1Institut Gustave Roussy, Paris, France; 2University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; 3University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD; 4Karmanos Cancer Center, Detroit, MI; 5Northwestern University, Chicago, IL; 6Cornell University, Ithaca, NY; 7New York Medical College, Valhalla, NY; 8Yale University, New Haven, CT; 9David Geffen School of Medicine at UCLA, Los Angeles, CA; 10Vanderbilt University, Nashville, TN; 11Oregon Health Sciences University, Portland, OR; 12FORMA Therapeutics, Inc., Watertown, MA; 13MD Anderson Cancer Center, Houston, TX

Presented at the 24th Annual Congress of the European Hematology Association • Amsterdam, Netherlands • June 15, 2019

FT-2102, an IDH1m Inhibitor, Induces Mutation Clearance in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Treated in Phase 1 Dose Escalation and Expansion Study

Stephane De Botton1; Justin M. Watts2; Maria R. Baer3; Jay Yang4; Shira N. Dinner5; Sangmin Lee6; Karen P. Seiter7; Thomas Prebet8; Gary J. Schiller9; P. Brent Ferrell, Jr10; Kim-Hein Dao11; Patrick Kelly12; Jennifer Sweeney12; Sanjeev Forsyth12; Julie Brevard12; Sylvie Guichard12; Qunli Xu12; Patrick Henrick12; Hesham Mohamed12; Jorge E. Cortes13

Background• Isocitrate dehydrogenase 1 mutations (IDH1m) occur

in 7-14% of AML pts and 3% of MDS pts and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation

• FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation

• We present updated clinical data and an initial mutational/VAF analysis of pts participating in the Phase 1 portion of our ongoing Phase 1/2 study of FT-2102 in pts with IDH1m AML and MDS (CT gov: NCT02719574)

Phase 1 Study in IDH1m AML and MDS

Examples of VAF Kinetics in FT-2102-Treated Patients

Study Conclusions• FT-2102 demonstrates clinical activity as SA and in

combination with AZA in a high-risk Phase 1 population of AML/MDS pts with IDH1 mutation

– In R/R AML, 41% and 46% pts achieve ORR with SA and CO treatment, respectively

• 90% of pts enrolled with a history of IDH1m determined locally had a IDH1m confirmed centrally

• Baseline co-mutation analyses demonstrated no correlation with clinical response (likely due to the small number of pts)

• FT-2102 induces IDH1 mutation clearance or significant reduction in TN and R/R AML pts regardless of IWG response

– Of the 25 pts achieving an objective response and with available samples (VAF at ≥ C3), 10 (40%) had clearance or significant VAF reduction to < 1%

– 6 SD pts had samples available and 3 (50%) had clearance or significant VAF reduction

• Initial analysis of pts who relapse/progress on FT-2102 suggests non-IDHm-driven mechanism of escape:

– FT-2102 combination therapy tailored to the emerging clone may provide additional clinical benefit vs. discontinuation of FT-2102

FT-2102

Acknowledgements: We would like to acknowledge the participating institutions, their study investigators, and clinical staff for the successful conduct of the study. Also Christophe Marzac, Valerie Camara-Clayette, and Stephane de Botton of Institut Gustave Roussy for the mutational analysis work. Most importantly, we sincerely thank our patients and their families for their participation. Abbreviations: 2-HG = 2-hydroxyglutarate; AE = adverse event; AZA = azacitidine; C = cycle; CO = combination study; CR = complete remission; CRh = complete remission with partial hematological recovery; CRi = complete remission with incomplete hematologic recovery; D = day; ddPCR = droplet digital polymerase chain reaction; EOS = end of study; HSCT = hematopoietic stem cell transplantation; LOQ = level of quantification; MLFS = morphologic leukemia-free state; ORR = overall response rate (CR + CRh + CRi + MLFS + Marrow CR); PD = progressive disease; PR = partial response; R/R = relapsed/refractory; SCR = screening; SD = stable disease; VAF = variant allele frequency; WB = whole blood

EHA-3251

Demographics and Disease History

Characteristic FT-2102 (n = 32)*

FT-2102 + AZA (n = 46)

Age, median (range), years 72 (35 - 87) 67 (31 - 88)

Female, % 50 52

ECOG PS - 0 / 1 / 2, % 28 / 50 / 22 28 / 57 / 15

AML, n 26 39

Relapsed > 12 mo ≤ 12 mo

144 10

111 10

Refractory 8 15

Treatment-naïve 4 13

Prior regimens, median (range)** 2 (0 – 9) 3 (0 – 6)

