Effective Control of Advanced Systemic Mastocytosis

with Avapritinib: Mutational Analysis from

the EXPLORER Clinical Study

Michael W. Deininger, MD, PhD,1 Daniel J. DeAngelo, MD, PhD,2 Deepti H. Radia, MD,3 Tracy I. George, MD,4

Guang Yang, PhD,5 Jayita Sen, PhD,5 Hui-Min Lin, PhD,5 Brenton G. Mar, MD, PhD,5 Jason Gotlib, MD, MS6

1Versiti Blood Research Institute and Medical College of Wisconsin, Milwaukee, WI, USA; 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 3Guy’s & St Thomas’ NHS Foundation Trust, London, UK;

4ARUP Laboratories, University of Utah, Salt Lake City, UT, USA; 5Blueprint Medicines Corporation, Cambridge, MA, USA; 6Stanford Cancer Institute/Stanford University School of Medicine, Stanford, CA, USA

Disclosures

Honorarium or consultancy fees: Blueprint Medicines Corporation, Incyte, Medscape, Sangamo,

Takeda, DisperSol, Fusion Pharma, Novartis

Research funding: Blueprint Medicines Corporation, Incyte, Leukemia & Lymphoma Society, Novartis,

Pfizer, SPARC, Takeda

Study management committees: Blueprint Medicines Corporation and Takeda

Study sponsored by Blueprint Medicines Corporation

AYVAKITTM (avapritinib) is approved by the US Food and Drug Administration (FDA) for the treatment of adults with unresectable or

metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18

mutation, including PDGFRA D842V mutations, and for the treatment of adults with advanced systemic mastocytosis (limitation of use:

patients with platelets count ≥50×109/L).

In Europe, AYVAKYT® (avapritinib) is approved by the European Medicines Agency (EMA) for the treatment of adult patients with

unresectable or metastatic GIST harboring the PDGFRA D842V mutation.

Clonal evolution

• Patients have complex genomics with multiple clones and co-mutations1,a

• ~60–70% of patients have a distinct, associated hematological neoplasm (SM-AHN)2

• Patients with SM-AHN have poor outcomes, with only a 49% two-year survival rate following treatment with midostaurin3

• Disease progression and mortality may occur due to the SM, AHN, or both4

SM-AHN (CMML) diagnosis

Neoplastic mast cell clones are driven by KIT D816V

AHN clones (i.e., neoplastic monocytes in CMML) often have

KIT D816V ± additional co-mutations

aOf note, non-advanced SM patients typically have only the KIT D816V mutation.

AHN, associated hematological neoplasm; CMML, chronic myelomonocytic leukemia; SM, systemic mastocytosis.

1. Jawar M et al. Leukemia 2015;29:1115–1122; 2. Shomali W & Gotlib J. Int J Mol Sci 2021;22:2983; 3. Gotlib J et al. N Engl J Med. 2016;374:2530–2541 (supplement);

4. Gotlib J et al. Nat Med. 2021 (in press).

Clo

ne s

ize

Advanced systemic mastocytosis (AdvSM) is a rare

hematologic neoplasm driven by KIT D816V in ~95% of cases

KIT D816V

TET LOF

GATA1 fs

NRAS G12D

• 75% response rate by mIWG-MRT-ECNM criteriaa, including 100% in ASM, 76% in SM-AHN and 69% in MCL1

• Responses regardless of prior therapy or high-risk SRSF2/ASXL1/RUNX1 (S/A/R) co-mutations1

• Generally well tolerated1

• Activity observed in mast cell and non-mast cell lineages, including reductions in the KIT D816V VAF1,2

• Patients with SM-AHN had a 67% two-year survival on avapritinib with 38 months median duration of response1

Reductions in absolute

eosinophil counts2,e,c

*SM-AHN patients with CEL

0

–20

–40

–80

–100

–60

20

* * *

Reduction in absolute

monocyte counts2,d,c

40

0

–20

–40

–80

–100

–60

20

Avapritinib, a selective KIT D816V inhibitor, induced deep

SM responses, including activity in patients with SM-AHN

aCR, CRh, PR, or CI. bPatients with SM-AHN. cAd hoc analysis. dPatients with SM-CMML. ePatients with baseline eosinophilia and SM-CEL.

ASM, aggressive systemic mastocytosis; CI, clinical improvement; CR, complete remission; CRh, complete remission with partial hematological recovery; CEL, chronic eosinophilic

leukemia; CMML, chronic myelomonocytic leukemia; MC, mast cell; MCL, mast cell leukemia; PR, partial remission; S/A/R, SRSF2 / ASXL1 / RUNX1; SM, systemic mastocytosis;

SM-CEL, systemic mastocytosis with chronic eosinophilic leukemia; VAF, variant allele fraction.

