Verastem, Inc. · NASDAQ:VSTM
Verastem — Investor Presentation (November 2022)
52 slides from Verastem's investor presentation, November 2022
Slide 1: Corporate Presentation
Corporate Presentation November 2022
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
Slide 3: Well Positioned to Capitalize on Growth Opportunities
Verastem Oncology Well Positioned to Capitalize on Growth Opportunities Lead clinical program has Avutometinib (VS-6766; RAF/MEK clamp) and defactinib (FAK best-in-class potential inhibitor) are clinically active against RAS mutant cancers FDA Breakthrough Therapy Designation in LGSOC; Rapid develop
Slide 4: Key VSTM Milestones 2021-2022
Key VSTM Milestones 2021-2022 1H2022 1H2021 2H2021 4Q2022 ✓RAMP 201 ✓RAMP 201 Target enrollment of Selection Phase Complete ✓RAMP 201 Second Interim Update Amended to Include KRAS wt patients in Initiated enrollment of Expansion Phase Selection Phase ✓Updated data from FRAME RAMP 201 FDA Meeting LGS
Slide 5: Avutometinib is a Differentiated, Potentially Best-in-Class Asset
Avutometinib is a Differentiated, Potentially Best-in-Class Asset Applicable Across Multiple Patient Populations • Unique RAF/MEK clamp mechanism of action • Novel intermittent dosing schedule; convenient oral regimen • Breakthrough Therapy Designation in recurrent low-grade serous ovarian cancer •
Slide 6: Robust Clinical Program: Avutometinib in multiple combinations
Robust Clinical Program: Avutometinib in multiple combinations across RAS/MAPK pathway-driven tumors CLINICAL STUDY COLLABORATION INDICATION REGIMEN NAME PRECLINICAL PHASE 1 PHASE 2 PHASE 3 WITH LGSOC1,2 Avutometinib +/- defactinib RAMP 201 R/R LGSOC Avutometinib + defactinib FRAME R/R endometrioid
Slide 7: Key Financial Statistics
Key Financial Statistics As of and for the quarter ended September 30, 2022 Cash, cash equivalents & investments $104.0M Non-GAAP Operating Expenses $16.4M Shares Outstanding 210.1M Oxford Finance LLC Credit Facility Loan Tranches Event A $25M At closing B $15M COPIKTRA PTCL approval in U.S. or $50M
Slide 8: Avutometinib RAF/MEK Clamp Program Overview
Avutometinib RAF/MEK Clamp Program Overview
Slide 9: Broad Development Opportunities Across RAS/MAPK Pathway-Driven Cancers
Broad Development Opportunities Across Multiple RAS/MAPK Pathway-Driven Cancers High Priority Registration Indication Key Signal Finding Registration-Directed Trial Initiated in 4Q20 Avutometinib + G12Ci in KRAS G12C NSCLC2 (RAMP 203 - sotorasib) & (RAMP 204 - adagrasib) LGSOC1,2 (RAMP 201) Av
Slide 10: Avutometinib is a Unique Small Molecule RAF/MEK Clamp
Avutometinib is a Unique Small Molecule RAF/MEK Clamp Growth factors Avutometinib inhibits MEK, RTK BRAF & CRAF by trapping these molecules in inactive complexes MEK inhibitors paradoxically % Inhibition % Inhibition induce MEK phosphorylation RAS (pMEK) by relieving ERK-dependent feedback inhib
Slide 11: Avutometinib Induces Inactive Complexes of MEK with ARAF, BRAF & CRAF
Avutometinib is a Unique RAF/MEK Clamp which Induces Inactive Complexes of MEK with ARAF, BRAF & CRAF Contrasting mechanism of action vs. trametinib DMSO Tram Avuto + Avutometinib + Trametinib Growth factors Growth factors RTK RTK RAS RAS Formation of DMSO Tram Avuto inactive RAF/MEK RAF complex to
Slide 12: Avutometinib Inhibits Cell Proliferation Across RAS/MAPK Alterations
Avutometinib Inhibits Cell Proliferation Across Multiple RAS/MAPK Pathway Alterations and Multiple Solid Tumor Histologies Avutometinib IC50 (3D proliferation assay) KRAS G12C KRAS G12D KRAS G12V Other KRAS mt BRAF mt NRAS mt NF1 mt Other mt Avutometinib IC50 (M) 10 1 0.1 0.01 H358 SW837 SKLU1 A427
Slide 13: Vertical Blockade: Avutometinib as Backbone of Therapy
Vertical Blockade: Establishing Avutometinib as the Backbone of Therapy for RAS/MAPK 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,
Slide 14: Parallel Pathway Inhibition: Avutometinib as Backbone of Therapy
Parallel Pathway Inhibition: Establishing Avutometinib as the Backbone of Therapy for RAS/MAPK 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,
Slide 15: 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 Avutometinib monotherapy RP2D RP2D Daily at MTD Avutometinib monotherapy (Avutometinib 3.2mg twice N=6 4mg twice weekly weekly + defactinib 200mg 28-day cycle N=26
Slide 16: Favorable Tolerability Profile at RP2D for Avutometinib plus Defactinib
Favorable Tolerability Profile at Recommended Phase 2 Dose for Avutometinib plus Defactinib Combination Regimen Avutometinib Avutometinib Treatment Related Adverse 4mg Twice Weekly 3.2mg Twice Weekly Summary of FRAME Safety Profile Events Details* Defactinib 200mg BID (4 wks of every 4 wks)1 (≥10% p
Slide 17: Avutometinib +/- Defactinib in Low-Grade Serous Ovarian Cancer
Avutometinib +/- Defactinib in Low-Grade Serous Ovarian Cancer
Slide 18: 70% of LGSOC Tumors Driven by Mutations in the RAS/MAPK Pathway
70% of LGSOC Tumors Driven by Mutations in the RAS/MAPK 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 diagno
Slide 19: LGSOC: Limited Treatment Options with High Unmet Need
LGSOC: Limited Treatment Options with High Unmet Need Low-Grade Ovarian Cancer – Treatment Algorithm1 Recent Clinical Trials in Recurrent LGSOC Stage IA-IB Stage IC Stage II-IV Response Rate Median PFS Discontinuation Therapy ORR Months (95% CI) Rate due to AEs Carbo-Pt + Paclitaxel + hormonal (2b)
Slide 20: Avutometinib + Defactinib (FRAME) Shows Promising ORR in Refractory LGSOC
Best response by RECIST KRAS D57-T58ins KRAS D33E, I24N Avutometinib in Combination with Defactinib (FRAME) Shows Promising ORR Undocumented Undocumented Undocumented Undocumented KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12D KRAS G12V with Durability in Refractory LGSOC with Expanded
Slide 21: RAMP 201 Registration-directed Phase 2 Trial in Recurrent LGSOC
RAMP 201 Registration-directed Phase 2 Trial of Avutometinib +/- Defactinib in Recurrent LGSOC KRAS Mutant (mt) and Wild Type (wt) Completed Enrollment Now Enrolling Expansion Phase Selection Phase* Expansion Phase** Avutometinib + Defactinib Avutometinib + Defactinib KRAS mt KRAS mt (n=16) (n=36) P
Slide 22: RAMP 201 Update-October 2022
RAMP 201 Update-October 2022 Update Next Steps • Completed second planned interim analysis • Full enrollment based on the study protocol on • Encouraging efficacy results include independently track and expected by the end of the year confirmed responses • Enrollment continues towards completion of