HMA (azacitidine/decitabine) 12 9

IDHm inhibitor 1 4

Investigational 2 2

HSCT 2 3

MDS, n 6 7

Relapsed / Refractory 4 2

Treatment-naïve 2 5

Prior regimens, median (range)** 1 (0 – 4) 0 (0 – 4)

HMA (azacitidine/decitabine) 4 2* Including 3 pts treated with 100 mg QD with food. ** Not inclusive of all types; pt could have received more than one type

Investigator-Reported Mutation Status at Study Entry

All SA and CO R/R AML (n = 48)

TN AML (n = 17)

MDS*

(n = 13)All AML +

MDS (n = 78)

IDH1 Mutation Type, n

R132C 23 10 5 38

R132H 13 3 6 22

R132S 6 2 0 8

R132G 5 2 1 8

R132L 1 0 0 1

Selected Concurrent Mutations, n

FLT3 12 0 1 13

NPM1 12 1 1 14

CEBPA 1 0 1 2

TP53 3 0 1 4

IDH2 1 1 0 2* One pt with R100 mutation

ResponseFT-2102 SA FT-2102 + AZA

R/R AML (n = 22)

All Pts (n = 32)

R/R AML (n = 26)

All Pts* (n = 45)

ORR, n (%) [95% CI]

9 (41) [21, 64]

12 (38) [21, 56]

12 (46) [27, 67]

26 (58) [42, 72]

CR, n (%) 4 (18) 5 (16) 3 (12) 14 (31)

CRh, n (%) 3 (14) 3 (9) 1 (4) 1 (2)

CRi, n (%) 2 (9) 3 (9) 6 (23) 9 (20)

MLFS, n (%) 0 0 2 (8) 2 (4)

Marrow CR, n (%) N/A 1 (3) N/A 0

SD, n (%) 5 (23) 9 (28) 11 (42) 14 (31)

PD, n (%) 2 (9) 3 (9) 1 (4) 1 (2)

NE, n (%) 6 (27) 8 (25) 2 (8) 4 (9)ORR = overall response rate (CR + CRh + CRi + MLFS + marrow CR)* One pt excluded from efficacy analysis due to the lack of an R132X mutation; pt continued on treatment and achieved a marrow CR

Reduction of IDH1 VAF in Patients with Clinical Response and Stable Disease

Dose Escalation (n = 19) Dose Expansion (n = 10)

R/R AML or MDSSA 150 mg BID (n = 10)

SA 150 mg QD (n = 8)SA 300 mg QD (n = 4)SA 150 mg BID (n = 7)

Dose Escalation (n = 15)

Dose Expansion (n = 31)

150 mg QD + AZA (n = 7)150 mg BID + AZA (n = 8)

R/R AML or MDS150 mg BID + AZA (n = 16)

TN AML or MDS150 mg BID + AZA (n = 15)

Data cutoff: 12 Apr 2019FT-2102 administered PO daily in 28-day cyclesAZA administered 75 mg/m2 IV or SC daily for 7 days of each 28-day cycle

Hypotheses for Mechanisms of Resistance/Escape

Presence of Additional Non-IDH1m Clones Drive Resistance

IDH2-Mediated Resistance

• TN AML secondary to MDS treated with SA FT-2102

• Pt remained stable for 15 cycles with no achievement of an IWG response, likely due to the presence of non-IDH1m clones; however, FT-2102 induced IDH1m clearance and normalization of 2-HG

• R/R AML pt with known IDH2m at baseline, treated with FT-2102 + AZA

• Remained in SD for 6 cycles then progressed

• FT-2102 induced clearance of the IDH1m clone, however AZA was not effective in controlling the IDH2m clone that eventually drove the clinical progression

• No correlation between the number of baseline co-mutations with clinical responses was observed, likely due to the small number of pts

DN

MT3

AN

PM1

SRSF

2N

RAS

RUN

X1

ASX

L1FL

T3ST

AG

2ID

H2

TET2

SMC

1ASF

3B1

U2A

F1PH

F6JA

K2

MPL

NF1

ASX

L2BC

OR

EED

WT1

CBL

CSF

3RET

NK1

PTPN

11A

TMTP

53

10

0

20

30

40

50

60

Patie

nts

with

Mut

atio

n (%

)

Baseline Co-Mutations Frequency (Central Determination)

Analysis of VAF by Methodology and Sample Type

Key Eligibility Criteria

• AML or MDS: documented IDH1-R132X mutation by local testing

• R/R to standard therapy or standard therapy is contraindicated

• No prior IDH1m inhibitor in SA cohorts

• Prior IDH1m inhibitor or HMA allowed in CO cohorts

• 229 samples (213 WB and 16 BMA) were obtained from 59 AML pts (SA or CO) in the Phase 1 study

