Verastem, Inc. · NASDAQ:VSTM

Verastem — Verastem Oncology — Investor Presentation (November 2021)

55 slides from Verastem's investor presentation, November 2021

  1. Slide 1: Corporate Presentation

    Corporate Presentation November 2021

  2. Slide 2: Safe Harbor Statement

    Safe Harbor Statement This presentation includes forward-looking statements about, among other things, Verastem Oncology’s programs and product candidates, including anticipated regulatory submissions, approvals, performance and potential benefits of Verastem Oncology’s product candidates, that are

  3. Slide 3: Well Positioned to Capitalize on Growth Opportunities

    Verastem Oncology Well Positioned to Capitalize on Growth Opportunities New lead clinical program VS-6766 (RAF/MEKi) and defactinib (FAKi) are clinically active against has best-in-class potential RAS mutant cancers FDA Breakthrough Therapy Designation in LGSOC; Supported We are a Rapid development

  4. Slide 4: Verastem Oncology Strategic Transformation

    Verastem Oncology Strategic Transformation Q1 2020: In-licensed global rights to VS-6766, best-in-class RAF/MEK inhibitor, from Chugai PIPE financing based on data for new clinical program Q3 2020: Divested global rights to Copiktra to Secura Bio Q4 2020: Initiated registration-directed ph. 2 study

  5. Slide 5: VS-6766 RAF/MEK Inhibitor Program Overview

    VS-6766 RAF/MEK Inhibitor Program Overview

  6. Slide 6: VS-6766 is a differentiated, best-in-class asset across multiple patient populations

    VS-6766 is a differentiated, best-in-class asset potentially applicable across multiple patient populations • Unique dual RAF/MEK targeting mechanism of action • Best-in-class safety & tolerability profile relative to marketed MEK inhibitors, with potential for combinability with agents from multipl

  7. Slide 7: High Priority Lead Indications with Multiple Growth Opportunities

    High Priority Lead Indications with Multiple Growth Opportunities High Priority Registration Indications Signal Finding Registration-Directed Trials Initiated in 4Q20  VS-6766 + G12Ci KRASG12C mt NSCLC2  LGSOC1,2  Pancreatic1,2 (10 pt cohort initiated)  KRAS mt endometrioid1 (10 pts initiated) 

  8. Slide 8: Robust Pipeline Targeting the RAS Pathway and Multiple Growth Opportunities

    Robust Pipeline Targeting the RAS Pathway and Multiple Growth Opportunities FDA Breakthrough Therapy Designation for VS-6766 + defactinib KRAS mt NSCLC | VS-6766 + sotorasib (G12Ci) Clinical Collaboration Initiated with *Pre-clinical studies ongoing in multiple KRAS mutant tumors RAMP 201 study = NC

  9. Slide 9: VS-6766 is a Unique Small Molecule RAF/MEK Inhibitor

    VS-6766 is a Unique Small Molecule RAF/MEK Inhibitor  VS-6766 inhibits both MEK & RAF kinase activities  MEK inhibitors paradoxically induce MEK phosphorylation (pMEK) by relieving ERK-dependent feedback inhibition of RAF  By inhibiting RAF phosphorylation of MEK, VS-6766 has advantage of not ind

  10. Slide 10: VS-6766 inhibits cell proliferation across multiple MAPK pathway alterations

    VS-6766 inhibits cell proliferation across VS-6766 IC50 multiple MAPK pathway alterations and multiple solid tumor indications (3D proliferation assay) Other NRAS Other KRAS G12C KRAS G12D KRAS G12V KRAS mt BRAF mt mt mt 10 VS-6766 IC50 (M) 1 0.1 0.01 SNG-M HPAC SNU-C2B SNU-C2A GAK AN3 CA RKO MIAPA

  11. Slide 11: Vertical Blockade: Establishing VS-6766 as the backbone of therapy

    Vertical Blockade: Establishing VS-6766 as the backbone of therapy for RAS pathway-driven tumors Growth factors ▪ Current Challenges RTK • Blocking any single target in the pathway is insufficient for maximum depth and EGFRi duration of anti-tumor efficacy FGFRi • e.g., SHP2i, KRAS-G12Ci, RAFi, MEKi

  12. Slide 12: Parallel Pathway Inhibition: Establishing VS-6766 as the backbone of therapy

    Parallel Pathway Inhibition: Establishing VS-6766 as the backbone of therapy for RAS pathway-driven tumors Growth factors Extracellular Matrix ▪ Current Challenges RTK Integrin • Blocking Ras pathway can be circumvented through EGFRi α parallel pathways β FGFRi • e.g., PI3K/AKT/mTOR, FAK, RhoA,YAP F

