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 <ul style="display: flex;"><li style="flex:1">4</li><li style="flex:1">5</li><li style="flex:1">9</li></ul>1University Hospitals Leuven, Leuven, Belgium; 2West German Cancer Center, Essen, Germany; 3OHSU Knight Cancer Institute, Portland, OR, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Monash 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; Mayo 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, HeliosKlinikum 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 • Patients were grouped into 4 subsets: any KIT exon 9, any KIT exon 11, any KIT exon 13, and any KIT exon 17 Figure 7. Hazard ratio of PFS with different mutation groups by combined tumor and liquid biopsy INTRODUCTION RESULTS • Patients were included in multiple groups if they had mutations in two or more exons • Ripretinib is a switch-control tyrosine kinase inhibitor designed to broadly inhibit mutant KIT/PDGFRA kinases (Figure 1) 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 Primary mutation subgroup analysis by tumor biopsy any KIT exon 11 group and the any KIT exon 17 group <ul style="display: flex;"><li style="flex:1">Ripretinib150 mg QD Placebo </li><li style="flex:1">Hazard ratio </li></ul><ul style="display: flex;"><li style="flex:1">(95% CI) </li><li style="flex:1">Mutation subgroup </li><li style="flex:1">(N) </li><li style="flex:1">(N) </li></ul><ul style="display: flex;"><li style="flex:1">KIT </li><li style="flex:1">PDGFRA </li></ul>• In May 2020, the US FDA approved ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib1 :Figure 4. Distribution of primary mutations and hazard ratios of PFS grouped by primary mutation <ul style="display: flex;"><li style="flex:1">All patients </li><li style="flex:1">85 </li><li style="flex:1">44 </li><li style="flex:1">0.16 (0.10, 0.27) </li></ul>0.13 (0.07, 0.24) 0.04 (0.00, 0.37) 0.05 (0.01, 0.23) 0.22 (0.08, 0.58) 0.07 (0.01, 0.66) 0.22 (0.08, 0.63) 0.21 (0.05, 0.95) 0.20 (0.04, 1.03) 0.17 (0.08, 0.38) 0.14 (0.07, 0.28) Figure 5. PFS by KIT mutation subgroup by combined tumor and liquid biopsy <ul style="display: flex;"><li style="flex:1">Ripretinib </li><li style="flex:1">Placebo </li></ul>100 80 60 40 20 0100 80 60 40 20 0Any KIT exon 11a Exon 11 + 13 only Exon 11 + 17 52 8 34 5A) Extracellular domain Any KIT exon 9 N = 23 Any KIT exon 11 N = 86 <ul style="display: flex;"><li style="flex:1">Primary mutations in the ripretinib arm (n = 85) </li><li style="flex:1">Primary mutations in the placebo arm (n = 44) </li></ul>• In the INVICTUS study, ripretinib significantly improved progression-free survival (PFS) compared with placebo (median PFS 6.3 vs 1.0 months, hazard ratio [HR] 0.15, P <0.0001), reducing the risk of disease progression or death by 85% and showing a clinically meaningful improvement in overall survival (OS, median OS 15.1 vs 6.6 months, HR 0.36)1 Exon 9 20 16 814 9Cell membrane Other (n = 12) 14.1% Other (n = 5) 11.4% <ul style="display: flex;"><li style="flex:1">p <0.0001 </li><li style="flex:1">p = 0.0023 </li></ul>Exon 11 + 13 + 17 Otherb <ul style="display: flex;"><li style="flex:1">KIT exon 11 </li><li style="flex:1">KIT exon 11 </li></ul>KIT/PDGFRAWT (n = 3) KIT/PDGFRAWT (n = 7) PDGFRA(n = 3) KIT other exona (n = 2) <ul style="display: flex;"><li style="flex:1">Exon 11 </li><li style="flex:1">Exon 12 </li></ul>KIT other exona (n = 2) <ul style="display: flex;"><li style="flex:1">(n = 28) </li><li style="flex:1">(n = 47) </li></ul>Juxtamembrane domain As shown in preclinical studies, ripretinib Not available/not done (n = 5) Exon 13 Exon 14 6TK I domain ATP-bindingpocket Exon 14 <ul style="display: flex;"><li style="flex:1">0</li><li style="flex:1">2</li><li style="flex:1">4</li><li style="flex:1">6</li><li style="flex:1">8</li><li style="flex:1">10 </li><li style="flex:1">12 </li></ul>• KIT/PDGFRA mutations are early oncogenic events in patients with GIST and remain oncogenic drivers in the metastatic setting2–4 (Figure 1) <ul style="display: flex;"><li style="flex:1">0</li><li style="flex:1">2</li><li style="flex:1">4</li><li style="flex:1">6</li><li style="flex:1">8</li><li