• NGS: Target enrichment was carried out using HaloPlex® Target followed by Illumina® sequencing; coverage > 100X across 75 genes

• ddPCR: Input 20 ng on Stilla 3-channel system, VAF data based on > 20,000 droplets

Mutational Analysis Methodology

Investigator-Assessed Response

IDH1 Variants (Central Determination)

• Of the 59 pts with local and central IDH1m results (all sample types included), central testing confirmed presence the of IDH1m at study entry in 56/59 (95%) of pts (plotted)

IDH1-R132G3 (5%)

IDH1-R132S8 (14%)

IDH1-R132H16 (29%)

IDH1-R132C28 (50%)

IDH1-R132L1 (2%)

• 25 pts achieving an IWG response had available longitudinal samples for analysis (VAF at ≥ C3)

• IDH1 mutation clearance / significant reduction (VAF to < 1%, plotted) is observed in 10/25 (40%) pts with an IWG response to FT-2102

• 6 pts with SD had available longitudinal samples for analysis (VAF at ≥ C3)

• In pts with stable disease, 3/6 (50%) had clearance / significant reduction (VAF to < 1%, plotted) of the IDH1m VAF

• A good correlation between NGS and ddPCR supported use of ddPCR for on-treatment assessment of IDH1 VAF (left)

• Detection of IDH1 from BMA can be useful in patients with low IDH1 VAF in WB (right)

• 57/59 (97%) of pts had ≥ 1 co-mutation

• 23/59 (39%) of pts had ≥ 3 co-mutations

WB (PaxGene®)collection at each

response assessment

FT-2102

EOSScreening 1 2

BMAWB (PaxGene®

+ EDTA)

Clinical Response is Associated with Decrease in 2-HG and Clearance of the IDH1m Clone

• Patient with TN AML on FT-2102 + AZA remains on treatment • Patient with R/R AML on SA FT-2102 remains on treatment

D1

D2

D8

D15

D22

SCR

Cycle 1 Cycle43 6 7 8 9 10 11 13 14 15 16 17 18D

2D

4D

15

Cycle 2

5 120

10

20

30

40

0

1000

2000

3000

4000

5000

VA

F (%

)

2-HG

(ng/m

L)

Patient 1IDH1_R132CSTAG2SRSF22-HGPR CR

0

100

200

300

400

500

0

1

2

3

4

VA

F (%

)

2-HG

(ng/m

L)

D1

D2

D8

D15

D22

SCR 2

Cycle11 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 32

Local Genoptix VAF data (peripheral blood NGS)

Cycle 1

CRm

Patient 2

IDH1_R132CNPM1

2-HG

12

CR at C4

0 1 2 3 4 5 6 7 8 9 10 110 2 4 6 8 10 12 14 16 18 20 22 24

40

35

30

25

20

15

10

5

0

45

40

35

30

25

20

15

10

5

0

IDH

1 V

AF

(%)

IDH

1 V

AF

(%)

Cycle Cycle

Patients with Clinical Response and VAF < 1%(CR/CRh/CRi/MLFS)

Patients with Stable Disease and VAF < 1%(SD)

0 1 2 3 4 5 6 7 8 9 10 110 2 4 6 8 10 12 14 16 18 20 22 24

40

35

30

25

20

15

10

5

0

45

40

35

30

25

20

15

10

5

0

IDH

1 V

AF

(%)

IDH

1 V

AF

(%)

Cycle Cycle

Patients with Clinical Response and VAF < 1%(CR/CRh/CRi/MLFS)

Patients with Stable Disease and VAF < 1%(SD)

IDH1_R132HIDH2_R140Q2-HG

SCR

C1D

2C

1D8

C1D

15C

1D22

C2D

1C

2D2

C2D

4C

2D15

C3D

1C

4D1

C4D

5C

5D1

C6D

1EO

S

0

10

20

30

40 600

400

200

0V

AF

(%)

2-HG

(ng/m

l)

Patient 3

Local Genoptix VAFdata (bone marrow NGS)

Patient 4

0

10

20

30

50

40

800

IDH1STAG2SRSF2RUNX1NRAS2-HG

600

400

200

0

VA

F (%

)

2-HG

(ng/m

l)

SCR

C1D

2C

1D8

C2D

1C

5D1

C6D

1C

8D1

C9D

1C

10D

1C

11D

1C

12D

1C

13D

1C

14D

1C

14D

22C

15D

1

R = 0.87, N = 15

0 10 20 30 40 500

10

20

30

40

50

BMA

WB (PaxGene®)

R = 0.96, N = 219p < 0.0001

ddPCR (WB)0 10 20 30 40 50

0

10

20

30

40

50

NG

S (W

B)