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Ripretinib Demonstrated Activity Across All KIT/PDGFRA Mutations In

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Ripretinib Demonstrated Activity Across All KIT/PDGFRA Mutations In Ripretinib demonstrated activity across all KIT/PDGFRA mutations in patients with fourth-line advanced gastrointestinal stromal tumor: Analysis from the phase 3 INVICTUS study Patrick Schöffski1, Sebastian Bauer2, Michael Heinrich3, Suzanne George4, John Zalcberg5, Hans Gelderblom6, Cesar Serrano Garcia7, Robin L Jones8, Steven Attia9, Gina D’Amato10, Ping Chi11, Peter Reichardt12, Julie Meade13, Kelvin Shi13, Ying Su13, Rodrigo Ruiz-Soto13, Margaret von Mehren14, Jean-Yves Blay15 1University Hospitals Leuven, Leuven, Belgium; 2West German Cancer Center, Essen, Germany; 3OHSU Knight Cancer Institute, Portland, OR, USA; 4Dana-Farber Cancer Institute, Boston, MA, USA; 5Monash University, Melbourne, VIC, Australia; 6Leiden University Medical Center, Leiden, Netherlands; 7Vall d’Hebron Institute of Oncology, Barcelona, Spain; 8Royal Marsden and Institute of Cancer Research, London, UK; 9Mayo Clinic, Jacksonville, FL, USA; 10Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; 11Memorial Sloan Kettering Cancer Center, New York, NY, USA; 12Sarcoma Center, Helios Klinikum Berlin-Buch, Berlin, Germany; 13Deciphera Pharmaceuticals, LLC, Waltham, MA, USA; 14Fox Chase Cancer Center, Philadelphia, PA, USA; 15Centre Leon Berard, Lyon, France KIT mutation analysis by combined tumor and liquid biopsy INTRODUCTION RESULTS Figure 7. Hazard ratio of PFS with different mutation groups by combined • Patients were grouped into 4 subsets: any KIT exon 9, any KIT exon 11, any KIT exon 13, and any KIT exon 17 tumor and liquid biopsy • Patients were included in multiple groups if they had mutations in two or more exons • Ripretinib is a switch-control tyrosine kinase Figure 1. KIT/PDGFRA structure and ripretinib mechanism of action – For example, a patient that has a primary mutation in exon 11 and a secondary mutation in exon 17 would fall into both the inhibitor designed to broadly inhibit mutant Primary mutation subgroup analysis by tumor biopsy any KIT exon 11 group and the any KIT exon 17 group KIT/PDGFRA kinases (Figure 1) Ripretinib 150 mg QD Placebo Hazard ratio Mutation subgroup (N) (N) (95% CI) In May 2020, the US FDA approved ripretinib for KIT PDGFRA • : Figure 4. Distribution of primary mutations and hazard ratios of PFS the treatment of adult patients with advanced Figure 5. PFS by KIT mutation subgroup by combined tumor and liquid biopsy All patients 85 44 0.16 (0.10, 0.27) gastrointestinal stromal tumor (GIST) who received grouped by primary mutation prior treatment with 3 or more kinase inhibitors, 100 Ripretinib Placebo 100 Any KIT exon 11a 52 34 0.13 (0.07, 0.24) including imatinib1 A) Extracellular domain Any KIT exon 9 Primary mutations in the ripretinib arm (n = 85) Primary mutations in the placebo arm (n = 44) 80 Any KIT exon 11 80 ) • In the INVICTUS study, ripretinib significantly N = 86 ) N = 23 % % ( ( Exon 11 + 13 only 8 5 0.04 (0.00, 0.37) Exon 9 y y t improved progression-free survival (PFS) t i i l l i i b 60 b 60 a compared with placebo (median PFS 6.3 vs 1.0 a b b o o r r p p months, hazard ratio [HR] 0.15, P <0.0001), l Exon 11 + 17 20 14 0.05 (0.01, 0.23) l a a v v i 40 i 40 v reducing the risk of disease progression or death v r Cell membrane Other (n = 12) Other (n = 5) r u u S by 85% and showing a clinically meaningful 14.1% 11.4% S p <0.0001 p = 0.0023 KIT exon 11 KIT exon 11 Exon 11 + 13 + 17 16 9 0.22 (0.08, 0.58) improvement in overall survival (OS, median OS KIT/PDGFRA WT (n = 7) KIT/PDGFRA WT (n = 3) 20 20 Juxtamembrane domain Exon 11 Exon 12 (n = 47) KIT other exona (n = 2) (n = 28) 1 PDGFRA(n = 3) 15.1 vs 6.6 months, HR 0.36) As shown in preclinical studies, ripretinib KIT other exona (n = 2) Exon 13 Not av ailable/not 0 0 Otherb 8 6 0.07 (0.01, 0.66) • KIT/PDGFRA mutations are early oncogenic TK I domain Exon 14 done (n = 5) 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 ATP-binding pocket Exon 14 11.4% Months Months events in patients with GIST and remain oncogenic 55.3% Number at risk Number at risk 2–4 drivers in the metastatic setting (Figure 1) Not av ailable/not 14.1% Exon 11--Ripretinib 52 41 35 26 