Ripretinib (DCC-2618)

Ripretinib (DCC-2618) is an oral inhibitor of KIT, PDGFR alpha, PDGFR beta, KDR, and cFMS that is currently in clinical development.

Manufacturer:  Deciphera Pharmaceuticals  www.deciphera.com

Ripretinib (DCC-2618) is a “switch pocket inhibitor” that has a different mechanism of action than current GIST drugs which are ATP-pocket inhibitors (they compete with ATP to bind a site on the KIT or PDGFRA receptor).  The “switch pocket” is a different location on the KIT or PDGFRA receptor that acts like a light switch to activate the receptor’s signaling. Ripretinib forces the switch to assume the “off” position.  Ripretinib is a novel, oral, potent pan-KIT and PDGFRα kinase inhibitor with activity across a broad range of  mutations. These include primary KIT exons 9, 11, or 17 as well as secondary KIT mutations across exons 13, 14, 17, and 18. The shape of the DCC-2618 molecule is designed to restore accessibility to the binding pocket when it is blocked by the presence of a loop activation mutation.

Ripretiniib is currently being evaluated in two Phase III clinical trials.

• The randomized Phase III “INVICTUS” trial, with the goal of approval as a fourth-line agent (after imatinib, sunitinib, and regorafenib). This is a placebo-controlled trial, with rapid crossover to the drug arm in cases of progression.  Accrual is complete and the study is anticipated to be completed by the end of 2020.
• The randomized open-label Phase III “INTRIGUE” trial, comparing the efficacy of ripretinib (DCC-2618) to sunitinib in GIST patients who progressed on or were intolerant to first-line anticancer treatment with imatinib.  As of 2020 this trial is still recruiting.  The Intrigue trial webpage has additional information.

In addition, ripretinib is also available in an  expanded access program  NCT04148092.  This is an open-label, single-arm, multicenter expanded access study to provide patients who have locally advanced unresectable or metastatic gastrointestinal stromal tumor (GIST) and have received treatment with at least 2 prior Food and Drug Administration (FDA)-approved therapies early access to ripretinib until such time that ripretinib becomes commercially available or the Sponsor chooses to discontinue the program.

In a sarcoma poster session on June 2, 2018 Dr. Suzanne George of Dana Farber Cancer Institute presented a broad analysis of mutational status in a large cohort of heavily pretreated GIST patients enrolled in the Phase I trial of ripretinib (DCC-2618). Both tissue and liquid biopsies were performed and tested via next-generation sequencing. Sixty-two percent of patients with confirmed KIT mutations had secondary mutations at exon 17/18; exon 13/14 mutations were detected in 30%. Multiple patients had mutations at both exons 13/14 and 17/18. The majority of patients in this Phase I trial showed tumor shrinkage and durable progression-free survival. Side effects have been modest, although Deciphera reported that there may be an increased incidence of squamous-cell skin carcinoma in this closely followed population.

As detailed in the poster presented by Scott Wise of Deciphera at the fall 2010 GIST Summit meeting, in cell studies DCC-2618 is able to inhibit not only normal KIT and PDGFRA, but also primary mutations of these genes and the secondary mutations that frequently cause patient resistance to imatinib and sunitinib. Successful tumor control has also been shown in a mouse tumor implantation (xenograft).