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 11 Any KIT exon 9 )

Primary mutations in the ripretinib arm (n = 85) Primary mutations in the placebo arm (n = 44) ) 80 80 %

• In the INVICTUS study, ripretinib significantly % N = 23 (

( N = 86

y Exon 11 + 13 only 8 5 0.04 (0.00, 0.37) t

Exon 9 t

i l

improved progression-free survival (PFS) l

b a

a 60 60 b

compared with placebo (median PFS 6.3 vs 1.0 b

months, hazard ratio [HR] 0.15, P <0.0001), l Exon 11 + 17 20 14 0.05 (0.01, 0.23)

v i

i 40 40 v

reducing the risk of disease progression or death v r

Cell membrane Other (n = 12) Other (n = 5) r

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

Any KIT exon 13 Any KIT exon 17 Exon 9 only 9 3 0.20 (0.04, 1.03) ) 5 )

spectrum of resistance (n = 14) 80 80

% % (

( N = 43 N = 71

y y

t t

i i

l l i

• Here, we report the results of an exploratory i

b b a

a 60 60 Any KIT exon 13 27 16 0.17 (0.08, 0.38)

b b o

analysis from INVICTUS assessing the efficacy of o

r r

p p

TK, tyrosine kinase. Adapted from Ding, et al. 2020; and Corless, et al. 2011. l a

ripretinib across KIT/PDGFRA mutation subgroups 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. INVICTUS study design Figure 3. INVICTUS PFS results done • meaningful activity in patients with ≥fourth-line advanced 100 Ripretinib Placebo GIST with multiple, heterogeneous genetic subsets of Double-Blind Period Open-Label Period Other (n = 14)c Median PFS, months (95% CI) Exon 11 + 17 Exon 9 only KIT/PDGFRA mutations INVICTUS (n = 34)a (n = 12) Exon 9 + 17

) Ripretinib 150 mg QD 6.3 (4.6, 8.1) c 80 Other 12 (14.1) 5 (11.4) 0.38 (0.11, 1.37) d

Dose escalate to (n = 11) %

ripretinib 150 mg BID ( Placebo 1.0 (0.9, 1.7) – Ripretinib showed PFS benefit vs placebo in all primary

y 16.3% t

or i l Ripretinib i 150 mg QD b mutation subgroups Continue ripretinib a 60

(28-day b 150 mg QD cycles) o Exon 11 + 13 only r 39.5% Randomization n = 85 or Dose escalate to p 52.2% 47.8% Disease (n = 13) 2:1 l progression ripretinib 150 mg BID By combining tumor and liquid biopsy (ctDNA), a wide a 0.01 0.1 1 10 15.1% –

