8-K
Verastem, Inc. (VSTM)
8-K
2022-06-06
For: 2022-06-06
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April 07, 2026
UNITED STATES SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the
Securities Exchange Act of 1934
Date of report (Date of earliest event reported): June 6, 2022
Verastem, Inc.
(Exact Name of Registrant as Specified in Charter)
| | | | | |
|---|---|---|---|---|
| Delaware | | 001-35403 | | 27-3269467 |
| (State or Other Jurisdiction<br>of Incorporation) | | (Commission<br>File Number) | | (IRS Employer<br>Identification No.)<br><br> |
| | | |
|---|---|---|
| 117 Kendrick Street , Suite 500 , Needham , MA | | 02494 |
| (Address of Principal Executive Offices) | | (Zip Code)<br><br> |
Registrant’s telephone number, including area code: (781) 292-4200
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Securities registered pursuant to Section 12(b) of the Act:
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|---|---|---|---|---|
| Title of each class | | Trading Symbol(s) | | Name of each exchange on which registered |
| Common stock, $0.0001 par value per share | | VSTM | | The Nasdaq Global Market<br><br> |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 7.01. Regulation FD Disclosure
On June 6, 2022, Verastem, Inc. (the “Company”) posted its corporate presentation on its website, a copy of which is furnished hereto as Exhibit 99.1 to this Current Report on Form 8-K.
Item 8.01. Other Events
On June 6, 2022, the Company issued a press release announcing an update from an interim analysis of its international phase 2 RAMP 201 trial evaluating VS-6766 ± defactinib in recurrent low-grade serous ovarian cancer, regardless of KRAS status. A copy of the press release is furnished as Exhibit 99.2 to this Current Report on Form 8-K.
Item 9.01. Financial Statements and Exhibits
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|---|---|---|
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| Exhibit No. | Description | |
| 99.1 | Corporate Presentation, dated June 6, 2022 | |
| 99.2 | | Press release, issued by Verastem, Inc. on June 6, 2022 |
| 104 | | Cover Page Interactive Data File (formatted in Inline XBRL and contained in Exhibit 101) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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|---|---|---|
| | VERASTEM, INC. | |
| | | |
| Dated: June 6, 2022 | By: | /s/ Brian M. Stuglik |
| | | Brian M. Stuglik |
| | | Chief Executive Officer |
Exhibit 99.1
| Corporate Presentation<br>June 2022 |
|---|
| 2<br>Safe Harbor Statement<br>This presentation includes forward<br>-<br>looking statements about, among other things, Verastem Oncology’s programs and<br>product candidates, including anticipated regulatory submissions, approvals, performance and potential benefits of<br>Verastem Oncology’s product candidates, that are subject to substantial risks and uncertainties that could cause actual<br>results to differ materially from those expressed or implied by such statements. Applicable risks and uncertainties<br>include the risks and uncertainties, among other things, regarding: the success in the development and potential<br>commercialization of our product candidates, including defactinib and other compounds in combination with VS<br>-<br>6766;<br>the occurrence of adverse safety events and/or unexpected concerns that may arise from additional data or analysis or<br>result in unmanageable safety profiles as compared to their levels of efficacy; or our ability to obtain, maintain and<br>enforce patent and other intellectual property protection for our product candidates.<br>Other risks and uncertainties include those identified under the heading “Risk Factors” in the Company’s Annual Report<br>on Form 10<br>-<br>K for the year ended<br>December 31, 2021,<br>as filed with the<br>Securities and Exchange Commission<br>(SEC)<br>on<br>March 28, 2022,<br>and in any subsequent filings with the<br>SEC, which are available at www.sec.gov and<br>www.verastem.com.<br>The forward<br>-<br>looking statements in this presentation speak only as of the original date of this presentation, and we<br>undertake no obligation to update or revise any of these statements. |