  13. Slide 13: VS-6766 +/- Defactinib in Low-Grade Serous Ovarian Cancer

    VS-6766 +/- Defactinib in Low- Grade Serous Ovarian Cancer

  14. Slide 14: Favorable Tolerability Profile with Novel Intermittent Dosing Regimen

    Favorable Tolerability Profile with Novel Intermittent Dosing Regimen Summary of Adverse Events Grade ≥ 3 Occurring in ≥ 5% of patients VS-6766 monotherapy RP2D RP2D Daily at MTD VS-6766 monotherapy (VS-6766 3.2mg twice weekly + N=6 4mg twice weekly defactinib 200mg twice daily) 28-day cycle N=26 N=

  15. Slide 15: Favorable Tolerability Profile at Recommended Phase 2 dose for combination

    Favorable Tolerability Profile at Recommended Phase 2 dose for VS-6766 plus defactinib combination regimen VS-6766 3.2mg Twice VS-6766 4mg Weekly Treatment Related Adverse Twice Weekly Def 200mg BID Summary of FRAME Safety Profile Events Details* (4 wks of (3 wks of  Most Adverse Events (AE) were G

  16. Slide 16: VS-6766 with Defactinib Shows Promising ORR with Durability in Refractory LGSOC

    Best response by RECIST KRAS D57-T58ins KRAS D33E, I24N VS-6766 in Combination with Defactinib Shows Promising ORR with Undocumented Undocumented Undocumented Undocumented KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12V Durability in Refractory LGSOC with Expanded Number of Pat

  17. Slide 17: LGSOC: Limited Treatment Options with High Unmet Need

    LGSOC: Limited Treatment Options with High Unmet Need Low-Grade Ovarian Cancer – Treatment Algorithm1 Stage IA-IB Stage IC Stage II-IV Median PFS Response Rate Discontinuation Therapy Months (95% ORR Rate due to AEs Pt Chemo Combo: CI) Carbo-Pt + Paclitaxel (preferred) Standard of Observe only + Bev

  18. Slide 18: 70% of LGSOC tumors driven by mutations in the RAS pathway

    70% of LGSOC tumors driven by mutations in the RAS pathway ~30% of LGSOC Patients Have KRAS mt LGSOC is a type of ovarian cancer that disproportionately ~70% of LGSOC Shows RAS Pathway-Associated mts affects younger women 1,000 to 2,000 patients in the U.S. and 15,000 to 30,000 worldwide diagnosed w

  19. Slide 19: RAMP 201: Phase 2 Recurrent LGSOC Adaptive Design for Potential Accelerated Approval

    RAMP 201: KRAS Mutated (mt) and Wild Type (wt), Phase 2, Recurrent LGSOC Adaptive Design for Potential Accelerated Approval Selection Phase* Defactinib+VS-6766 Expansion Phase**  Recurrent KRAS-mt LGSOC (n=16)  Measurable disease (RECIST VS-6766 Mono Selected Regimen based on ORR Primary Endpoint

  20. Slide 20: LGSOC market opportunity larger or comparable to other KRAS opportunities

    LGSOC market opportunity larger or comparable to other high unmet need KRAS opportunities Prevalence Patient-months of Therapy Per Year2 (across all 2L+ patients) ~6K - 50,000 100,000 150,000 patients US1 NSCLC KRAS G12C3 Pancreatic3 LGSOC3 ~4k ~2k Endometrioid3 wild KRAS type mutation Metastatic uv

  21. Slide 21: VS-6766 +/- Defactinib in NSCLC

    VS-6766 +/- Defactinib in NSCLC

  22. Slide 22: High Unmet Need in Refractory KRAS mt NSCLC Adenocarcinoma

    High Unmet Need in Refractory KRAS mt NSCLC Adenocarcinoma Advanced or Metastatic NSCL Cancer NSCLC Adenocarcinoma3 Recommend Histologic and Molecular Subtyping5 15 EGFR/ALK/ROS1/BRAF Non-targeted Non-Targeted US Annual Incidence1,2: 92K (targeted) PD-(L)1  1% PD-(L)1  1% WW Annual Incidence1,2: 8

  23. Slide 23: VS-6766 Inhibits CRAF - The key driver of KRAS-G12V mutant NSCLC

    VS-6766 Inhibits CRAF - The key driver of KRAS-G12V mutant NSCLC A Precision Approach to KRAS-G12V Driven NSCLC CRAF Drives KRAS G12V mt NSCLC1 CRAF KO Shows Strong KRASG12V Efficacy CRAF BRAF PI3K +83% OS MEK/ERK AKT/mTOR BRAF KO Has No Effect Tumor Growth  KRASG12V signals mainly through RAF/MEK

