Slide 1: Delivering Novel Therapies in RAS/MAPK Pathway Driven Cancers
Delivering Novel Therapies in RAS/MAPK Pathway Driven Cancers May 2024 Corporate Presentation
Slide 2: Disclaimers
2 Disclaimers F orward - Looking This presentation includes forward - looking statements about, among other things, Verastem Oncology’s (the “Company”) programs an d product candidates, strategy, future plans and prospects, including statements related to the timing of the planned rolling New Drug A
Slide 3: Positioned to deliver on potential 2024 catalysts
3 Verastem Oncology Positioned to deliver on potential 2024 catalysts » Potential to be the first approved therapy in LGSOC • Topline data from RAMP 201 evaluating avutometinib, a RAF/MEK Clamp in combination with defactinib, a FAK inhibitor, have continued to demonstrate robust responses in patient
Slide 4: Clinical Program Designed to Address LGSOC and Beyond
4 Clinical Program Designed to Address LGSOC and Beyond Trial/Regimen IND - Enabling/ Preclinical Phase 1 Phase 2 Phase 3 Anticipated Milestones Collaboration Avutometinib + Defactinib: Recurrent LGSOC RAMP 301 RAF/MEK Clamp + FAKi vs ICT RAMP 301 Ongoing Enrollment RAMP 201 RAF/MEK Clamp + FAKi RAM
Slide 5: Avutometinib, RAF/MEK Clamp Program Overview
Avutometinib, RAF/MEK Clamp Program Overview
Slide 6: Avutometinib is a Differentiated Agent with Potential to Serve as Backbone
6 Avutometinib is a Differentiated Agent with the Potential to Serve as the Backbone for Combinations Across RAS Pathway - Driven Cancers • Differentiated investigational RAF/MEK clamp mechanism of action • Novel intermittent dosing schedule; convenient oral regimen • Orphan Drug Designation for avu
Slide 7: Avutometinib is a Differentiated Small Molecule RAF/MEK Clamp
7 Avutometinib is a Differentiated Small Molecule RAF/MEK Clamp Contrasting Mechanism of Action vs. MEK - Only Inhibitors Coma et al., AACR 2022; Ishii et al., Cancer Res , 2013; Lito et al., Cancer Cell , 2014 RTK Growth factors Avutometinib RAS RAF MEK ERK Tumor Growth Avutometinib conc. (µmol/L)
Slide 8: Avutometinib Inhibits Cell Proliferation Across RAS/MAPK Pathway Alterations
8 Avutometinib Inhibits Cell Proliferation Across Multiple RAS/MAPK Pathway Alterations and Multiple Solid Tumor Histologies Verastem, unpublished data S W 1 4 6 3 M I A P A C A 2 H 3 5 8 H 1 3 7 3 S W 8 3 7 H 2 1 2 2 H 2 0 3 0 S W 1 5 7 3 H P A C A S P C 1 H P A F I I S N U - C 2 B L S 5 1 3 L S 1
Slide 9: Novel Combination of Avutometinib + Defactinib
9 Novel Combination of Investigational Avutometinib + Defactinib with Aim to Improve Patient Outcomes 1 Coma et al., AACR 2022; 2 Ishii et al., Cancer Res , 2013; 3 Lito et al., Cancer Cell , 2014; 4 Gershenson et al., Lancet 2022 (Study GOG 281); 5 Monk et al., J Clin Oncol 2020 (MILO Study); 6 Ban
Slide 10: Scientific Rationale for Avutometinib and FAK Inhibitor Combination
10 Scientific Rationale for Avutometinib and FAK Inhibitor Combination KRAS mutant LGSOC PDX model RTK RAS RAF MEK ERK YAP Growth factors β α Y397 Integrin FAK Extracellular Matrix SRC RhoA Tumor Growth P AKT defactinib Feedback Reactivation 0 10 20 30 0 100 200 300 Tumor growth Days after first dos
Slide 11: Optimized Dosing Schedule Defined: Favorable Tolerability Profile
11 Optimized Dosing Schedule Defined: Favorable Tolerability Profile with Novel Intermittent Dosing Regimen Avutometinib monotherapy Daily at MTD N=6 28 - day cycle RP2D Avutometinib monotherapy 4mg twice weekly N=26 28 - day cycle RP2D (Avutometinib 3.2mg twice weekly + defactinib 200mg twice daily
Slide 12: Low-Grade Serous Ovarian Cancer (LGSOC)
Low - Grade Serous Ovarian Cancer (LGSOC)
Slide 13: LGSOC is a Rare Ovarian Cancer that is Insidious, Persistent, and Ultimately Fatal
13 Greater than 80% of patients with LGSOC will experience a recurrence 1 Affects a younger patient population and can disproportionately impact health, fertility, and long - term quality of life 9,10 Current SOC treatments offer poor to moderate response rates (6 - 13%) 5,9,14 Median overall surviv
Slide 14: Low-Grade and High-Grade Serous Ovarian Cancer Are Different Diseases
14 Low - Grade and High - Grade Serous Ovarian Cancer Are Different Diseases LGSOC HGSOC Nuclear atypia Uniform round to oval with little variation +++ Marked variation Mitotic Index <12 mitoses per 10 hpf >12 mitoses per 10 hpf Chromatin and variation in size of nucleus Little Marked (nuclear size
Slide 15: RAMP 201: Topline Data Parts A + B + C
Avutometinib Defactinib in Low - Grade Serous Ovarian Cancer RAMP 201: Topline Data Parts A + B + C
Slide 16: Topline RAMP Data Support Rolling NDA Submission in Recurrent KRAS mt LGSOC
16 Topline RAMP 201 Data Support Rolling NDA Submission in Recurrent KRAS mt LGSOC • RAMP 201 topline data represent larger dataset of patients treated at the RP2D with a minimum follow up of 5 months at last data analysis (Parts A, B and C combined: n=115*; KRAS mt: n=58; KRAS wt : n=57) • Moving f
Slide 17: RAMP 201 (ENGOTov60/GOG3052) Trial Design
17 RAMP 201 (ENGOTov60/GOG3052) Inclusion Criteria Recurrent LGSOC Prior chemotherapy Measurable disease (RECIST 1.1) Prior MEKi allowed Avutometinib + Defactinib KRAS mt (Total n=36) KRAS wt (Total n=36) N=72 (incl Part A+B) Avutometinib + Defactinib KRAS mt KRAS wt Expanded Enrollment +40 pts Avut
Slide 18: Topline Data Pooled ORR RAMP Parts A + B + C
18 Topline Data Pooled ORR RAMP 201 Parts A + B + C, Data cutoff: Feb. 2024 Minimum follow - up: 5 months Avutometinib 3.2 mg + Defactinib 200 mg IRC ORR Overall Population (Confirmed ORR by BICR) 27% (29/109)* 95% CI (19% - 36%) KRAS mt 37% (21/57) KRAS wt 15% (8/52) Clinical Bene
Slide 19: RAMP 201 Part A Response Rate Improved Through First Year of Follow Up
19 Initial Portion of RAMP 201, Part A, Response Rate Improved Through First Year of Follow Up Avutometinib + Defactinib Total (n=29) Minimum follow - up of 12 months ORR, % (n) 45% (13) 95% CI: (26%, 64%) KRAS mt 60% (9/15) KRAS wt 29% (4/14) Patients with reduction in tumor , % (n) 86% (25) Median
Slide 20: FRAME Study: High Rate of Durable Responses
20 FRAME Study: High Rate of Durable Responses with the Combination of Avutometinib and Defactinib in Recurrent LGSOC (n=26) 28 - day cycles DoR: Duration of Response PFS: Progression free survival NR: Not reached • Overall response rate (ORR) = 42% (11 confirmed PRs/26) o KRAS mutant ORR = 58% (7 c
Slide 21: Recent LGSOC Trials Provide Relevant SOC Comparator
21 Recent LGSOC Trials Provide Relevant SOC Comparator Trial Number of Prior Systemic Therapies Median (range) Prior MEK allowed Prior Bevacizuma b Therapy Response Rate ORR Image Assessment Median PFS Months (95% CI) Discontinuation Rate due to AEs GOG 281 1 2 (1 - 10) No * Low % SoC (n=130) 6% 95%
Slide 22: Regulatory Update
Avutometinib + Defactinib in Low - Grade Serous Ovarian Cancer Regulatory Update
Slide 23: Avutometinib + Defactinib for Recurrent LGSOC: Path to Accelerated Approval
23 Avutometinib + Defactinib for Recurrent LGSOC: Path to Accelerated Approval a Gershenson et al, Lancet 2022; Monk et al, JCO 2020 b Breakthrough Therapy Designation for combination of avutometinib and defactinib for treatment of recurrent LGSOC after one or m ore prior lines of therapy including
Slide 24: Commercial Opportunity in Low-Grade Serous Ovarian Cancer
Commercial Opportunity for Avutometinib + Defactinib in Low - Grade Serous Ovarian Cancer
Slide 25: Potential to Rapidly Penetrate the Current Prevalent Patient Population
25 Potential for Avutometinib + Defactinib to Rapidly Penetrate the Current Prevalent Patient Population, if Approved STAGE II - IV DISEASE 1 MOS: ∼ 10 YEARS 2 FRONTLINE TREATMENT INITIAL RECURRENCE SUBSEQUENT RECURRENCE ± Neoadjuvant platinum/ taxane Debulking surgery ± Platinum/ taxane chemotherap
Slide 26: Concentrated Market Opportunity, Potential for Relatively Quick Adoption
26 Anticipate Concentrated Market Opportunity, Potential for Relatively Quick Adoption Given Limitations of SOC Plan for a focused commercial launch, if approved • Top 400 HCPs and top 100 HCOs collectively cover nearly half of the LGSOC population 1 ; focused sales force of 14 - 18 reps Substantial
Slide 27: RAMP 301: Phase 3 Confirmatory Trial
Avutometinib + Defactinib in Low - Grade Serous Ovarian Cancer RAMP 301: Phase 3 Confirmatory Trial
Slide 28: RAMP 301 Phase 3 Trial Design
28 • Confirmed LGSOC diagnosis • Recurrent disease after prior platinum therapy • Documented KRAS mutation status • Measurable disease per RECIST v1.1 • Prior MEKi allowed • Prior Bevacizumab allowed Inclusion Criteria 1:1 Randomization n = 270 Stratification Factors: KRAS mutation status ( wt vs. m
Slide 29: Topline Data from RAMP 205 in First-Line Metastatic Pancreatic Cancer
Topline Data from RAMP 205: Avutometinib + Defactinib + SOC in First - Line Metastatic Pancreatic Cancer
Slide 30: RAMP 205: Designed to Identify and Evaluate RP2D
30 RAMP 205: Designed to Identify and Evaluate RP2D in C ombination with Chemotherapy for Tr eatment of Newly Diagnosed mPDAC Inclusion Criteria Part A: Dose Evaluation (3+3 DLT Assessment) Part B: Dose Expansion (Primary Endpoint: ORR) • Histologic or cytologic confirmed metastatic pancreatic ducta
Slide 31: RAMP 205: Initial Interim Safety and Efficacy Results
31 RAMP 205: Initial Interim Safety and Efficacy Results • Encouraging early interim data from ongoing Phase 1/2 RAMP 205 study evaluating avutometinib + defactinib + gemcitabine + Nab - paclitaxel in first - line metastatic pancreatic cancer • As of data cutoff of May 14, 2024, Dose Level 1 mature
Slide 32: Landmark Trials in First-Line Metastatic Pancreatic Cancer
32 Landmark Trials in First - Line Metastatic Pancreatic Cancer Trial/PI/Reported (# Patients) Intervention Comparator ORR by Investigator (95% CI) mPFS (95% CI) mOS (95% CI) MPACT Von Hoff 2013 (N=861) Gem/NabP * (n=431) Gem (n=430) Gem/NabP 5.5 months (4.5 - 5.9) 8.5 months (7.89 - 9.53) 29% (25 -
Slide 33: RAMP 205: Evaluating Multiple Regimens in Parallel
33 RAMP 205: Evaluating Multiple Regimens in Parallel to Efficiently Identify RP2D in First - Line mPC Duration of Treatment for All Patients; Safety Population (n=41) Data Cutoff Date:14 MAY 2024 Source: Program: F_TR_SWIMMER.sas In Dose Level 1: • 1 of 6 patients achieved objective response by mon
Slide 34: RAMP 205: Best Percent Change in Target Lesion Sum of Diameters
34 RAMP 205: Best Percent Change in Target Lesion Sum of Diameters Includes Patients Who Have Had At Least First Scan (n=26) Data Cutoff Date:14 MAY 2024 Source: Program: F_TR_WATERFALL_BYDOSE2 Threshold for PR
Slide 35: Avutometinib with KRAS G12C Inhibitors in Non-Small Cell Lung Cancer
Avutometinib with KRAS G12C Inhibitors in Non - Small Cell Lung Cancer
Slide 36: High Unmet Need in Refractory NSCLC
36 High Unmet Need in Refractory NSCLC Adenocarcinoma Advanced or Metastatic NSCL Cancer Recommend Histologic and Molecular Subtyping 5 Appropriate targeted agent Chemotherapy Docetaxel Gemcitabine Pemetrexed Prior PD - (L)1 No Prior PD - (L)1 PD - (L)1 Chemo PD - (L)1 PD - (L)1 single agent or PD -
Slide 37: Preclinical Synergy of Avutometinib + G12C Inhibitors
37 0 10 20 30 0 500 1000 1500 2000 Tumor growth Days after first dose T u m o r v o l u m e ( m m 3 + / - S E M ) vehicle sotorasib sotorasib + avutometinib sotorasib + avutometinib + FAKi avutometinib trametinib **** **** **** Preclinical Synergy of Avutometinib + G12C Inhibitors in KRAS G12C Model
Slide 38: Avutometinib + FAKi Restores Anti-Tumor Activity of Sotorasib in Resistant Models
38 Avutometinib FAKi Restores Anti - Tumor Activity of Sotorasib in G12Ci - Resistant KRAS G12C Models Avutometinib inhibits proliferation of cells harboring acquired KRAS mutations that occur clinically upon progression on G 1 2C inhibitors Addition of avutometinib + FAKi restores anti - tumor acti
Slide 39: RAMP 203: Phase 1/2 Trial of Avutometinib + Sotorasib
39 Inclusion Criteria Part A: Dose Evaluation (3+3 DLT Assessment) Part B: Dose Expansion (Primary endpoint: ORR) Cohort 1 Patients without Prior KRAS G12C Inhibitor Treatment Stage 1 : ~20 patients Stage 2 : expand • Documented KRAS G12C mutation determined using validated test • Treatment with 1 b
Slide 40: RAMP 203: Objective Responses in KRAS G12C NSCLC
40 *On treatment at time of data cutoff; + Patient with - 38.4% tumor reduction classified as SD due to disease progression prior to confirmatory scan. Awad et al., EORTC - NCI – AACR Conference Oct 2023 Avutometinib + Sotorasib Percentage Change in Target Lesion Sum with time on treatment RAMP 203:
Slide 41: RAMP 204: Phase 1/2 Trial of Avutometinib + Adagrasib
41 • Documented KRAS G12C mutation determined using validated test • Treatment with >1 but no more than 3 prior systemic regimens, for Stage 3B - C or 4 NSCLC • Must have received prior therapy with a KRAS G12C inhibitor and experienced progressive disease • Measurable disease per RECIST v1.1 • ECOG
Slide 42: RAS Pathway-Driven Cancers and Rational Avutometinib Combinations
RAS Pathway - Driven Cancers and Rational Avutometinib Combinations
Slide 43: Investigator-Sponsored Studies Across RAS Pathway-Driven Indications
43 Indication Incidence/ Prevalence Biomarker % Regimen Setting Phase Institution Gynecologic Cancers LGSOC Prevalence 6k 1 70% Avutometinib + defactinib + letrozole Low - grade serous ovarian cancer without prior systemic treatment Phase 1/2 Memorial Sloan Kettering Cancer Center Gynecologic Basket
Slide 44: Discovery Efforts
Discovery Efforts
Slide 45: Discovery and Development Collaboration with GenFleet
45 Discovery and Development Collaboration with GenFleet Strengthens Pipeline Targeting RAS Pathway - Driven Cancers • Increases the breadth of Verastem’s oncology pipeline with strategically - aligned RAS pathway focus o Exclusive options for Verastem to exclusively license up to 3 programs with de
Slide 46: Rationale for Oral KRAS G12D (ON/OFF) Inhibitor
46 GEF GTP GDP GTP GDP KRAS G12D (ON/OFF) inhibitor RAS/MAPK pathway signaling GEF: Guanine nucleotide exchange factor GAP: GTPase - activating protein GAP P KRAS OFF (inactive) KRAS ON (active) Rationale for Designing a Potent and Selective Orally Bioavailable Inhibitor of KRAS G12D (ON/OFF) for th
Slide 47: GFH375 (VS-7375) is an Oral KRAS G12D (ON/OFF) Inhibitor
47 GFH375 (VS - 7375) is an Oral KRAS G12D (ON/OFF) Inhibitor • GFH375 (VS - 7375) is a potent and selective orally bioavailable inhibitor of KRAS G12D (ON/OFF) with potent anti - tumor efficacy demonstrated across preclinical models • Dual inhibitor of ON (GTP) and OFF (GDP) states of KRAS G12D • O
Slide 48: Financials
Financials
Slide 49: Key Financial Statistics
49 Key Financial Statistics Cash, cash equivalents & investments $110.1M GAAP Operating Expenses $28.1M Non - GAAP Operating Expenses* $26.6M Shares Outstanding 25.3M** As of and for the quarter ended March 31, 2024 • Oxford Finance LLC Credit Facility • Up to $150M available in a series of term loa
Slide 50: Recent Corporate Achievements and Upcoming Milestones
50 Avutometinib + Defactinib: Recurrent LGSOC Avutometinib + Defactinib: Metastatic Pancreatic Cancer Avutometinib + KRAS G12C Inhibitors: NSCLC GFH375/VS - 7375: Oral G12D (ON/OFF) Inhibitor Recent Corporate Achievements x Initiating rolling NDA submission in recurrent KRAS mt LGSOC x Received FDA
Slide 51: Thank You
THANK YOU
Slide 52: Addendum
Addendum
Slide 53: Recurrent LGSOC: High Medical Need
53 Recurrent LGSOC: High Medical Need 1 NCCN guidelines v1.2023 No Category 1 recommendations (high - level evidence). Category 2a (lower - level evidence with uniform NCCN consensus) unless otherwise indicated f: There is no standard sequencing of drugs for recurrent disease. Considerations include
Slide 54: Avutometinib Patent Exclusivity
54 Avutometinib Patent Exclusivity Composition of Matter Method of Making Sept 2032 Dosing Protocol May 2038 Combination w/ Defactinib Dec 2042 Feb 2027 + 5 yrs (PTE) = 2032 Sept 2040 Solid Form PTE 2041 - 2042 if issued Methods or Treating; Combinations
Slide 55: Experienced Senior Management Team
55 Experienced Senior Management Team Previous experience: • CEO, The DNA Repair Co. (now On - Q - ity ) • PharMetrics (now IMS) • Axion Daniel Paterson President and Chief Executive Officer Dan Calkins Chief Financial Officer Cathy Carew Chief Organizational Effectiveness Officer Mike Crowther Chie