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| 3<br>We are a<br>biopharmaceutical<br>company<br>committed to<br>developing and<br>commercializing<br>new medicines for<br>patients battling cancer<br>Verastem Oncology<br>Well Positioned to Capitalize on Growth Opportunities<br>VS<br>-<br>6766 (RAF/MEKi) and defactinib (FAKi) are clinically active against<br>RAS mutant cancers<br>30% of all human cancers are driven by mutations in RAS<br>;<br>VS<br>-<br>6766 combinations potentially broadly applicable across a variety of<br>tumor types.<br>Clinical collaborations with Amgen & Mirati<br>evaluating the<br>combinations of VS<br>-<br>6766 with sotorasib & adagrasib, respectively, in<br>KRAS G12C mutant NSCLC supported by strong pre<br>-<br>clinical rationale<br>Multiple clinical opportunities<br>within NSCLC and other tumor<br>areas based on preclinical data<br>Up to $150 million of non<br>-<br>dilutive funding available from new credit facility<br>Cash balance of $106.3 million as of March 31, 2022<br>Company ended Quarter 1 2022 with $18 million non<br>-<br>GAAP operating<br>expenses<br>Cash position, credit facility and expected COPIKTRA milestones extend<br>expected cash runway through 2025 to support continued development and<br>potential commercial launches<br>Lead clinical program has<br>best<br>-<br>in<br>-<br>class potential<br>Significant downstream<br>market opportunity and<br>blockbuster potential<br>Strong balance sheet<br>Rapid development paths<br>to market<br>FDA Breakthrough Therapy Designation in LGSOC;<br>Supported<br>by clinical results (FRAME study) achieved in low<br>-<br>grade serous ovarian<br>cancer (LGSOC), strong signal in KRAS G12V mutant NSCLC;<br>registration<br>-<br>directed trials initiated in 4Q 2020<br>* Q1 2022 GAAP operating expenses<br>-<br>$19.6M minus Q1 2022 stock compensation<br>-<br>$1.6M = $18.0M Q1 2022 non<br>-<br>GAAP operating expenses |
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| 4<br>Key VSTM Milestones 2021<br>-<br>2022<br>LGSOC<br>NSCLC<br>1H2021<br>2H2021<br>1Q2022<br>RAMP<br>-<br>201<br>Amended to Include<br>KRAS wt patients in<br>Selection Phase<br>RAMP<br>-<br>201 Target<br>enrollment of<br>Selection Phase<br>Complete<br>Initiated enrollment of<br>Expansion Phase<br>RAMP<br>-<br>202 Complete<br>enrollment of<br>Selection Phase<br>Updated data from<br>FRAME NSCLC<br>cohort Presented at<br>AACR<br>Updated data<br>from FRAME<br>LGSOC cohort<br>Presenting at<br>ESMO<br>FDA Breakthrough<br>Therapy<br>Designation<br>VS<br>-<br>6766 + Sotorasib<br>Collaboration<br>w/Amgen<br>VS<br>-<br>6766 + Adagrasib<br>Collaboration<br>w/Mirati<br>2Q2022<br>2H2022<br>Additional<br>Indications*<br>Initiate combo study<br>of VS<br>-<br>6766 +<br>cetuximab in KRAS<br>mt CRC<br>RAMP<br>-<br>201 Selection<br>Phase Update*<br>RAMP<br>-<br>201 Complete<br>enrollment of<br>Expansion Phase<br>Translational data<br>from FRAME<br>LGSOC cohort<br>presented at AACR<br>Initiate RAMP<br>-<br>204<br>(VS<br>-<br>6766 + adagrasib)<br>in KRAS G12C (Mirati)<br>Initiate RAMP<br>-<br>203<br>(VS<br>-<br>6766 + sotorasib)<br>in KRAS G12C<br>(Amgen)<br>Top<br>-<br>Line Data from<br>RAMP<br>-<br>202 Selection<br>Phase<br>Top<br>-<br>Line