21 16 12 9 6 3 0 Exon 9--Ripretinib 16 10 7 4 2 1 0 Any KIT exon 9a 16 7 0.22 (0.08, 0.63) a done (n = 12) Exon 11--Placebo 34 4 3 0 0 0 0 0 0 0 0 Exon 9--Placebo 7 1 0 0 0 0 0 Ripretinib • Clonal evolution of additional mutations represent 63.6% 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 13.6% the major mechanism of resistance to KIT tyrosine Exon 17 KIT exon 9 Exon 9 + 17 7 4 0.21 (0.05, 0.95) TK II domain Exon 18 16.5% (n = 6) 100 100 kinase inhibitors, and previously approved drugs Activation loop Exon 18 inhibit only a limited number of mutations on the KIT exon 9 5 Any KIT exon 13 Any KIT exon 17 Exon 9 only 9 3 0.20 (0.04, 1.03) spectrum of resistance (n = 14) 80 80 ) ) N = 43 N = 71 % % ( ( y y t t i i l • Here, we report the results of an exploratory l i i b b 60 60 a a Any KIT exon 13 27 16 0.17 (0.08, 0.38) b analysis from INVICTUS assessing the efficacy of b o o r r p p TK, tyrosine kinase. l ripretinib across KIT/PDGFRA mutation subgroups Adapted from Ding, et al. 2020; and Corless, et al. 2011. l a a v v i i 40 40 v v r r u u Any KIT exon 17 44 27 0.14 (0.07, 0.28) S S p <0.0001 p <0.0001 B) 20 20 0.001 0.01 0.1 1 10 METHODS 0 0 Baseline primary Ripretinib 150 mg QD Placebo Hazard ratio of PFS 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 Months Months mutation n (%) n (%) (95% CI) Number at risk Number at risk In favor of ripretinib In favor of placebo • INVICTUS (NCT03353753) is a phase 3, randomized, double-blind, placebo-controlled trial in which patients with advanced GIST who were previously treated Exon 13--Ripretinib 27 19 14 9 8 5 4 4 2 2 1 1 0 Exon 17--Ripretinib 44 36 29 23 17 12 10 7 4 2 0 with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg once daily or placebo (Figure 2) Exon 13--Placebo 16 2 1 0 0 0 0 0 0 0 0 0 0 Exon 17--Placebo 27 5 3 0 0 0 0 0 0 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 • Tumor biopsies were collected after patients received their last anticancer therapy prior to entry into the phase 3 INVICTUS study KIT exon 11 47 (55.3) 28 (63.6) 0.15 (0.08, 0.29) Patients may be included in multiple subgroups if they had multiple mutations. Due to low numbers, patients with any KIT exon 14 (n = 6), any KIT exon 18 (n = 6), Patients may be included in multiple subgroups if they had multiple mutations. Due to low numbers, patients with any KIT exon 14 (n = 6), any KIT exon 18 (n = 6), or PDGFRA (n = 3) or PDGFRA (n = 3) mutations were excluded from this analysis. Please refer to Figure 6 for each subgroup. • Tumor biopsies were sequenced using a next-generation sequencing panel (324 genes) from FoundationOne mutations were excluded from this analysis. aOne patient had both KIT exon 11 and KIT exon 9 mutations detected in liquid biopsy. bIncludesexon 11 only mutations (n = 13) and exon 11+18 mutations (n = 1). c • Plasma circulating tumor DNA (ctDNA) was collected predose on Cycle 1 Day 1, and was profiled using a next-generation sequencing liquid biopsy assay (73 PFS, progression-free survival. Positive for KIT exon 9 mutation and negative for KIT exon 17 mutation. CI, confidence interval; PFS, progression-free survival; QD, once daily. genes) from Guardant360 • Primary mutation subgroups and KIT/PDGFRA wild-type (WT) status were determined via tumor biopsy • Patients receiving ripretinib showed PFS benefit over placebo in all assessed subgroups (Figure 5) • The HRs of PFS within different mutation subgroups all favored treatment with ripretinib, which is in line with the primary outcome of this clinical trial (Figure 7) • Secondary mutation subgroups were determined by combining results from tumor and liquid biopsies KIT exon 9 14 (16.5) 6 (13.6) 0.22 (0.07, 0.69) • Correlations between KIT/PDGFRA mutational status and clinical outcomes from the INVICTUS study were assessed Figure 6. Secondary mutations for patients with primary KIT exon 11 or 9 mutations by • This retrospective analysis was not part of the study protocol combined tumor and liquid biopsy CONCLUSIONS • The data cutoff for this analysis was March 9, 2020 Subgroup with KIT exon 11 mutation detected (n = 86) Subgroup with KIT exon 9 mutation detected (n = 23) Not available/not b 12 (14.1) 5 (11.4) 0.13 (0.02, 0.66) In this exploratory analysis, ripretinib demonstrated clinically Figure 2.
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