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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 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

  • 4
  • 5
  • 9

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

  • Ripretinib150 mg QD Placebo
  • Hazard ratio

  • (95% CI)
  • Mutation subgroup
  • (N)
  • (N)

  • KIT
  • PDGFRA

• 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

  • All patients
  • 85
  • 44
  • 0.16 (0.10, 0.27)

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

  • Ripretinib
  • Placebo

100

80 60 40 20
0

100
80 60 40 20
0

Any KIT exon 11a

Exon 11 + 13 only Exon 11 + 17
52
8
34
5

A)

Extracellular domain

Any KIT exon 9 N = 23
Any KIT exon 11 N = 86

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

• 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

8

14
9

Cell membrane

Other (n = 12)
14.1%
Other (n = 5)
11.4%

  • p <0.0001
  • p = 0.0023

Exon 11 + 13 + 17

Otherb

  • KIT exon 11
  • KIT exon 11

KIT/PDGFRAWT (n = 3)

KIT/PDGFRAWT (n = 7)

PDGFRA(n = 3)

KIT other exona (n = 2)

  • Exon 11
  • Exon 12

KIT other exona (n = 2)

  • (n = 28)
  • (n = 47)

Juxtamembrane domain

As shown in preclinical studies, ripretinib

Not available/not done (n = 5)

Exon 13

Exon 14

6

TK I domain ATP-bindingpocket
Exon 14

  • 0
  • 2
  • 4
  • 6
  • 8
  • 10
  • 12

• KIT/PDGFRA mutations are early oncogenic events in patients with GIST and remain oncogenic drivers in the metastatic setting2–4 (Figure 1)

  • 0
  • 2
  • 4
  • 6
  • 8
  • 10
  • 12
  • 14
  • 16
  • 18
  • 20

Months

Months

11.4%

Number at risk

16

Number at risk

55.3%

Any KIT exon 9a

Exon 9 + 17
16
7
7

Exon 11--Ripretinib

Exon 11--Placebo

52

34

0

41

4

35

3

26

0

21

0

16

0

12

0

9

0

6

0

3

0

0

0

Exon 9--Ripretinib

Exon 9--Placebo

10

1

7

0

4

4

0

6

2

0

8

1

0

0

0

14.1%

Not available/not donea (n = 12)

7

0

Ripretinib

• 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%

  • 2
  • 4
  • 6
  • 8
  • 10
  • 12
  • 14
  • 16
  • 18
  • 20
  • 2
  • 10
  • 12

13.6%

KIT exon 9

(n = 6)

Exon 17

Exon 18

4

TK II domain

Activation loop

Exon 18

16.5%

100
80 60 40 20
0
100
80 60 40 20
0

KIT exon 9 (n = 14)

  • Exon 9 only
  • 9
  • 3

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.

  • p <0.0001
  • p <0.0001

B)

10

In favor of ripretinib In favor of placebo

  • 0.001 0.01 0.1
  • 1

METHODS

  • 0
  • 2
  • 4
  • 6
  • 8
  • 10 12 14 16 18 20 22 24

Months

  • 0
  • 2
  • 4
  • 6
  • 8
  • 10
  • 12
  • 14
  • 16
  • 18
  • 20

Baseline primary mutation
Ripretinib150 mg QD n (%)
Placebo n (%)
Hazard ratio of PFS (95% CI)

Months

  • Number at risk
  • Number at risk

  • Exon 13--Ripretinib 27
  • 19

2

14

1

9

0

6

8

0

8

5

0

4

0

4

0

2

0

2

0

1

0

1

0

0

0

Exon 17--Ripretinib

Exon 17--Placebo

44

27

0

36

5

  • 29
  • 23

0

17

0

12

0

10

0

7

0

4

0

2

0

0

0

• 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

0

3

4

with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg once daily or placebo (Figure 2)

  • 2
  • 4
  • 10
  • 12
  • 14
  • 16
  • 18
  • 20
  • 22
  • 24
  • 2
  • 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

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)

  • 28 (63.6)
  • 0.15 (0.08, 0.29)

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

  • Figure 2. INVICTUS study design
  • Figure 3. INVICTUS PFS results

  • Ripretinib
  • Placebo

100

80 60 40 20
0

Other (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

  • 52.2%
  • 47.8%

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%

  • 0.01
  • 0.1
  • 1
  • 10

by

Discontinue study

blinded independent central

or

Stratification

Prior treatments:

3 vs ≥4

ECOG PS: 0 vs 1 or 2

treatment

  • In favor of ripretinib
  • In favor of placebo

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

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    James Patient Education Handouts (A – Z) Click on the title to see the handout To narrow your search use “Ctrl + F” and enter a keyword Abdomen CT Scan - The James Abemaciclib Abiraterone (Zytiga) About Hospice Care About Your Visit at The James Gastrointestinal (GI) Clinic AC: Doxorubicin and Cyclophosphamide Acalabrutinib (Calquence) Acute Leukemia Ado-Trastuzumab Emtansine Advance Directives Afatinib (Gilotrif) Alectinib (Alecensa) After Your Breast Cancer Surgery After Your Spine or Joint Injection All About Me All About Me - Russian All About Me - Somali All About Me - Spanish Allogeneic Stem Cell Transplant Amyloidosis Clinic Physical Therapy Recommendations Anal Cancer Anastrozole (Arimidex) for Females Anastrozole (Arimidex) for Males Anticipatory Grief in Family/Caregivers Anticipatory Grief in Patients Antithymocyte Globulin (ATG) Apheresis Approaching the Final Days Areola Tattooing Aromatherapy Autologous Stem Cell Transplant Automated Whole Breast Ultrasound (ABUS) Avapritinib (Ayvakit) Axillary Web Syndrome Exercise Program Axitinib (Inlyta) Basics of Blood Sugars Basic Pilates Mat Routine BCG Therapy - Intravesical Treatment for Bladder Cancer Before Your Breast Cancer Surgery Benign Breast Surgery The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 9/15/2021 James Patient Education Handouts (A – Z) Click on the title to see the handout To narrow your search use “Ctrl + F” and enter a keyword Benign Pituitary Tumor Bevacizumab (Avastin) Bexarotene (Targretin) Bicalutamide (Casodex) Binimetinib (Mektovi) Bisphosphonates (taken by mouth) Bladder Cancer Internet Resources Bladder Irrigation Treatment for Bladder Cancer Blank Notes Page - The James Blood and Bone Marrow Question and Answer Sheet Blood and Marrow Transplant Blood Value Record Blood and Marrow Transplant Unit - B.M.T.U.
  • November 18 - 21, 2020