  24. Slide 24: VS-6766 +/- FAKi induces tumor regression in KRAS G12V mt NSCLC in vivo model

    VS-6766 +/- FAKi induces significant tumor regression in KRAS G12V mt NSCLC in vivo model, with clear differentiation from trametinib KRAS G12V mutant;Tp53 KO NSCLC 80 Doses Tested Tumor volume fold change 60 Trametinib: 0.1 mg/kg QD (5 days/week) VS-6766: 0.1 mg/kg QD (5 days/week) 40 FAKi: 50 mg/k

  25. Slide 25: Case Study: Response to VS-6766 + defactinib in KRAS G12V mutant NSCLC

    Case Study: Response to VS-6766 + defactinib in a patient with KRAS G12V mutant NSCLC VS-6766 + Defactinib May 2019: Diagnosed with NSCLC June 2019 - Sept 2019: Treated with first line Carboplatin + Pemetrexed + Pembrolizumab Oct 2019: Progression, palliative RT to right hip Nov 2019 – present: On t

  26. Slide 26: Strong Signal Identified in KRASG12V to Be Further Validated

    Strong Signal Identified in KRASG12V to Be Further Validated VS-6766 ± Defactinib Has a Confirmed 57% ORR in KRASG12V mt NSCLC in Integrated Analysis Best ResponseBest by RECIST in by response KRAS G12V mt NSCLC RECIST Time on Treatment for KRASG12V mt NSCLC Time on Treatment 10 NSCLC (57% ORR; N=7)

  27. Slide 27: NSCLC Clinical Strategy: KRAS Mutant, Enriched G12V, Phase 2

    NSCLC Clinical Strategy: KRAS Mutant (mt), Enriched G12V, Phase 2, Recurrent NSCLC for Potential Accelerated Approval Selection Phase Expansion Phase  Recurrent NSCLC Defactinib+VS-67661  1-2 prior regimens KRAS mt G12V  1 prior platinum- N=16 containing chemo; KRAS Mutant – G12V  Prior CPI unle

  28. Slide 28: Preclinical synergy of VS-6766 + G12C inhibitors in KRAS G12C mt models

    Preclinical synergy of VS-6766 + G12C inhibitors in KRAS G12C mt models Synergy of VS-6766 + G12C inhibitor AMG 510 across VS-6766 & FAKi potentiate AMG 510 efficacy in KRAS G12C mutant G12C mutant NSCLC, CRC & Pancreatic cancer cell lines Tumor NSCLC in vivo; Tumor growthin all mice with triple com

  29. Slide 29: Acquired resistance mechanisms to KRAS G12Ci treatment support combination with VS-6766

    Acquired resistance mechanisms to KRAS G12Ci treatment in patients further support combination of KRAS G12Ci with VS-6766 Summary of Putative Mechanisms of Acquired • Mechanisms of acquired resistance to KRAS G12Ci Resistance to Adagrasib Treatment adagrasib treatment in patients recently reported1,

  30. Slide 30: Clinical collaboration with Amgen: VS-6766 + sotorasib in NSCLC KRAS G12C

    We have just initiated a clinical collaboration with Amgen to explore the combination of VS-6766 + sotorasib in NSCLC KRAS G12C mt patients  Patients must have Part A: Dose Evaluation Part B: Dose Expansion at RP2D known G12C KRAS (3+3 DLT Assessment) (Primary endpoint ORR) mutation determined usin

  31. Slide 31: Future Opportunities: VS-6766 as Backbone of RAS Therapy

    Future Opportunities: VS-6766 as Backbone of RAS Therapy

  32. Slide 32: Vertical Blockade: Preclinical synergy in combination with several promising targets

    Vertical Blockade: Preclinical synergy in combination with several promising targets VS-6766 + pan-HERi (Afatinib) VS-6766 + SHP2i (RMC-4550) VS-6766 + SOS1i (BI-3406) VS-6766 + Afatinib VS-6766 + BI-3406 80% (4/5) 100% (5/5) 100% (6/6) 100% (5/5) 60% (3/5) 83% (5/6) 40 40 Combined Synergy Score Com