1. DeAngelo D et al. Nat Med. 2021 (In press); 2. Reiter et al. EHA 2021.

Reduction in bone marrow

mast cells2

MC aggregates eliminated

20

Maxim

um

pe

rcen

t ch

an

ge

fro

m b

aseli

ne

0

–20

–40

–80

–100

–60

Reduction in peripheral blood

KIT D816V VAF2,b,c

VAF <1%

20

0

–20

–40

–80

–100

–60

Exploratory analysis of reasons for progression

• EXPLORER (NCT02561988) is a phase I dose escalation study of avapritinib in 86 patients

with local diagnosis of AdvSM, of which 69 were centrally confirmed1

• Avapritinib 30–400 mg was studied with expansion cohorts at 200 mg and 300 mg QD

Data cut-off: May 27, 2020 (median follow-up of 23 months).aAs determined by investigator; a subset with AML met the mIWG-MRT-ECNM criteria definition for progressive disease.

AML, acute myeloid leukemia; mIWG-MRT-ECNM, (modified) International Working Group-Myeloproliferative Neoplasms Research and Treatment & European Competence Network on

Mastocytosis; QD, once-daily.

1. DeAngelo D et al. Nat Med. 2021 [In press].

• Only 14 (20%) patients had clinical

progressiona on treatment

‒ 10 (21%) patients with SM-AHN, 4 (31%)

with MCL, and 0 with ASM had clinical

progression

• Median duration of treatment was 9.5 months

• The majority were AHN or AML progressions

in patients with baseline AHN

• Only 2 patients, both with MCL, had a SM

progression

Baseline diagnosis

Characteristic All AdvSM

(n=69)

Median age, years (range) / Male, n (%) 67 (34–83) / 41 (59)

ECOG PS 0–1 / 2–3, n (%) 48 (70) / 21 (30)

Prior anti neoplastic therapy, n (%) 41 (59)

Midostaurin 23 (33)

Cladribine 10 (14)

KIT D816V or Y positive, n (%)a 65 (94)

Any myeloid co-mutation, n (%) 64 (93)

SRSF2 / ASXL1 / RUNX1 positive, n (%) 36 (52)

1 / 2 / 3 genes mutated 22 (32) / 11 (16) / 3 (4)

Median BM MC burden, % (range) 40 (5–95)

Median serum tryptase, ng/mL (range) 173 (12–1414)

Median KIT D816V VAF, % (range) 17 (0–81)

Baseline characteristics

aAssessed by central D816V ddPCR assay and Trusight Myeloid Panel (for D816Y). VAF (%) assessed using validated ddPCR by central assay with limit

of detection of 0.17%.

BM, bone marrow; ECOG PS, Eastern Cooperative Oncology Group performance status.

Baseline characteristics in patients with and without progression

18%22%

20%22%

14%23%

31%21%

20%

82%78%

80%78%

86%77%

69%79%

100%

80%

No (n=33)

Yes (n=36)

SRSF2 / ASXL1 / RUNX1 positive

No (n=46)

Yes (n=23)

Prior midostaurin

2–3 (n=21)

0–1 (n=48)

ECOG PS

MCL (n=13)

SM-AHN (n=48)

ASM (n=8)

Ad

All AdvSM (n=69)

Median age (range) 70 years (34–83) 66 years (40–82)

Median BM MC burden (range) 45% (10–90) 40% (5–95)

Median serum tryptase (range) 205 ng/mL (21–765) 172 ng/mL (12–1414)

Median KIT D816V VAF (range) 16% (0–81) 23% (0–50)

AdvSM subtype

Clinical progression (n=14) No clinical progression (n=55)

ECOG PS

Prior midostaurin

SRSF2 / ASXL1 / RUNX1

positive

All AdvSM (n=69)

Majority of patients had deep responses in bone marrow mast

cell burden at last assessment regardless of progression

Ma

xim

um

ch

an

ge in

BM

ma

st

ce

lls

fro

m b

as

eli

ne

(%

)

H H H M H H H H M M H M H H M A H H A H A H M H H M H H A A H H H H H H H H A A M H H H H H H A M H H M H H H H H M M H M H H

Clinical

progressionWithout clinical progression

Change at best response

Change at last assessmentTransformation to AML

Progression of AHN

A: ASM

H: SM-AHN

M: MCL

SM progression

Undetermined

20

0

–50

–100

No statistical analysis conducted.

n=67

Majority of patients had deep responses in serum tryptase at

last assessment regardless of progression

Ma

xim

um

ch

an

ge in

se

rum

tryp

tas

e f

rom

ba

se

lin

e (

%)

H M H H H H H H H H M M M H H M H H M A A H H M H H H M H A H M H H M H H H H M H A H H H H H A A H M H H H H H H H H H A H H H A H H M H

Clinical

progression20

0

–50

–100

100

700

No statistical analysis conducted.

n=69Change at best response

Change at last assessmentTransformation to AML

Progression of AHN

A: ASM

H: SM-AHN

M: MCL

SM progression

Undetermined

Without clinical progression

Majority of patients had deep responses in BM KIT D816V VAF

at last assessment regardless of progression

Ma

xim

um

ch

an

ge in

BM

KIT

D81

6V

VA

F f

rom

ba

se

lin

e (

%) Change at best response

Change at last assessmentTransformation to AML

Progression of AHN

A: ASM

H: SM-AHN

M: MCL

H H H H H H M M H H H M H H A H H H H H H H M H H H H A M M M H H H H H M H H M M A H A M H H A H H M H H H H H H

Clinical

progression

Without clinical progression

SM progression

Undetermined

20

0

100

400

–50

–100

Clinical progression Without clinical progression

BM KIT D816V VAF 68% median reduction 95% median reduction

>50% reduction 67% of patients (8/12) 87% of patients (39/45)

No statistical analysis conducted.

n=57

*

Reduced mutation (VAF change >5% reduction)

Cleared mutations (last assessed VAF <LoD)

KIT D816Y

aOnly a random subset of non-progressing patients had serial mutational profiling; 12 of 14 patients who progressed had serial

profiling. bOther mutations found in single patients were KRAS, SF3B1, U2AF1, ATRX, BCORL1, SMC3, NPM1, CDKN2A, STAG2,

IDH1, IDH2, and MYD88. LoD, limit of detection; UND, undetermined.

• 83% (10 of 12)a of progressions were not

associated with increased KIT D816V/Y VAF

• 2 (17%) patients with baseline MCL had SM

progressions with increased KIT D816V/Y

VAF, but no additional mutations in KIT were

identified

• No clear pattern of increasing or decreasing

VAF was observed for most mutations

Complex pattern of co-mutation evolution regardless of outcome

• TruSightTM Myeloid Panel at baseline in all patients and on

study in a subset of patients with/without progressiona

Without

clinical progressiona,b

Clinical progressiona,b

AML AHN SM UND

*

Emergent mutations (baseline VAF <LoD)

Increased mutation (VAF change > 5% increase)

Persistent mutation (VAF change ≤ ±5%)

KIT D816V/Y (21)TET2 (12)SRSF2 (9)ASXL1 (8)

DNMT3A (7)RUNX1 (6)BCOR (5)

CBL (5)GATA2 (5)

CUX1 (4)EZH2 (4)IKZF1 (4)NRAS (4)

CEBPA (3)KDM6A (3)ZRSR2 (3)

TP53 (3)JAK2 (2)

SETBP1 (2)

Hgb, hemoglobin; Plts, platelets; WHO, World Health Organization.

1. Jawhar M et al. J Clin Oncol. 2019;37:2846–2856.

Overall survival is more favorable in patients with a low

baseline Mutation-Adjusted Risk Score (MARS)

MARS1 is a validated, WHO-independent

prognostic score based on 5 parameters:

1) >60 years of age

2) Anemia (Hgb <10 g/dL)

3) Thrombocytopenia (Plts <100× 109/L)

4) 1 S/A/R mutation

5) ≥2 S/A/R mutations

MARS

category

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Log-rank P=0.0015

0–1

23–5

25

15

29

25

15

27

25

14

26

22

11

22

19

10

19

19

9

17

17

9

15

15

5

12

12

5

9

11

5

7

9

4

6

5

3

6

4

2

5

4

2

3

3

2

2

3

2

0

1

1

0

0

Months from first dose

Pro

bab

ility

aliv

e

Censored

0–1

3–5

2

• Avapritinib showed profound and durable reductions in objective disease

burden in patients with AdvSM, in both the SM and AHN components

• With a median follow-up of 23 months, only 20% of patients have progressed

on treatment, driven in most cases by KIT D816V-negative AHN clones

• Overall survival was more favorable in patients with lower baseline MARS

scores

• In most patients who progressed, KIT D816V remained suppressed,

suggesting a rationale for the addition of AHN-directed therapies

• These data highlight the potential value of single cell sequencing of SM and

AHN components of AdvSM

Conclusions

• Participating patients and families

• Avapritinib investigators and research coordinators

• Colleagues at Blueprint Medicines Corporation

• Medical writing support was provided by Kenny Tran, MSc, and editorial support was provided by Travis Taylor, BA, all of Paragon,

Knutsford, UK, supported by Blueprint Medicines Corporation, Cambridge, MA, USA, according to Good Publication Practice

guidelines

Acknowledgments