    November 18 - 21, 2020

    November 18 - 21, 2020 ALL TIMES ARE EASTERN STANDARD TIME (EST) Wednesday, 18 November, 2020 8:00 am - 11:00 am TARPSWG Meeting (email: [email protected]) – Chair: Alessandro Gronchi 11:00 am - 1:00 pm Ultra Rare Sarcoma Meeting – Chair: Silvia Stacchiotti 1:00 pm - 3:00 pm SARC Meeting 3:00 pm - 5:00 pm SELNET Meeting: State of Art of Management for Localized STS in Limbs and Retroperitoneum – Chair: Javier Martin-Broto Thursday, 19 November, 2020 8:00 am - 9:00 am – Session 1 – OPENING CEREMONY INTRODUCTION TO CTOS 2020 President: Kirsten Sundby Hall Program Chairs: Silvia Stacchiotti, Margaret von Mehren, Inga-Marie Schaefer 25 YEAR RETROSPECTIVE Presenter: Shreyas Patel 9:00 am - 10:00 am – Session 2 – IMMUNOTHERAPY IN SARCOMA: ALVEOLAR SOFT PART SARCOMA, CLEAR CELL SARCOMA, SYNOVIAL SARCOMA Chair: Seth Pollack Discussant: Breelyn Wilky Panelists: Armelle Dufresne, Bob Maki, Enrico Grignani Presenters: Akira Kawai, Nadia Hindi, Sandra d'Angelo, Brian van Tine Paper #01 3421748 EFFICACY AND SAFETY OF NIVOLUMAB MONOTHERAPY IN PATIENTS WITH UNRESECTABLE CLEAR CELL SARCOMA AND ALVEOLAR SOFT PART SARCOMA (OSCAR TRIAL, NCCH1510): A MULTICENTER, PHASE 2 CLINICAL TRIAL Akira Kawai2, Tadaaki Nishikawa1, Mamiko Kawasaki3, Sawako Tomatsuri3, Nobuko Okamura3, Gakuto Ogawa3, Akihiro Hirakawa4, Taro Shibata3, Kenichi Nakamura3, Shigeki Kakunaga5, Kenji Tamura1, Masashi Ando6, Toshifumi Ozaki7, Takafumi Ueda5, Kan Yonemori1 1Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, JAPAN; 2Oncology and Rehabilitation Medicine, National
  • (CHMP) Agenda for the Meeting on 17-20 May 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes

    (CHMP) Agenda for the Meeting on 17-20 May 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes

    17 May 2021 EMA/CHMP/276743/2021 Human Medicines Division Committee for medicinal products for human use (CHMP) Agenda for the meeting on 17-20 May 2021 Chair: Harald Enzmann – Vice-Chair: Bruno Sepodes 17 May 2021, 09:00 – 19:30, virtual meeting/ room 1C 18 May 2021, 08:30 – 19:30, virtual meeting/ room 1C 19 May 2021, 08:30 – 19:30, virtual meeting/ room 1C 20 May 2021, 08:30 – 19:30, virtual meeting/ room 1C Disclaimers Some of the information contained in this agenda is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the CHMP meeting highlights once the procedures are finalised and start of referrals will also be available. Of note, this agenda is a working document primarily designed for CHMP members and the work the Committee undertakes. Note on access to documents Some documents mentioned in the agenda cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on- going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006). Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021.
  • Revolutions in Treatment Options in Gastrointestinal Stromal Tumours (Gists): the Latest Updates Revolutions in Treatment Options in GIST

    Revolutions in Treatment Options in Gastrointestinal Stromal Tumours (Gists): the Latest Updates Revolutions in Treatment Options in GIST

    Curr. Treat. Options in Oncol. (2020) 21:55 DOI 10.1007/s11864-020-00754-8 Sarcoma (SH Okuno, Section Editor) Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates Revolutions in treatment options in GIST Sheima Farag, MD1 Myles J. Smith, MB, BCh, BAO, PhD, FRCSI, FRCS1 Nicos Fotiadis, MD, PhD, FRCR1 Anastasia Constantinidou, MD, MSc, MRCP, PhD2 Robin L. Jones, BSc, MB, BS, MRCP, MD(Res)1,* Address *,1Sarcoma Unit, The Royal Marsden Hospital (NHS Foundation Trust) and Institute of Cancer Research, Fulham Road, London, SW3 6JJ, UK Email: [email protected] 2Medical School University of Cyprus and BoC Oncology Centre, Nicosia, Cyprus * The Author(s) 2020 Anastasia Constantinidou and Robin L. Jones contributed equally to this work. This article is part of the Topical Collection on Sarcoma Keywords Gastrointestinal stromal tumour I GIST I Tyrosine kinase inhibitors I TKI I Avapritinib I Ripretinib Opinion statement The treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup.