THE CANCER STEM CELL INHIBITORS VS-6063 AND VS-5584 EXHIBIT SYNERGISTIC ANTICANCER ACTIVITY IN PRECLINICAL MODELS OF MESOTHELIOMA

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1 THE CANCER STEM CELL INHIBITORS VS-6063 AND VS-5584 EXHIBIT SYNERGISTIC ANTICANCER ACTIVITY IN PRECLINICAL MODELS OF MESOTHELIOMA Mitchell Keegan, Ph.D. Vice President of Development, Verastem, Inc. 1

2 Disclosure I am an employee and stockholder of Verastem Inc. I will be discussing investigational drugs 2

3 Developing potential treatment options throughout the mesothelioma patient journey Ongoing studies: Neo adjuvant + Relapsed MPM 80% 4 6 cycles Pem/Cis Treatment holiday 2 nd line chemo or clinical trial Surgery 20% We want to maximize the potential treatment options for patients with mesothelioma 3

4 Standard of care chemotherapy enriches cancer stem cells in both mesothelioma cell lines and patient tumors Mesothelioma CSCs in vitro H2052 cell line Mesothelioma CSCs in vivo Paired patient biopsies Pre treatment Post treatment Mean H Score / Patient Pem/Cis MPM cells treated with SOC chemotherapies are enriched for cancer stem cells Brown = ALDH+ (cancer stem cells) Treatment of MPM tumors with SOC chemotherapy enriches for cancer stem cells Pre Post 4

5 Profiles of & (defactinib) Potent, selective inhibitor of FAK & PYK2 tyrosine kinases Preferentially targets Cancer Stem Cells (CSCs) Lead compound, studied in 300+ patients to date with good safety profile Ongoing registration directed trial in mesothelioma Orphan designation in US and EU for mesothelioma FAK EC 50 = 15 nm PYK2 EC 50 = 95 nm Potent, selective inhibitor of PI3K & mtor kinases Preferentially targets Cancer Stem Cells (CSCs) Currently in Phase 1 with intermittent dosing schedule (3x weekly) mtor IC 50 (nm) PI3K isoform IC 50 (nm) α β δ γ AKT mtorc1 PI3K RTKs AKT mtorc2 Tumor cell/csc survival & proliferation 5

6 Rationale: Combination of (FAK) with (PI3K/mTOR) for the treatment of relapsed/refractory mesothelioma Both FAK & PI3K/mTOR inhibitors have shown early signs of clinical activity in mesothelioma 29 patients evaluated by GSK with their FAK inhibitor in Phase 1: Treatment resulted in median PFS of 4.5 months (vs. 6 weeks) 1 patient in Phase 1 in Japanese subjects: Symptom improvement and PFS of 5.6 months PI3K/mTOR dual inhibitor GDC 0980 showed 4 PRs among 33 mesothelioma patients in a Phase 1 study (ECCO 2013) FAK & PI3K/mTOR inhibition may combine for more robust shut down of AKT survival signaling PI3K mtorc1 RTKs Akt SRC mtorc2 FAK P Y397 Proliferation/Survival/CSC Function Integrin p130cas 6

7 inhibits tumor initiation in mouse mesothelioma models Control H28 meso cell line Pemetrexed & Pemetrexed Recovery Tumor initiation in vivo Tumor free mice, % Pem Pemetrexed Control Weeks 7

8 Oral administration of targets cancer stem cells in mesothelioma tumors grown in mouse lungs treatment, MM87 mesothelioma xenograft model: 50 mg/kg, po BID x 2 wks * p<0.05 Control Cancer Stem Cells (ALDH+) DAPI 8

9 preferentially targets CSCs: ~ 70 fold reduction in tumor initiating frequency in a SCLC model treatment, H841 SCLC model: Control Liberase CSC Assays Viable cells Re implantation in limiting dilutions Antitumor Efficacy SP CSC Assay Tumor Initiation 50 Tumor Initiating Cells / 1 million Vehicle p < **** 9

10 & exhibit synergistic combination activity in mesothelioma cell lines in vitro Combination Index Analysis Highest Single Agent Analysis Combination Index Combination Index H2052 mesothelioma ED50 ED75 ED90. + Mero 41 mesothelioma ED50 ED75 ED90 Antagonism Synergism Antagonism Synergism Synergy µm M µm HSA Additivity Model 10

11 Synergistic combination of and for targeting tumor initiating cells Meso cell line Control & Recovery Aldefluor assay Limiting dilutions assay Aldefluor+ CSCs (% of Control) Aldefluor+ CSCs Mero 14 cell line 0.1 µm 0.3 µm Combo TIC per 10 6 cells Limiting dilution tumor initiation H28 cell line 150 fold decrease 196 fold decrease decrease Control & 11

12 Synergistic combination of and for enhanced anti tumor efficacy compared to single agent in orthotopic meso model MM87 meso cell line Injection Mesothelioma tumor grown in lungs for 11 days Control (BID) (M/W/F) & Treatment for 2 weeks Tumor burden assessment % of tumor area Tumor burden after treatment p < p < Control VS out of 10 mice tumor free in the + combination group No tumor free mice in other groups 12

13 Summary & conclusions (defactinib) is a potent/selective FAK kinase inhibitor is a potent/selective inhibitor of PI3K & mtorc1/2 Both agents preferentially target CSCs and also reduce bulk tumor growth in preclinical mesothelioma models Synergistic activity of & on CSCs & bulk tumor has been observed in preclinical models These data support an ongoing Phase I combination study of & VS 5583 in patients with relapsed/refractory mesothelioma Additional study details will be presented at Poster #P