptor, which is widely expressed on mast cells, stimulates signaling pathways that control cell growth, differentiation and survival. The gain-of-function mutation, D816V, enables mast cells to proliferate in the absence of normal activation signals.
As a broad spectrum KIT inhibitor, DCC-2618 potently inhibits the D816V mutation. We are enrolling ASM patients within an expansion cohort of our Phase 1 trial.