Olutasidenib (FT-2102) Induces Rapid Remissions in Patients with - - PowerPoint PPT Presentation

Olutasidenib (FT-2102) Induces Rapid Remissions in Patients with IDH1-Mutant Myelodysplastic Syndrome: Results of Phase 1/2 Single-Agent Treatment and Combination with Azacitidine

Jorge E. Cortes,1 Eunice S. Wang,2 Justin M. Watts,3 Sangmin Lee,4 Maria R. Baer,5 Kim-Hein Dao,6 Shira N. Dinner,7 Jay Yang,8 William B. Donnellan,9 Anthony Schwarer,10 Christian Recher,11 Patrick Kelly,12 Jennifer Sweeney,12 Julie Brevard,12 Patrick Henrick,12 Sanjeev Forsyth,12 Sylvie Guichard,12 Hesham Mohamed,12 Andrew H. Wei13

1Georgia Cancer Center, Augusta, GA; 2Roswell Park Comprehensive Cancer Institute, Buffalo, NY; 3Sylvester Comprehensive Cancer Center, University of

Miami Health System, Miami, FL; 4Weill Cornell Medicine, New York, NY; 5University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD; 6Oregon Health Sciences University, Portland, OR; 7Northwestern University, Chicago, IL; 8Karmanos Cancer Center, Detroit, MI;

9Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 10Box Hill Hospital, Box Hill, VIC, Australia; 11Institut Universitaire du Cancer de

Toulouse Oncopole, CHU de Toulouse and Université de Toulouse III, Toulouse, France; 12FORMA Therapeutics, Inc., Watertown, MA; 13The Alfred Hospital and Monash University, Melbourne, VIC, Australia

1

• IDH1 mutations occur in approximately 4% of patients with MDS, yielding hypermethylated DNA

and histones

• Olutasidenib (FT-2102) is an oral highly potent and selective inhibitor of IDH1m with clinical activity

in AML (ORR, 41%; monotherapy in R/R AML)

Introduction

Olutasidenib (FT-2102)

FT-2102 in MDS: Study Design

4 Monotherapy and 4 Olutasidenib + AZA cohorts Cohort 5 (Olutasidenib + AZA): Patients with R/R MDS and an inadequate response to or progression on prior HMA n = 10 Objectives Primary

• Phase 1: Safety and

tolerability

• Phase 2: Efficacy (CR rate)

Secondary and exploratory

• Phase 1: Clinical activity,

PK, biomarkers, mutation analysis

• Phase 2: Clinical activity,

safety and tolerability, PK, biomarkers, mutation analysis

a Olutasidenib given daily over continuous 28-day cycles (RP2D 150 mg BID). b AZA (75 mg/m2 IV ) given daily on days 1-7 of each 28-day cycle.

Dose Expansion Dose Escalation

Olutasideniba n = 6 Olutasideniba + AZAb n = 7

Key inclusion criteria:

• Intermediate to very

high-risk MDS with IDH1m

• R/R
• Treatment naive
• Adequate cardiac,

renal, and hepatic function

• ECOG PS 0-2

Phase 1 Phase 2

150 mg QD 150 mg BID 150 mg BID 150 mg QD 300 mg QD 150 mg BID 150 mg BID Results of Phase 1 AML cohort presented in Session 616, Saturday, December 7 Abstract # 231

FT-2102 in MDS: Baseline Demographics and Disease Characteristics

a Not inclusive of all types; patient could have received > 1 type of prior regimen.

