A Phase 1b/2 Study of Olutasidenib in Patients with Relapsed/Refractory IDH1 Mutant Gliomas: Safety and Clinical Activity as a Single Agent and in Combination with AzacitidineMacarena I. De La Fuente,1 Howard Colman,2 Mark Rosenthal,3 Brian Andrew Van Tine,4 Danijela Levacic,5

Tobias Walbert,6 Hui Kong Gan,7 Maria Vieito,8 Mohammed M. Milhem,9 Kate Lipford,10 Sanjeev Forsyth,10

Sylvie Mireille Guichard,10 Yelena Mikhailov,10 Alexander Sedkov,10 Blythe Thomson,10 Patrick Francis Kelly,10

Varun Monga9

1Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL; 2Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; 3Peter MacCallum Cancer Centre, Melbourne, Australia; 4Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO; 5Baylor Scott and White Vasicek Cancer Center, Baylor University, Temple, TX; 6Henry Ford Cancer Institute, Henry Ford University, Detroit, MI; 7Austin Health, Heidelberg, Australia; 8Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 9Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA; 10Forma Therapeutics, Inc., Watertown, MA

Introduction

• Isocitrate dehydrogenase 1 mutations (mIDH1) are present in > 70% of patients with grade II/III gliomas and up to 5% of glioblastoma1,2

• This mutation results in production and accumulation of (R)-2-hydroxyglutarate (2-HG) causing DNA hypermethylation and promoting tumorigenesis3-6

• Olutasidenib (FT-2102) is an oral, potent, CNS penetrant, and selective inhibitor of mIDH17-10

Olutasidenib (FT-2102)

Phase 1b/2 Study Design11

a Olutasidenib (150 mg BID) given orally daily over continuous 28-day cyclesb AZA (75 mg/m2 IV ) given daily on days 1-7 of each 28-day cycle

Glioma Cohort

Primary Objectives• Safety and tolerability• Clinical activity as assessed by Investigator per RANO criteria

Secondary and Exploratory Objectives• Clinical activity, PK, biomarkers

Data cutoff: March 31, 2020

Key Inclusion Criteria:•Histologically or cytologically confirmed IDH1 R132X-mutated advanced glioma

•Recurred or progressed tumor following standard therapy or not responding to standard therapy

•No prior IDH1 inhibitor•Adequate cardiac, renal, and hepatic function

• ECOG PS 0-2

Safety Lead-in

Olutasideniba

150 mg BID +

AZAb 75 mg/m2

Olutasideniba

150 mg BID

Clinical Activity

Olutasidenib150 mg BID N = 26

N = 6

Baseline Demographics and Disease Characteristics

CharacteristicOlutasidenib

(N = 26)Olutasidenib + AZA

(N = 6)Age, median (range), years 45 (23-64) 43 (29-49)Male, n (%) 17 (65) 4 (67)ECOG PS, % 0, 1, 2 35, 50, 12 33, 67, -Time since initial diagnosis, median (range), years 6 (1-19) 9 (3-27)Tumor histology, n (%) Anaplastic astrocytoma 11 (42) -

Oligodendroglioma 4 (15) 4 (67)Glioblastoma 8 (31) 1 (17)Anaplastic oligodendroglioma 2 (8) 1 (17)Diffuse astrocytoma 1 (4) -

Tumor grade, n (%) II 4 (15) 1 (17)III 13 (50) 4 (67)IV 8 (31) 1 (17)Unknown 1 (4) -

Tumor type, n (%) Enhancing 23 (88) 5 (83)Non-enhancing 3 (12) 1 (17)

R132X mutation, n R132H, R132L, R132C, R132G, Other 22, 2, 1, 1, - 4, -, -, -, 1Unknown - 1

Prior regimens, median (range) 2 (1-5) 3 (1-4)≥ 3 prior regimens, n (%) 10 (38) 3 (50)Prior TMZ, n (%)Prior radiation, n (%)

23 (88)26 (100)

5 (83)6 (100)

Patient Disposition

CharacteristicOlutasidenib

(N = 26)Olutasidenib + AZA

(N = 6)

Treatment ongoing, n (%) 10 (38) 1 (17)a

Treatment discontinued, n (%)

Disease progression 13 (50) 4 (67)

Adverse event 2 (8) 1 (17)

Withdrew consent 1 (4) ‒

a Pt continuing on monotherapy at data cutoff.