style="flex:1">10 </li><li style="flex:1">12 </li><li style="flex:1">14 </li><li style="flex:1">16 </li><li style="flex:1">18 </li><li style="flex:1">20 </li></ul>Months Months 11.4% Number at risk 16 Number at risk 55.3% Any KIT exon 9a Exon 9 + 17 16 7 7Exon 11--Ripretinib Exon 11--Placebo 52 34 041 435 326 021 016 012 090603000Exon 9--Ripretinib Exon 9--Placebo 10 1704406208100014.1% Not available/not donea (n = 12) 70Ripretinib • Clonal evolution of additional mutations represent the major mechanism of resistance to KIT tyrosine kinase inhibitors, and previously approved drugs inhibit only a limited number of mutations on the spectrum of resistance5 63.6% <ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">4</li><li style="flex:1">6</li><li style="flex:1">8</li><li style="flex:1">10 </li><li style="flex:1">12 </li><li style="flex:1">14 </li><li style="flex:1">16 </li><li style="flex:1">18 </li><li style="flex:1">20 </li><li style="flex:1">2</li><li style="flex:1">10 </li><li style="flex:1">12 </li></ul>13.6% KIT exon 9 (n = 6) Exon 17 Exon 18 4TK II domain Activation loop Exon 18 16.5% 100 80 60 40 20 0 100 80 60 40 20 0KIT exon 9 (n = 14) <ul style="display: flex;"><li style="flex:1">Exon 9 only </li><li style="flex:1">9</li><li style="flex:1">3</li></ul>Any KIT exon 13 N = 43 Any KIT exon 17 N = 71 • Here, we report the results of an exploratory analysis from INVICTUS assessing the efficacy of ripretinib across KIT/PDGFRA mutation subgroups Any KIT exon 13 Any KIT exon 17 27 44 16 27 TK, tyrosine kinase. Adapted from Ding, et al.2020; andCorless, et al. 2011. <ul style="display: flex;"><li style="flex:1">p <0.0001 </li><li style="flex:1">p <0.0001 </li></ul>B) 10 In favor of ripretinib In favor of placebo <ul style="display: flex;"><li style="flex:1">0.001 0.01 0.1 </li><li style="flex:1">1</li></ul>METHODS <ul style="display: flex;"><li style="flex:1">0</li><li style="flex:1">2</li><li style="flex:1">4</li><li style="flex:1">6</li><li style="flex:1">8</li><li style="flex:1">10 12 14 16 18 20 22 24 </li></ul>Months <ul style="display: flex;"><li style="flex:1">0</li><li style="flex:1">2</li><li style="flex:1">4</li><li style="flex:1">6</li><li style="flex:1">8</li><li style="flex:1">10 </li><li style="flex:1">12 </li><li style="flex:1">14 </li><li style="flex:1">16 </li><li style="flex:1">18 </li><li style="flex:1">20 </li></ul>Baseline primary mutation Ripretinib150 mg QD n (%) Placebo n (%) Hazard ratio of PFS (95% CI) Months <ul style="display: flex;"><li style="flex:1">Number at risk </li><li style="flex:1">Number at risk </li></ul><ul style="display: flex;"><li style="flex:1">Exon 13--Ripretinib 27 </li><li style="flex:1">19 </li></ul>214 19068085040402020101000Exon 17--Ripretinib Exon 17--Placebo 44 27 036 5<ul style="display: flex;"><li style="flex:1">29 </li><li style="flex:1">23 </li></ul>017 012 010 070402000• INVICTUS (NCT03353753) is a phase 3, randomized, double-blind, placebo-controlled trial in which patients with advanced GIST who were previously treated Exon 13--Placebo 16 034with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg once daily or placebo (Figure 2) <ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">4</li><li style="flex:1">10 </li><li style="flex:1">12 </li><li style="flex:1">14 </li><li style="flex:1">16 </li><li style="flex:1">18 </li><li style="flex:1">20 </li><li style="flex:1">22 </li><li style="flex:1">24 </li><li style="flex:1">2</li><li style="flex:1">6</li><li style="flex:1">8</li><li style="flex:1">10 </li><li style="flex:1">12 </li><li style="flex:1">14 </li><li style="flex:1">16 </li><li style="flex:1">18 </li><li style="flex:1">20 </li></ul>• Tumor biopsies were collected after patients received their last anticancer therapy prior to entry into the phase 3 INVICTUS study Patientsmay be includedin multiplesubgroupsif they had multiple mutations. Due to low numbers, patientswith any KIT exon 14 (n = 6), any KIT exon 18 (n = 6), or PDGFRA (n = 3) mutationswere excluded from thisanalysis. Please refer to Figure 6 for each subgroup. KIT exon 11 47 (55.3) 14 (16.5) 12 (14.1) 12 (14.1) <ul style="display: flex;"><li