Characteristic Olutasidenib (n = 6) Olutasidenib + AZA (n = 17) Age, median (range), years 77 (66-87) 72 (59-82) ECOG PS 0/1/2, n 0/4/2 3/14/0 Time since initial diagnosis, median (range), months 17.8 (1.4-77.7) 13.8 (0.5-196.8) Disease state, n (%) R/R 4 (67) 12 (71) Treatment naive 2 (33) 5 (29) MDS risk category, n (%) Intermediate 4 (24) High 5 (83) 10 (59) Very high 1 (17) 3 (18) Cytogenetic risk category, n (%) Good/very good 1 (17) 9 (53) Intermediate 1 (17) 3 (18) Poor/very poor 2 (33) 2 (12) Unknown 2 (33) 3 (18) Prior regimens, median (range), na 1 (0-4) 1 (0-4) Prior HMA, n (%) 4 (67) 11 (65) Duration of prior HMA, median (range), months 17.4 (3.6-45.2) 6.8 (0.2-37.0) Time between HMA and first olutasidenib dose, median (range), months 1.2 (0.3-64.0) 3.1 (1.2-17.0)

FT-2102 in MDS: Patient Disposition

Characteristic Olutasidenib (n = 6) Olutasidenib + AZA (n = 17) Treatment ongoing, n (%) 2 (33) 10 (59) Treatment discontinued, n (%) 4 (67) 7 (41) Transplant 3 (18) Disease progression 3 (50) 1 (6) Death 1 (6) Adverse event 1 (17) Othera 2 (12) Time on treatment, median, months 6.3 15

a Other reasons included alternative treatments.

• The median time on treatment for all patients with MDS treated with olutasidenib (± AZA) was 8.0 months

FT-2102 in MDS: Clinical Activity

Olutasidenib (n = 6) Olutasidenib + AZA (n = 16)a Investigator-Assessed Response, n (%) ORRb [95% CI] 3 (50) [11.8-88.2] 9 (56) [29.9-80.2] CR 2 (33) 4 (25) Marrow CR 1 (17) 5 (31) Clinical benefit (CB = SD ≥ 8 weeks) 1 (17) 5 (31) PD 1 (17) 1 (6) NE 1 (17) 1 (6) Time to first response, median (range), months 8.3 (< 1 to 9.7) 2.8 (< 1 to 5.1) Duration of overall response, median (range), months NR (6.7-NR) 12.9 (< 1 to NR)

a Efficacy-evaluable population. One patient was excluded from efficacy analysis due to lack of R132X mutation. b ORR = CR + marrow CR + PR. NR, not reached

• 12 of 22 patients (55%) achieved CR/marrow CR
• 3 Patients proceeded to transplant
• 12 Patients remain on treatment

FT-2102 in MDS: Time on Treatment

* This patient had R100X mutation, a non-R132 mutation, and was not included in the efficacy-evaluable set.

Off treatment Continuing on study SCT First response CR Marrow CR CB PD NE 10 20 30 40 50 60 70 80 90 100 110 120 Weeks on Study

*

FT-2102 in MDS: Hematologic Improvement in Clinical Benefit and Marrow CR

Response, n (%) Olutasidenib (n = 6) Olutasidenib + AZA (n = 16)a

Patients with CB or marrow CR 2 (33) 10 (63) Patients with hematologic improvement 2 (100) 9 (90) Erythroid improvement Baseline hemoglobin < 11 g/dL 2 (100) 9 (90) Hemoglobin increased by ≥ 1.5 g/dL from baseline 2 (100) 4 (44) Platelet improvement Baseline platelet < 100 × 109/L 2 (100) 7 (70) Any improvement 1 (50) 2 (29) Change > 30 × 109/L (baseline, ≥ 20 × 109/L ) 1 (50) 1 (14) At least 100% increase to > 20 × 109/L (baseline, < 20 × 109/L ) 1 (14) Neutrophil improvement Baseline neutrophils < 1 × 109/L 1 (50) 8 (80) Increase > 0.5 × 109/L and ≥ 100% increase from baseline 1 (100) 8 (100)

a Efficacy-evaluable population. One patient was excluded from efficacy analysis due to lack of R132X mutation.