  33. Slide 33: Parallel Pathway Inhibition: Two synergistic combinations progressed to clinical stage

    Parallel Pathway Inhibition: Two synergistic combinations already progressed to clinical stage VS-6766 + p70S6K/AKTi (M2698) VS-6766 + mTORi (Everolimus) VS-6766 + M2698 80% (4/5) 80% (4/5) 66% (4/6) 40 Combined Synergy Score 20 Synergy Antagonism 0 NSCLC Panc -20 -40 HPAFII H1373 H358 H2122 A427 H2

  34. Slide 34: Corporate

    Corporate

  35. Slide 35: Key VSTM Milestones 2020-2022

    Key VSTM Milestones 2020-2022 1H2020 2H2020 1H2021 2H2021 1H2022 VS-6766 In- Licensed from Chugai Copiktra divested Retired Corporate to Secura Bio Outstanding Debt PIPE Financing for New Clinical Program RAMP-201 Amended to Include KRAS wt patients in Updated data Selection Phase from FRAME RAMP-20

  36. Slide 36: Key Financial Statistics

    Key Financial Statistics As of September 30, 2021 Cash, cash equivalents & investments $103.4M Shares fully diluted 196.9M Insider ownership (outstanding / vested) 8.1% / 5.1% * The 2018 Notes have an initial conversion rate of 139.5771 shares of Common Stock per $1,000 which translates to an initia

  37. Slide 37: Backup Slides

    Backup Slides

  38. Slide 38: High Unmet Needs in RAS/RAF/MEK/ERK-Driven Cancers

    High Unmet Needs in RAS/RAF/MEK/ERK-Driven Cancers KRAS-mutant NSCLC 31% Pancreatic Uterine 21% Colorectal Ovarian 45% 5% Incidence3,5: Incidence5: Endometrioid Incidence5: Incidence5: Cancers1 194K 58K 98% Incidence4,5: 59K 105K 22K NRAS-mutant Melanoma 28% Multiple Myeloma 20% Incidence5: Incidenc

  39. Slide 39: KRAS G12V and G12D Represent ~50% of KRAS Mutations across Human Cancers

    KRAS G12V and G12D Represent ~50% of KRAS Mutations across Human Cancers Pancreatic Cancer Pancreatic Adenocarcinoma1 30 % frequency in a total of 780 cancer patients with KRAS mutations1 Annual Incidence3: 58K % of patients 20 10 21.40% G12V 0 25.30% G12D G12D G12V G12R Q61H Q61R G12A G12C 5.10% G1

  40. Slide 40: VS-6766 and FAK inhibitor combination leads to more robust anti-tumor efficacy in vivo

    VS-6766 and FAK inhibitor combination leads to more robust anti-tumor efficacy in vivo KRASmt Ovarian TOV-21G Tumor growth in vivo Model1 KRASmt NSCLC H358 in vivo Model2 VS-4718 + CH5126766 500 Tumor growth Vehicle 600 400 Vehicle (mm3 +/- SEM) Tumor volume Trametinib 0.3 mg/kg QD Tumor volume (mm3

  41. Slide 41: Overcoming Key Resistance Mechanisms to MEK Inhibitors

    Overcoming Key Resistance Mechanisms to MEK Inhibitors p-FAK • MEK inhibition induces 150 compensatory activation of pFAK preclinically and clinically o Trametinib induced ↑ pFAK (Y397) 100 preclinically in KRAS mt NSCLC cell lines H-Score o Also observed in patients 50 • VS-6766 induced ↑ pFAK (Y39

  42. Slide 42: Pharmacokinetic Profiles of VS-6766 + Defactinib in Combination

    Pharmacokinetic Profiles of VS-6766 + Defactinib in Combination Similar to that seen in Single Agent Studies VS-6766 Defactinib Dose AUC0-24h Cmax AUClast Cmax Cohort N Subject Cohort Dose (mg) N Subject (mg) (h*ng/mL) (ng/mL) (h*ng/mL) (ng/mL) 3.2 Mean 6179 354 Mean 2071 273 1 3 200 (with 200mg VS)

  43. Slide 43: NSCLC Responses with VS-6766 + Defactinib Combination (n=20)

    NSCLC Responses with VS-6766 + Defactinib Combination (n=20) Confirmed responses Best response inin2/2 by RECIST KRASpatients mt NSCLC with KRAS G12V mt NSCLC Tumor reduction in 4/6 patients with KRAS G12C mt NSCLC G12D G12C G12D G12C G12D G12D G12D G12D G12C G12C G12D G12C G12C G12A Q61H G12A G12V