Slide 23: 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 Pancreatic Cancer3 LGSOC3 ~4k ~2k Endometrioid Cancer3 wild KRAS type mutation
Slide 24: Avutometinib Combinations in NSCLC
Avutometinib Combinations in NSCLC
Slide 25: High Unmet Need in Refractory mt NSCLC Adenocarcinoma
High Unmet Need in Refractory mt NSCLC Adenocarcinoma Advanced or Metastatic NSCL Cancer NSCLC Adenocarcinoma3 Recommend Histologic and Molecular Subtyping5 15 EGFR/ALK/ROS1/BRAF/ Non-targeted Non-Targeted KRAS G12C (targeted) PD-(L)1 1% PD-(L)1 1% US Annual Incidence1,2: 92K WW Annual Incidence
Slide 26: RAMP 202: Phase 2 Trial in Advanced NSCLC, KRAS G12V Cohort
RAMP 202: Phase 2 Trial of Avutometinib +/- Defactinib in Advanced NSCLC Primary Cohort: KRAS G12V NSCLC Selection Phase Expansion Phase Advanced NSCLC 1-2 prior regimens Completed Enrollment 1 prior platinum- containing chemo; Avutometinib + Defactinib1 Prior CPI unless KRAS G12V contraindi
Slide 27: RAMP 202 Results–August 2022
RAMP 202 Results–August 2022 Findings Next Steps • The confirmed ORR was 11% (2/19) in KRAS • Results of Part A of RAMP 202 trial in KRAS G12V NSCLC patients treated with avutometinib G12V NSCLC show avutometinib ± defactinib + defactinib with a disease control rate of 37% did not meet criteria to c
Slide 28: RAMP 202: Avutometinib + Defactinib in BRAF mt NSCLC
RAMP 202: Avutometinib + Defactinib in BRAF mt NSCLC Advanced NSCLC Initial Phase Analysis 1-2 prior regimens 1 prior platinum- containing chemo; Prior CPI unless contraindicated Avutometinib + Defactinib1 Measurable disease BRAF V600E (RECIST 1.1) n=15 BRAF Mutant BRAF Cohorts Appropr
Slide 29: Preclinical Synergy of Avutometinib + G12C Inhibitors in KRAS G12C Models
Preclinical Synergy of Avutometinib + G12C Inhibitors in KRAS G12C Models Avutometinib & FAKi potentiate sotorasib efficacy in KRAS G12C Synergy of avutometinib + G12C inhibitors across NSCLC in vivo; Tumor regression in all mice with triple combination G12C mutant NSCLC, CRC & Pancreatic cancer cel
Slide 30: Acquired Resistance Mechanisms to KRAS G12Ci Support Combination with Avutometinib
Acquired Resistance Mechanisms to KRAS G12Ci Treatment in Patients Further Support Combination of KRAS G12Ci with Avutometinib Summary of Putative Mechanisms of Acquired • Mechanisms of acquired resistance to KRAS G12Ci Resistance to Adagrasib Treatment adagrasib treatment in patients recently repor
Slide 31: RAMP 203: Phase 1/2 Trial of Avutometinib + Sotorasib in KRAS G12C NSCLC
RAMP 203: Phase 1/2 Trial of Avutometinib + LUMAKRASTM (sotorasib) in KRAS G12C Advanced NSCLC Part A: Dose Evaluation Part B: Dose Expansion at RP2D Patients must have a (3+3 DLT Assessment) (Primary endpoint ORR) KRAS G12C mutation determined using validated test Cohort 1 Treatment with at lea
Slide 32: RAMP 204: Phase 1/2 Trial of Avutometinib + Adagrasib in KRAS G12C NSCLC
RAMP 204: Phase 1/2 Trial of Avutometinib + Adagrasib in KRAS G12C Advanced NSCLC Part A: Dose Evaluation Part B: Dose Expansion Patients must have a (3+3 DLT Assessment) (Primary endpoint ORR) KRAS G12C mutation determined using validated test Treatment with at least 1 but no more than 3 prior
Slide 33: Future Opportunities: Avutometinib as Backbone of RAS Therapy
Future Opportunities: Avutometinib as Backbone of RAS Therapy
Slide 34: High Unmet Needs in RAS/MAPK Pathway-Driven Cancers
High Unmet Needs in RAS/MAPK Pathway-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 148K 22K NRAS-mutant Melanoma 28% Multiple Myeloma 20% Incidence5: Inciden
Slide 35: Preclinical Synergy of Avutometinib with Promising Agents
Preclinical Synergy of Avutometinib in Combination with Promising Agents for Clinical Investigation Vertical MAPK Pathway Inhibition Parallel Pathway Inhibition VS-6766 + Palbociclib Avutometinib + pan-HERi (afatinib) Avutometinib + SHP2i (RMC-4550) Avutometinib + SOS1i (BI-3406) Avutometinib 100% (
Slide 36: Avutometinib + Everolimus Clinical Data Presented at ASCO
Avutometinib + Everolimus Clinical Data Presented at ASCO Pre-treatment Avutometinib + Everolimus • Well-tolerated RP2D established for avutometinib + everolimus with intermittent NRAS Q61K dosing of both agents (twice weekly; 3 wks Anaplastic on/1 wk off) thyroid cancer o No DLTs reported at RP2D (
Slide 37: Avutometinib with anti-EGFR mAb Induces Regression in KRAS mt Colorectal PDX Model
Combination of Avutometinib with anti-EGFR mAb Induces Tumor Regression in a KRAS mt Colorectal PDX Model • Avutometinib + anti-EGFR (panitumumab) induces tumor regression in a KRAS G12V CRC patient-derived xenograft model vehicle • G12Ci + anti-EGFR (sotorasib + panitumumab and adagrasib + cetuxima
Slide 38: Avutometinib Patent Exclusivity
Avutometinib Patent Exclusivity Composition of Matter PTE Feb 2027 + 5 yrs (PTE) = 2032 Method of Making Sept 2032 Dosing Protocol May 2038 Combination w/ Defactinib Sept 2040 Methods of Treating 2041 - 2042 if issued Combinations 2041 - 2042 if issued 38
Slide 39: Backup Slides
Backup Slides
Slide 40: Avutometinib Inhibits CRAF - The key driver of KRAS G12V NSCLC
Avutometinib Inhibits CRAF - The key driver of KRAS G12V NSCLC A Precision Approach to KRAS G12V Driven NSCLC CRAF Drives KRAS G12V NSCLC1 CRAF KO Shows Strong KRAS G12V Efficacy CRAF BRAF PI3K +83% OS MEK/ERK AKT/mTOR BRAF KO Has No Effect Tumor Growth KRAS G12V signals mainly through RAF/MEK in
Slide 41: Avutometinib +/- FAKi Induces Tumor Regression in KRAS G12V NSCLC Model
Avutometinib +/- FAKi Induces Significant Tumor Regression in KRAS G12V NSCLC in vivo Model, with Clear Differentiation from Trametinib KRAS G12V;Tp53 KO NSCLC 20 80 Tumor volume fold change Tumor volume fold change 60 Doses Tested 40 15 Avutometinib: 0.1 mg/kg PO QD (5 days/week) (Mean SEM) 20 FAK
Slide 42: Case Study: Response to Avutometinib + Defactinib in KRAS G12V NSCLC
Updated to remove mutant from Case Study: Response to Avutometinib + Defactinib in a Patient with KRAS G12V NSCLC Avutometinib + Defactinib May 2019: Diagnosed with NSCLC June 2019 - Sept 2019: Treated with first line Carboplatin + Pemetrexed + Pembrolizumab Oct 2019: Progression, palliative RT to r
Slide 43: Strong Signal Identified in KRAS G12V NSCLC