FT-2102 in MDS: TEAEs (> 20% Overall) Regardless of Causality

TEAE, n (%) Olutasidenib (n = 6) Olutasidenib + AZA (n = 17) Overall (N = 23) Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Hematologic Thrombocytopenia 2 (33) 2 (33) 7 (41) 4 (24) 9 (39) Neutropenia 1 (17) 1 (17) 6 (35) 6 (35) 7 (30) Nonhematologic Nausea 4 (67) 9 (53) 1 (6) 13 (57) Fatigue 4 (67) 1 (17) 6 (35) 2 (12) 10 (43) Arthralgia 4 (67) 1 (17) 5 (29) 9 (39) Constipation 1 (17) 8 (47) 9 (39) Dyspnea 2 (33) 5 (29) 1 (6) 7 (30) Vomiting 2 (33) 5 (29) 7 (30) Cough 1 (17) 5 (29) 6 (26) Dizziness 1 (17) 5 (29) 6 (26) Headache 2 (33) 4 (24) 6 (26) Diarrhea 1 (17) 4 (24) 1 (6) 5 (22) Hematuria 2 (33) 3 (18) 1 (6) 5 (22) Pain in extremity 3 (50) 2 (12) 1 (6) 5 (22)

• IDH differentiation syndrome was observed in 3 patients (13%)
• LFT (AST, AST, bilirubin) abnormalities were observed in 4 patients; 2 (G1, G3) continued dosing through the elevation, 1

(G3) improved with dose reduction, and 1 (G3) discontinued treatment after a positive re-challenge

• 22 Mutations were identified in 17 patients

with samples available for central analysis

• 3 Patients had multiple baseline IDH1

mutations

FT-2102 in MDS: Mutations Consistent With Previous MDS Studies

Baseline Co-Mutations

Median = 3 (range, 0-5) R132C, 41.2% R132H, 58.8% R132G, 17.6%

S R S F 2 A S X L 1 R U N X 1 D N M T 3 A C S F 3 R N P M 1 S T A G 2 E Z H 2 U 2 A F 1 A S X L 2 S E T B P 1 N R A S F L T 3 G A T A 2 T P 5 3 C B P C U X 1

5 10 15 20 25 30 35 40 45 50 Patients with co-mutations, % 5% 32% 44% 14% 5% R132G R132H WT R132C R132L

• 44% of patients (4/9)

experienced mutation clearance (VAF < 1%)a

• Rapid reduction of 2-HG
• ccurred by the end of

cycle 1

2-HG; 2 hydroxyglutarate; VAF, variant allele frequency

a Only patients who received ≥ 3 cycles of treatment and ≥ 1 postbaseline VAF assessment were analyzed for mutation clearance.

FT-2102 in MDS: Olutasidenib Induces IDH1 Mutation Clearance and Reduces 2-HG

VAF, n 16 11 4 4 5 4 3 2 3 2-HG, n 16 14 12 12 11 10 6 5 5

5 4 3 2 1 C1D1 C2D1 C3D1 C4D1 C5D1 C6D1 C7D1 C8D1 C9D1 Baseline Normalized Value VAF 2-HG

• Olutasidenib is well tolerated as a single agent and in combination with AZA
• Patients with MDS remained on treatment for a median of 8 months
• Olutasidenib demonstrated preliminary clinical activity as a single agent and in

combination with AZA in treatment-naive and relapsed/refractory patients with MDS:

• 50% of patients treated with olutasidenib monotherapy achieved CR/mCR
• 56% of patients treated with olutasidenib + AZA achieved CR/mCR
• Clinical benefit with hematologic improvement was observed with olutasidenib

monotherapy and olutasidenib + AZA in 17% and 31% of patients, respectively

• Mutation clearance was observed in 44% of evaluable patients
• Rapid and sustained reduction of 2-HG was seen by the end of cycle 1

FT-2102 in MDS: Conclusions

• The authors thank the patients and their families for 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 claim is intended or implied
• Medical writing and editorial assistance was provided by Alex Loeb, PhD, CMPP, of Chrysalis

Medical Communications, Hamilton, NJ

Acknowledgments