Abstract C077: Updated results of phase 1 study of ripretinib (DCC-2618), a broad-spectrum KIT and PDGFRA inhibitor, in patients with gastrointestinal stromal tumor (GIST) by line of therapy (NCT02571036)
Authors: Chi Ping , Janku Filip , Heinrich Michael , Ganjoo Kristen , Gelderblom Hans , Gordon Michael , Jones Robin , Razak Albiruni , Trent Jonathan , Mehren Margaret von , Hu Simin , Su Ying , Ruiz-Soto Rodrigo , George Suzanne 
Published: March 2020

Abstract
Objective: Ripretinib (DCC-2618) is a kinase switch control inhibitor designed to broadly inhibit KIT and PDGFRA mutations. Based on clinical activity observed in heavily pretreated patients (pts) with GIST in a Phase 1 study (NCT02571036), ripretinib is under evaluation in two Phase 3 studies: INVICTUS (NCT03353753) in ≥4th-line pts and INTRIGUE (NCT03673501) in 2nd-line pts, each at the recommended dose of 150 mg once daily (QD). This abstract reports updated results from the escalation and expansion phases of the Phase 1 study for pts treated with ≥100 mg daily dose. Methods: The Phase 1 study includes a dose-escalation phase that tested oral ripretinib QD or twice daily (BID) in 28-day cycles, followed by an expansion phase with the recommended Phase 2 dose (RP2D) of 150 mg QD in 6 cohorts, including cohorts for pts with GIST based on prior regimens (2nd/ 3rd, 4th, and &gt;4th-line). Local Response Evaluation Criteria in Solid Tumors (RECIST) response assessments were performed every 2 cycles and pts who progressed per RECIST in the expansion cohorts were allowed to dose escalate to 150 mg BID. Results: At a cut-off date of March 01, 2019, 179 pts with GIST in the escalation and expansion phases (median follow-up of 10.4 months; range, 0.1–32.3) were enrolled at dose levels of ≥100 mg daily with KIT-driven (169 pts), PDGFRA-driven (9 pts), or wild-type-driven GIST (1 pt). Of 178 pts with GIST treated at the ≥100 mg daily dose (1 pt was not included in the intent-to-treat population as the pt only participated in the food effect portion of the study), there were 37 2nd-line pts, 31 3rd-line pts, 60 4th-line pts, and 50 &gt;4th-line pts. The objective response rate (ORR) by best response was 30% in 2nd-line pts (n=11; includes 3 unconfirmed responses), 23% in 3rd-line pts (n=7; includes 3 unconfirmed responses), and 11% in ≥4th-line pts (n=12; includes 4 unconfirmed responses); responses ≥4th-line include 15% in 4th-line pts (n=9; includes 4 unconfirmed responses) and 6% in &gt;4th-line pts (n=3; includes no unconfirmed responses). In 2nd-line pts, the disease control rate (DCR) was 31% (n=9) at 52 weeks. The median progression-free survival (mPFS) was 42 weeks in 2nd-line pts, 40 weeks in 3rd-line pts, and 24 weeks in ≥4th-line pts (includes 30 weeks in 4th-line pts and 16 weeks in &gt;4th-line pts). In 2nd-line pts, the median duration of response was 80 weeks and the median duration of treatment was 44 weeks. For any line, 13% of pts (n=24) experienced treatment-emergent adverse events (TEAEs) leading to study treatment discontinuation, 17% of pts (n=31) experienced TEAEs leading to dose reduction and 49% (n=88) had TEAEs leading to study drug interruption. Grade 3 or 4 TEAEs in &gt;5% of pts were lipase increased (18%; n=33), anemia (11%; n=20), hypertension (7%; n=13), and abdominal pain (6%; n=11). Conclusion: In this Phase 1 study, ripretinib demonstrated encouraging clinical benefit (as measured by mPFS, ORR [best response] and DCR) and was generally well-tolerated in pts with GIST treated in the 2nd-line or later. Preliminary data from this Phase 1 study further supports testing in the ongoing Phase 3 study in 2nd-line GIST.
Citation Format: Ping Chi, Filip Janku, Michael Heinrich, Kristen Ganjoo, Hans Gelderblom, Michael Gordon, Robin Jones, Albiruni Razak, Jonathan Trent, Margaret von Mehren, Simin Hu, Ying Su, Rodrigo Ruiz-Soto, Suzanne George. Updated results of phase 1 study of ripretinib (DCC-2618), a broad-spectrum KIT and PDGFRA inhibitor, in patients with gastrointestinal stromal tumor (GIST) by line of therapy (NCT02571036) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C077. doi:10.1158/1535-7163.TARG-19-C077