  44. Slide 44: Target exposure for preclinical tumor regression covered by twice weekly dosing

    Target exposure for preclinical tumor regression is covered by twice weekly dosing of 4 mg VS-6766 3 wks on/1 wk off Cav for tumor regression from KRAS G12V mt NSCLC GEMM model  Modeling of PK for 4 mg VS-6766 2/wk, 3 wks on/1 wk off, based on 4 mg single dose PK data (study NO21895)  Relationship

  45. Slide 45: Status: Combination of VS-6766 with Everolimus (mTOR inhibitor)

    Status: Combination of VS-6766 with Everolimus (mTOR inhibitor) • Synergy of VS-6766 + everolimus observed broadly VS-6766 + Everolimus across cancer cell lines with various KRAS mutation variants • A well-tolerated RP2D for VS-6766 + everolimus has been established with intermittent dosing of both

  46. Slide 46: VS-6766 with anti-EGFR mAb induces tumor regression in KRAS mt Colorectal PDX model

    Combination of VS-6766 with anti-EGFR mAb induces tumor regression in a KRAS mt Colorectal PDX model • VS-6766 + anti-EGFR (panitumumab) induces tumor regression in a KRAS G12V mt CRC patient-derived xenograft model Vehicle • G12Ci + anti-EGFR (sotorasib + panitumumab and adagrasib + cetuximab) have

  47. Slide 47: VS-6766 monotherapy has shown clinical activity in several cancer indications

    VS-6766 monotherapy has shown clinical activity in several cancer indications, including NSCLC Best Response 47 Guo et al., Lancet Oncology 2020

  48. Slide 48: VS-6766 upregulates MHC Class I antigens on tumor cells

    VS-6766 upregulates MHC Class I antigens on tumor cells: a mechanism for potentiation of I/O efficacy B2M HLA-A 6 8 DMSO Relative mRNA Levels DMSO Relative mRNA Levels VS-6766 VS-6766 6 4 4 RAS/RAF mutation 2 Cell Line Tumor type 2 status 0 A549 TOV21g SKMEL5 IGR1 WM115 0 A549 TOV21g SKMEL5 IGR1 WM1

  49. Slide 49: VS-6766 enhances tumor growth inhibition combined with anti-PD-1

    VS-6766 enhances tumor growth inhibition when combined with anti-PD-1 in the CT26 KRAS (G12D) syngeneic model Tumor growth Survival 1200 100 Vehicle 1000 80 VS-6766 0.5 mg/kg QD x 28 days Vehicle Percent survival anti-PD-1 3 mg/kg 2xW x 4 doses Tumor volume (mm3 +/- SEM) 800 VS-6766 0.5 mg/kg QD 60

  50. Slide 50: LGSOC Market Opportunity – Reference Calculations

    LGSOC Market Opportunity – Reference Calculations Number of Patients (2L+)2 Average months on Patient-months of Therapy Therapy (per patient)2 Per Year (across all 2L+ patients)2 - 10,000 20,000 30,000 40,000 - 5.00 10.00 15.00 - 50,000 100,000 150,000 NSCLC KRAS G12C3 Pancreatic3 LGSOC1 Endometrioi

  51. Slide 51: A drug with a Breakthrough designation will have...

    A drug with a Breakthrough designation will have(1)… • Increased communication with FDA during drug development and review • FDA guidance to ensure that the design of clinical trials are as efficient as practicable • A cross-disciplinary project lead assigned to the FDA review team and increased inv

  52. Slide 52: List of Oncology Drugs that Received Breakthrough Therapy Designation

    List of Oncology Drugs that Received Breakthrough Therapy Designation Sr no. Proprietary Name Established Name Current Approval Status Company 1. Zykadia Ceritinib Approved Novartis 2. Ibrance Palbociclib Approved Pfizer 3. Keytruda Pembrolizumab Approved Merck 4. Opdivo Nivolumab Approved Bristol M

  53. Slide 53: Strong Patent Protection

    Strong Patent Protection • COM for VS-6766 to 2027 & defactinib to 2028, Hatch Waxman should extend to 2032 • VS-6766 intermittent dosing regimen until 2038 if granted • FAK/MEK combination to 2035 • VS-6766/defactinib combination until 2040 if granted • Method of manufacture for VS-6766 to 2032 • O

  54. Slide 54: Experienced Senior Management Team

    Experienced Senior Management Team Brian Stuglik Daniel Paterson Rob Gagnon President and Chief Operating Chief Business and Chief Executive Officer Officer Financial Officer  Global VP & Chief Marketing  CEO – The DNA Repair Co. (now  CFO – Harvard Bioscience, Clean Officer – Lilly Oncology On-Q

  55. Slide 55: Thank You

    W VERASTEM ONCOLOGY

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