Olutasidenib in Plasma

• Consistent plasma concentrations at levels predicted to safely provide benefit were achieved and maintained over the treatment duration

• Co-administration with azacitidine did not alter the pharmacokinetics of olutasidenib

Olutasidenib in CSF

• Evidence of olutasidenib brain penetration was observed at a clinically relevant dose• The unbound brain partition coefficient (Kpuu)

for olutasidenib in humans was 0.54

• Olutasidenib CSF concentration is predicted to be at the IC75 for 2-HG reduction

Pharmacokinetics and BBB Penetration

Cycle/Day

MatrixObserved Conc,

ng/mLUnbound Conc,

ng/mL

Brain PartitionCoefficient,

Kpuu

C3D1 Plasma 1070 58.90.54

C3D7 CSF 31.8 31.8

(N = 32)

(N = 1)

FT-2

102

Plas

ma

Con

cent

ratio

n (n

g/m

L) 8000

6400

4800

3200

1600

0

IC90 (2-HG)

QTc Prolongation Risk (non-human primate)

C1D1C1D2

C1D8C1D15

C1D22C2D1

C3D1C4D1

C5D1C6D1

C7D1C8D1

C9D1C10D1

C11D1

Cycle Day

• 6 (23%) monotherapy and 3 (50%) combination pts experienced ≥ Gr 3 LFT abnormalityo Led to treatment discontinuation in 2 pts (1 monotherapy; 1 combination)

• 2 DLTs (≥ Gr 3 transaminase elevations) observed for combination treatment, meeting stopping criteria

TEAEs (≥ 15%)a Regardless of Causality

a TEAE cutoff applied to monotherapy population (N = 26)

TEAE, n (%)Olutasidenib

(N = 26)Olutasidenib + AZA

(N = 6)Any Grade Grade 3/4 Any Grade Grade 3/4

Nausea 14 (54) 1 (4) 4 (67) ‒Fatigue 13 (50) ‒ 2 (33) ‒ALT increased 8 (31) 3 (12) 5 (83) 3 (50)Diarrhea 8 (31) ‒ 1 (17) ‒Headache 8 (31) 1 (4) 1 (17) ‒Constipation 7 (27) ‒ 2 (33) ‒Fall 7 (27) ‒ ‒ ‒AST increased 5 (19) 3 (12) 4 (67) 1 (17)Dysgeusia 5 (19) ‒ 1 (17) ‒Seizure 5 (19) ‒ ‒ ‒Vomiting 5 (19) 1 (4) 1 (17) ‒Dizziness 4 (15) ‒ ‒ ‒Thrombocytopenia 4 (15) 1 (4) 2 (33) ‒

Monotherapy Treatment: Duration and Best Overall Response

a Pt did not have measurable disease at baseline and was not included in the response analysis. b Pt discontinued treatment after 1 dose due to AE, was non-evaluable, and was not included in the clinical activity analyses.

Duration of Olutasidenib Treatment (Months)0 5 10 15

b

• Disease control (PR + SD) in 50% of patientso 9 (38%) patients stable > 4 months

• Median duration of treatment: 4.2 months (range: 0.03 to 15.9)o Enhancing patients: 3.7 months (range: 0.03 to 15.9)

• Time to response: 1.9 months• Duration of response: 10.1 months

*

*

*a

*†

†

†

Treatment ongoing

PRSDPDNon-evaluable

† Non-enhancingRemained on study with PD due to clinical benefits

*

RANO vs. Volumetric Assessment of Tumor Burden

a Changes > 100% are reported as 100%. b Response-evaluable analysis set; 2 patients were non-evaluable (for volumetric assessment, an additional 2 pts had no data at data cutoff).

Investigator Assessment(RANO)

Investigator-Assessed Best Response per RANO, n (%)

Olutasidenib(N = 24)b

PR 1 (4)

SD 11 (46)

PD 12 (50)

-100

-50

0

50

100

% C

hang

e fr

om B

asel

inea

†

† †

PR SD PD † Non-enhancing

Central Volumetric Assessment (BICR)

Independent Central Volumetric Assessment, n (%)

Olutasidenib(N = 22)b

≥ 50% decrease 4 (18)

> 25% decrease but < 50% decrease 1 (5)

≤ 25% decrease and ≤ 25% increase 7 (32)

> 25% increase 10 (45)

-100

-50

0

50

100

% C

hang

e fro

m B

aseli

nea

†

†

PR SD PD † Non-enhancing

†

Tumor Response in 50 y/o Female with Glioblastoma

March 2019Baseline

C9: -3%Stopped

dexamethasone

C3 : +22%Started

dexamethasone

C12: -30%

March 2019• Olutasidenib 150 mg BID

April 2020• Remains on

treatment, off steroids, and clinically stable

Sept 2014• Diagnosed• Gross total

resection• Concurrent

chemoradiation followed by adjuvant TMZ

2015• Bevacizumab

added

2016• SRS 15 Gy

in 1 fraction

2018• Dose-dense TMZ

Radiographic progression Radiation or chemoradiationSystemic treatmentNew lesion

C15: -40%

Conclusions

• Olutasidenib (150 mg BID) is well tolerated as monotherapyin patients with glioma

• Olutasidenib plasma concentrations, at levels predicted to safely provide benefit, were maintained over the treatment duration

– Clinically-relevant concentrations of olutasidenib were observed in the CSF, confirming the CNS penetration observed in preclinical models

• Olutasidenib demonstrates a preliminary disease control rate of 50% in heavily pretreated patients with predominantly enhancing recurrent mIDH1 glioma

‒ Nine patients with SD > 4 months

‒ One patient achieved a PR per investigator assessment by RANO

‒ Four patients achieved > 50% tumor reduction by blinded independent central volumetric assessment (BICR)

• The authors thank the patients and their familiesfor participation in the study

• This study was funded by Forma Therapeutics, Inc., Watertown, MA • Olutasidenib (FT-2102) is an investigational drug, no efficacy or safety

claims are intended or implied• Medical writing and editorial assistance was provided by Elizabeth

Cameron, PhD, of Chrysalis Medical Communications, Hamilton, NJ

Acknowledgments

1. Yan H, et al. N Engl J Med. 2009;360:765-773.

2. Cohen AL, et al. Curr Neurol Neurosci Rep. 2013;13:345.

3. Reitman ZJ, Yan H. J Natl Cancer Inst. 2010;102:932-941.

4. Huang J, et al. Front Oncol. 2019;9:506.

5. Golub D et al, Front Oncol 2019; 9:417.

6. Prensner JR, Chinnaiyan AM. Nat Med. 2011;17:291-293.

7. Megías-Vericat JE, et al. Blood Lymphat Cancer. 2019;9:19-32.

8. Cortes JE, et al. HemaSphere. 2019;3(S1):86-87.

9. Carvella JA, et al. J Med Chem. 2020;63:1612-1623.

10. De la Fuente MI, et al. Presented at the Society for NeuroOncology Annual Meeting; November 20-24, 2019; Phoenix, AZ. Abstract ACTR-52.

11. ClinicalTrials.gov. NCT03684811.

References and Abbreviations

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AZA, azacitidine; BICR, blind independent central review committee; BID, twice daily; CSF, cerebrospinal fluid; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; LFT, liver function test; mIDH1, isocitrate dehydrogenase 1 mutations; PD, progressive disease; PK, pharmacokinetics; PR, partial response; pt, patient; RANO, response assessment in neuro-oncology; SD, stable disease; TMZ, temozolomide.