Strong Signal Identified in KRAS G12V NSCLC Avutometinib ± Defactinib Has Shown a 57% ORR in KRAS G12V NSCLC in Integrated Analysis Best Response by RECIST in KRAS G12V NSCLC Time on Treatment for KRAS G12V NSCLC Time on Treatment NSCLC (57% ORR; N=7) Weeks on treatment Mono 216 Combo 70 * Mono 58 M
Slide 44: Avutometinib Monotherapy Has Shown Clinical Activity in RAS/RAF Mutant Cancers
Avutometinib Monotherapy Has Shown Clinical Activity in Several RAS/RAF Mutant Cancer Indications, Including NSCLC and Gynecologic Cancers Confirmed responses especially in patients with KRAS G12V mutation KRAS G12R 44 Guo et al., Lancet Oncology 2020
Slide 45: Overcoming Key Resistance Mechanisms to MEK Inhibitors
Overcoming Key Resistance Mechanisms to MEK Inhibitors Growth factors Extracellular Matrix pFAK • MEK inhibition induces RTK Integrin 150 compensatory activation of β α pFAK preclinically and clinically FAK defactinib 100 P H-Score Y397 SRC o Trametinib induced ↑ pFAK (Y397) RAS preclinically in KRA
Slide 46: Avutometinib and FAK Inhibitor Combination Leads to More Robust Anti-Tumor Efficacy
Avutometinib and FAK Inhibitor Combination Leads to More Robust Anti-Tumor Efficacy in vivo KRAS mt Ovarian TOV-21G in vivo Model1 KRAS mt NSCLC H358 in vivo Model2 Tumor growth Tumor growth 500 600 vehicle vehicle 400 trametinib 0.3 mg/kg QD Tumor volume (mm3 +/- SEM) (m m3 +/- SEM) Tumor volume 40
Slide 47: NSCLC Responses with Avutometinib + Defactinib Combination (FRAME)
NSCLC Responses with Avutometinib + Defactinib Combination (FRAME) (n=20) Confirmed responses Best response inin2/2 by RECIST KRASpatients mt NSCLC with KRAS G12V NSCLC Tumor reduction in 4/6 patients with KRAS G12C NSCLC G12D G12C G12D G12C G12D G12D G12D G12D G12C G12C G12D G12C G12C G12A Q61H G12
Slide 48: Target Exposures Covered by Twice Weekly Dosing of 3.2 mg Avutometinib
Target exposures for preclinical tumor regression & pERK inhibition in human subjects are covered by twice weekly dosing of 3.2 mg avutometinib, 3 wks on/1 wk off Avutometinb Concentration (ng/mL) Cav for tumor regression from KRAS G12V NSCLC GEMM model IC50 for pERK inhibition in PBMCs of orally do
Slide 49: Avutometinib Upregulates MHC Class I Antigens on Tumor Cells
Avutometinib Upregulates MHC Class I Antigens on Tumor Cells: A mechanism for potentiation of I/O efficacy B2M HLA-A 6 8 DMSO DMSO Relative mRNA levels Relative mRNA levels avutometinib avutometinib 6 4 4 2 2 RAS/RAF mutation Cell Line Tumor type status 0 0 A549 TOV21g SKMEL5 IGR1 WM115 A549 TOV21g
Slide 50: Avutometinib Enhances Tumor Growth Inhibition with Anti-PD-1 in CT26 Model
Avutometinib Enhances Tumor Growth Inhibition when Combined with Anti-PD-1 in the CT26 KRAS G12D Syngeneic Model Survival Tumor growth 1200 100 Vehicle 1000 80 VS-6766 0.5 mg/kg QD x 28 days Percent survival vehicle anti-PD-1 3 mg/kg 2xW x 4 doses Tumor volume (m m3 +/- SEM) 800 avutometinib 0.5 mg/
Slide 51: Experienced Senior Management Team
Experienced Senior Management Team Brian Stuglik Daniel Paterson Cathy Carew President and Chief Operating Chief Organizational Chief Executive Officer Officer Effectiveness Officer Global VP & Chief Marketing CEO – The DNA Repair Co. (now Principal – HR Collaborative Officer – Lilly Oncology
Slide 52: Thank You
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