1623MO - Ripretinib intra-patient dose escalation (IPDE) following disease progression provides clinically meaningful progression-free survival (PFS) in gastrointestinal stromal tumor (GIST) in phase I study

Background

Ripretinib is an FDA-approved switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits mutant KIT and PDGFRA kinase signaling. In the phase III study INVICTUS (NCT03353753), ripretinib significantly improved PFS vs placebo in patients (pts) with ≥4th-line GIST. Here, we report the phase I study (NCT02571036) IPDE experience in GIST pts across multiple lines of therapy.

Methods

In this dose-escalation and expansion phase I study, pts with 2^nd, 3^rd, and ≥4^th-line GIST were treated with ripretinib 150 mg QD. Investigator-assessed RECIST response assessments were performed every 2 cycles and pts with progressive disease (PD) could dose escalate to ripretinib 150 mg twice a day (BID). PFS period 1 (PFS1; 150 mg QD) was calculated from Cycle 1, Day 1 to PD; PFS2 (150 mg BID) from date of IPDE to 2^nd PD or death. Treatment-emergent adverse events (TEAEs) were summarized by PFS1 and PFS2 onset periods and compared descriptively.

Results

In the phase I study, 142 GIST pts (2^nd line, n=31; 3^rd line, n=28; and ≥4^th line, n=83) were enrolled in dose-escalation and expansion phases and received at least 1 dose of ripretinib 150 mg QD. In all lines, patients received additional benefit from ripretinib 150 mg BID (table; data as of Aug 31, 2019). TEAEs reported by the 64 pts in PFS1 and PFS2 periods were similar; the most common TEAEs (≥10%) were alopecia, myalgia, nausea, fatigue, palmar-plantar erythrodysesthesia, muscle spasms, rash, weight decreased, abdominal pain, diarrhea, back pain, vomiting and decreased appetite. In PFS2, anemia and dyspnea were also reported in ≥10% of pts. Table: 1623MO

Conclusions

Ripretinib dose escalation to 150 mg BID after PD showed an additional PFS clinical benefit across all treatment lines with a similar safety profile compared to that observed with a 150 mg QD dosing regimen. The phase III INTRIGUE study (NCT03673501) in 2^nd-line GIST is investigating ripretinib vs sunitinib.

Clinical trial identification

NCT02571036.

Editorial acknowledgement

Medical writing and editorial support were provided by Lauren Hanlon, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC (King of Prussia, PA).

Legal entity responsible for the study

Deciphera Pharmaceuticals, LLC.

Funding

Deciphera Pharmaceuticals, LLC.

Disclosure

F. Janku: Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): BioMed Valley Discoveries; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Plexxikon; Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Asana; Research grant/Funding (institution): Astex; Research grant/Funding (institution): SpringBank Pharma; Advisory/Consultancy, Research grant/Funding (institution): Synlogic; Advisory/Consultancy, Research grant/Funding (institution): Sotio; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): SynthoRx; Research grant/Funding (institution): Ideaya; Research grant/Funding (institution): FujiFilm; Research grant/Funding (institution): Merck; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Cardiff Oncology; Advisory/Consultancy: Immunomet. P. Chi: Advisory/Consultancy, Research grant/Funding (institution), Clinical Research Support: Deciphera; Advisory/Consultancy: Exelixis; Research grant/Funding (institution), Clinical Research Support: Novartis; Research grant/Funding (institution), Clinical Research Support: Array. M. Heinrich: Advisory/Consultancy, Speaker Bureau/Expert testimony, Licensing/Royalties, Expert Testimony: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Deciphera; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Blueprint; Advisory/Consultancy: Molecular MD. M. von Mehren: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Deciphera; Advisory/Consultancy, Research grant/Funding (institution): Blueprint; Advisory/Consultancy: Exelexis; Research grant/Funding (institution): Arog; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Gradalis; Research grant/Funding (institution): GenMab; Travel/Accommodation/Expenses: NCCN. R.L. Jones: Honoraria (self), Advisory/Consultancy: Adaptimmune; Honoraria (self), Advisory/Consultancy: Athenex; Honoraria (self), Advisory/Consultancy: Blueprint; Honoraria (self), Advisory/Consultancy: Clinigen; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Epizyme; Honoraria (self), Advisory/Consultancy: Daiichi; Honoraria (self), Advisory/Consultancy: Deciphera; Honoraria (self), Advisory/Consultancy: Immunedesign; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Pharmamar; Honoraria (self), Advisory/Consultancy: Upto Date; Advisory/Consultancy: Tracon; Research grant/Funding (institution), Clinical trial: MSD. K. Ganjoo: Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Foundation Medicine; Research grant/Funding (institution): Deciphera. J. Trent: Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution): Deciphera ; Advisory/Consultancy: Daiichi-Sankyo; Advisory/Consultancy: Epizyme; Advisory/Consultancy, Research grant/Funding (institution): Agios; Research grant/Funding (institution): Plexxicon; Research grant/Funding (institution): Advanchen. H. Gelderblom: Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Debio; Research grant/Funding (institution): Boehringer; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): TEVA. A. Abdul Razak: Research grant/Funding (institution): Deciphera. M. Gordon: Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Advisory/Consultancy, Research grant/Funding (institution): Tracon; Advisory/Consultancy, Research grant/Funding (institution): ImaginAB; Advisory/Consultancy: Imaging Endpoints; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Agenus; Advisory/Consultancy, Research grant/Funding (institution): Salarius; Advisory/Consultancy, Research grant/Funding (institution): RedHill Bipharma; Leadership role, Officer/Board of Directors: CareMission; Research grant/Funding (institution): Medimmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): ABBVIE; Research grant/Funding (institution): Aeglea; Research grant/Funding (institution): Arcus; Research grant/Funding (institution): Astex; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Calithera; Research grant/Funding (institution): CellDex; Research grant/Funding (institution): Corcept; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Endocyte; Research grant/Funding (institution): Five Prime; Research grant/Funding (institution): Genocea; Research grant/Funding (institution): Neon; Research grant/Funding (institution): Plexxicon; Research grant/Funding (institution): Revolution Medicine; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Serono; Research grant/Funding (institution): SynDevRx; Research grant/Funding (institution): Tolero; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Syndax; Research grant/Funding (institution): FujiFilm; Research grant/Funding (institution): Veru; Shareholder/Stockholder/Stock options: Medelis. N. Somaiah: Honoraria (self), Advisory/Consultancy: Deciphera; Advisory/Consultancy: Blueprint. J. Jennings: Full/Part-time employment: Deciphera. K. Shi: Shareholder/Stockholder/Stock options: Alnylam; Shareholder/Stockholder/Stock options: Immunogen; Shareholder/Stockholder/Stock options: Karyopharm; Full/Part-time employment: Deciphera. R. Ruiz-Soto: Shareholder/Stockholder/Stock options, Full/Part-time employment: Deciphera. S. George: Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution): Deciphera; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Exelixis; Leadership role: Alliance Foundation; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Novartis; Shareholder/Stockholder/Stock options: Abbott Labs; Shareholder/Stockholder/Stock options: Allergan; Licensing/Royalties, UpToDate: Wolters Kluwer Health.