by v i 40 blinded Discontinue study or v Stratification independent treatment r In favor of ripretinib In favor of placebo u array of secondary mutations were detected, and Prior central treatments: review S 3 vs ≥4 Continue (BICR)/ Cross over to ripretinib Disease Patients grouped by tumor biopsy analysis only. KIT/PDGFRA WT patients had either no detectable mutations, or mutations in SDH or NF1. Plot represents hazard ECOG PS: unblinding 150 mg QD progression ripretinib 150 mg QD ripretinib showed PFS benefit in all mutation subgroups 0 vs 1 or 2 20 Placebo ratio of PFS by primary mutation with 95% CI error bars. a b (28-day or or KIT other exon includes any mutation in a KIT exon that is not 9 or 11. Includes patients who failed sequencing due to low tumor content and patients with no cycles) specimen. cIncludes other KIT exon mutations, PDGFRA mutations, and KIT/PDGFRA WT patients. Please refer to Figure 4A n = 44 29.1% Overall, these results demonstrate that ripretinib can inhibit a CI, confidence interval; PFS, progression-free survival; QD, once daily; WT, wild-type. • Discontinue study Discontinue study treatment treatment 0 Exon 11 + 13 + 17 0 2 4 6 8 10 12 14 16 18 20 22 24 (n = 25)b broad spectrum of KIT/PDGFRA mutations in patients with Months advanced GIST who have received prior treatment with ≥3 Primary Endpoint Select Secondary Endpoints A subset of patients did not have exon 11 or 9 primary mutations: exon 13 only (n = 2), exon 17 only (n = 1), and exon 13+14+17 (n = 1). Number at risk • Patients in the INVICTUS study were not randomized by stratification of primary mutation status aIncludespatients with exon 11+17 only mutations (n = 32), exon 11+17+18 mutations (n = 1), and exon 9+11+14+17 mutations (n = 1); bIncludespatients with exon 11+13+17 only mutations kinase inhibitors, including imatinib PFS • Objective response rate (ORR) c (per modif ied RECIST based on assessed by BICR (key endpoint) (n = 21), exon 11+13+14+17 mutations (n = 1), exon 11+13+17+18 mutations (n = 2) and exon 11+13+14+17+18 mutations (n = 1); Includespatients with exon 11 only mutations (n = 13) and d BICR) • Overall survival (OS) • Independent of mutational status, in INVICTUS, ripretinib demonstrated a significant improvement in PFS exon 11+18 mutations (n = 1). Includespatients with exon 9+17 only mutations (n = 6), exon 9+14+17 mutations (n = 1), exon 9+14+17+18 mutations (n = 1), exon 9+13+17 mutations (n = 2), Ripretinib 85 65 52 37 28 22 16 12 8 5 2 1 0 compared with placebo (Figure 3) and exon 9+11+14+17 mutations (n = 1). • These results support the proposed broad mechanism of Post-primary follow-up data cut • More than half of the patients in each treatment arm had primary KIT exon 11 mutations (Figure 4A) 9 March 2020 Placebo 44 7 4 1 1 1 0 • Patients from this study had tumors with complex and heterogenous mutational landscapes (Figure 6) action of ripretinib with its specific receptor binding • Ripretinib showed PFS benefit in all primary mutation subgroups compared with placebo (Figure 4B) • By combining tumor and liquid biopsies, a wider array of secondary resistance mutations was detected as compared with 0 2 4 6 8 10 12 14 16 18 20 22 24 • KIT/PDGFRA WT status was similar among the randomization arms (2:1 randomization; 7 ripretinib, 3 placebo) conventional tumor-based mutational analysis properties Presentation only shows data from the double-blind period (highlighted with orange box). • The median PFS for KIT/PDGFRA WT patients receiving ripretinib was 5.7 months, while the median PFS for BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance score; PFS, progression-free • Combined tumor and liquid biopsies allowed for detection of resistance mutations in 73% of patients; resistance mutations KIT/PDGFRA WT patients receiving placebo was 2.1 months survival; RECIST, Response Evaluation Criteria in Solid Tumors; QD, once daily. CI, confidence interval; PFS, progression-free survival; QD, once daily. were detected in up to 4 exons within a single patient

Presented at the 2020 CTOS Virtual Meeting Disclaimer Acknowledgments References Copies of this ePoster obtained through QR, AR, and/or text key codes are for personal use only and may not be reproduced w ithout w ritten permission We w ould like to thank the patients, their families and caregivers, the investigators, and the investigational site staff of the INVICTUS study. The INVICTUS study w as 1) Blay J-Y, et al. Lancet Oncol. 2020;21:923–34; 2) Nishida T, et al, Gastric Cancer. 2016;19:3–14; 3) Serrano C., et al. Ther Adv Med Onc. 2014;6:115– of the authors. sponsored by Deciphera Pharmaceuticals, LLC, Waltham, MA, USA. Writing and editorial support w as provided by Lauren Hanlon, PhD, of AlphaBioCom, LLC, King of Prussia, 27; 4) NCCN Guidelines. Soft Tissue Sarcoma. Version 2.2020; 5) Hemming ML, et al. Ann Oncol. 2018;29:2037–45; 6) Ding H, et al. Oncol Rep. November 18–21, 2020 PA, USA, and w as funded by Deciphera Pharmaceuticals, LLC. 2020;43:751–64; 7) Corless CL, et al. Nat Rev Cancer. 2011;11:865–78.