style="flex:1">28 (63.6) </li><li style="flex:1">0.15 (0.08, 0.29) </li></ul>0.22 (0.07, 0.69) 0.13 (0.02, 0.66) Patientsmay be includedin multiplesubgroupsif they had multiple mutations. Due to low numbers, patientswith any KIT exon 14 (n = 6), any KIT exon 18 (n = 6), or PDGFRA (n = 3) mutationswere excludedfrom thisanalysis. PFS, progression-free survival. • Tumor biopsies were sequenced using a next-generation sequencing panel (324 genes) from FoundationOne aOne patient had both KIT exon11 and KIT exon 9 mutationsdetected inliquidbiopsy. bIncludesexon 11 only mutations(n = 13) and exon 11+18 mutations(n = 1). cPositive for KIT exon 9 mutation and negative for KIT exon17 mutation.CI, confidence interval; PFS, progression-free survival; QD, once daily. • 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 genes) from Guardant360 • 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 • Primary mutation subgroups and KIT/PDGFRA wild-type (WT) status were determined via tumor biopsy • Secondary mutation subgroups were determined by combining results from tumor and liquid biopsies • Correlations between KIT/PDGFRA mutational status and clinical outcomes from the INVICTUS study were assessed • This retrospective analysis was not part of the study protocol the primary outcome of this clinical trial (Figure 7) KIT exon 9 6 (13.6) 5 (11.4) 5 (11.4) Figure 6. Secondary mutations for patients with primary KIT exon 11 or 9 mutations by combined tumor and liquid biopsy CONCLUSIONS • The data cutoff for this analysis was March 9, 2020 Subgroup with KIT exon 9 mutation detected (n = 23) Subgroup with KIT exon 11 mutation detected (n = 86) Not available/not doneb • In this exploratory analysis, ripretinib demonstrated clinically meaningful activity in patients with ≥fourth-line advanced GIST with multiple, heterogeneous genetic subsets of KIT/PDGFRA mutations <ul style="display: flex;"><li style="flex:1">Figure 2. INVICTUS study design </li><li style="flex:1">Figure 3. INVICTUS PFS results </li></ul><ul style="display: flex;"><li style="flex:1">Ripretinib </li><li style="flex:1">Placebo </li></ul>100 80 60 40 20 0Other (n = 14)c Exon 11 + 17 Double-Blind Period Open-Label Period Median PFS, months (95% CI) Exon 9 only (n = 12) INVICTUS (n = 34)a Exon 9 + 17 (n = 11)d Otherc 0.38 (0.11, 1.37) Ripretinib 150 mg QD 6.3 (4.6, 8.1) Placebo 1.0 (0.9, 1.7) Dose escalate to ripretinib 150 mg BID – Ripretinib showed PFS benefit vs placebo in all primary 16.3% or Ripretinib mutation subgroups 150 mg QD Continue ripretinib (28-day 150 mg QD cycles) Exon 11 + 13 only 39.5% Randomization n = 85 Dose escalate to ripretinib 150 mg BID <ul style="display: flex;"><li style="flex:1">52.2% </li><li style="flex:1">47.8% </li></ul>or Disease progression (n = 13) 2:1 – By combining tumor and liquid biopsy (ctDNA), a wide array of secondary mutations were detected, and ripretinib showed PFS benefit in all mutation subgroups 15.1% <ul style="display: flex;"><li style="flex:1">0.01 </li><li style="flex:1">0.1 </li><li style="flex:1">1</li><li style="flex:1">10 </li></ul>by Discontinue study blinded independent central or Stratification Prior treatments: 3 vs ≥4 ECOG PS: 0 vs 1 or 2 treatment <ul style="display: flex;"><li style="flex:1">In favor of ripretinib </li><li style="flex:1">In favor of placebo </li></ul>review (BICR)/ unblinding Continue ripretinib 150 mg QD Cross over to ripretinib 150 mg QD Disease progression Patientsgrouped by tumor biopsy analysisonly. KIT/PDGFRA WT patientshad either no detectable mutations, or mutationsin SDH or NF1. Plot representshazard ratio of PFS by primary mutation with 95% CI error bars. aKIT other exon includesany mutation in a KIT exon that isnot 9 or 11. bIncludespatientswho failed sequencingdue to low tumor content andpatientswith no specimen. cIncludesotherKIT exon mutations, PDGFRA mutations, and KIT/PDGFRA WT patients. Please referto Figure 4A CI, confidenceinterval;PFS, progression-free survival; QD, once daily; WT, wild-type. Placebo (28-day cycles) n = 44

Ripretinib Demonstrated Activity Across All KIT/PDGFRA Mutations In

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