Data from<br>VS<br>-<br>6766 + everolimus<br>in KRAS mt<br>Initiate combo study<br>of VS<br>-<br>6766 +<br>abemaciclib and<br>fulvestrant in ER+<br>breast cancer<br>Initial readout of<br>RAMP 203 data<br>*Next RAMP<br>-<br>201 update expected to be provided once go<br>-<br>forward treatment regimen determined, timing of which will be driven by da<br>ta maturity<br>**Investigator<br>-<br>sponsored research<br>Initiate basket trial of<br>VS<br>-<br>6766 + defactinib in<br>RAS pathway<br>-<br>driven<br>gynecological cancers<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓ |
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| VS<br>-<br>6766 RAF/MEK Clamp Program<br>Overview |
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| 6<br>VS<br>-<br>6766 is a differentiated, potentially best<br>-<br>in<br>-<br>class asset applicable across<br>multiple patient populations<br>•<br>Unique dual RAF/MEK targeting mechanism of action<br>•<br>Novel intermittent dosing schedule; convenient oral regimen<br>•<br>Breakthrough Therapy Designation in recurrent low<br>-<br>grade serous ovarian cancer<br>•<br>Potential best<br>-<br>in<br>-<br>class safety & tolerability profile relative to marketed MEK inhibitors, with potential for<br>combinability with agents from multiple target classes<br>•<br>Promising signals of clinical activity in various RAS<br>-<br>driven cancers, including in patients whose tumors previously<br>progressed on other MEK inhibitors<br>•<br>Preclinical anti<br>-<br>proliferative activity across multiple MAPK pathway alterations (e.g. KRAS, NRAS, BRAF, NF1 mt) and<br>multiple solid tumor indications<br>•<br>Strong preclinical combination data with other agents targeting RAS pathway and parallel pathways |
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| 7<br>High Priority Lead Indications with Multiple Growth Opportunities<br>VS<br>-<br>6766<br>High Priority Registration Indications<br>Registration<br>-<br>Directed Trials Initiated in 4Q20<br><br>LGSOC<br>1,2<br>(RAMP 201)<br><br>KRAS G12V mt NSCLC<br>1,2<br>(RAMP 202)<br>Key Signal Finding<br><br>VS<br>-<br>6766 + G12Ci KRAS G12C mt NSCLC<br>2<br>(RAMP 203<br>-<br>sotorasib) & (RAMP 204<br>-<br>adagrasib)<br><br>KRAS non<br>-<br>G12V<br>1,2<br>mt NSCLC (RAMP 202)<br><br>BRAF mt NSCLC<br>1,2<br>(RAMP 202)<br><br>Pancreatic<br>2<br>(10 pt cohort initiated)<br><br>KRAS mt endometrioid<br>1<br>(10 pts initiated)<br><br>Uveal Melanoma<br>2<br>(IST initiated)<br><br>VS<br>-<br>6766 + Everolimus KRAS mt NSCLC<br>1,2<br>Rational Combinations<br><br>G12Ci<br>1,2<br><br>Anti<br>-<br>EGFR<br>2<br><br>CDK4/6 inhibitor<br>2<br><br>Everolimus<br>1,2<br><br>SOS1 or SHP2 inhibitor<br>2<br><br>Anti<br>-<br>PD<br>-<br>1<br>1,2<br>RAS Pathway Dependent Cancers<br><br>Gynecological<br>1,2<br><br>NSCLC<br>1,2<br><br>Colorectal<br>1,2<br><br>Melanoma<br>1,2<br><br>Pancreatic<br>2<br>Biomarker Selection<br><br>KRAS mt<br>1,2<br><br>BRAF mt (V600 & non<br>-<br>V600)<br>1,2<br><br>NRAS mt<br>1,2<br><br>CRAF mt/fusions<br>2<br>1<br>Supported by clinical data<br>2<br>Supported by preclinical data |
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| 8<br>INDICATION<br>REGIMEN<br>STUDY<br>NAME<br>PRECLINICAL<br>PHASE 1<br>PHASE 2<br>PHASE 3<br>CLINICAL<br>COLLABORATION<br>WITH<br>LGSOC<br>1,2<br>VS<br>-<br>6766 +/<br>-<br>defactinib<br>RAMP 201<br>R/R LGSOC<br>4<br>VS<br>-<br>6766 + defactinib<br>FRAME<br>R/R endometrioid cancer (KRAS<br>mt)<br>4<br>VS<br>-<br>6766 + defactinib<br>FRAME<br>Gynecological cancers (RAS<br>Pathway<br>-<br>driven)<br>4<br>VS<br>-<br>6766 + defactinib<br>IST<br>Mesonephric<br>4<br>VS<br>-<br>6766 + defactinib<br>IST<br>R/R NSCLC (KRAS G12V mt)<br>2<br>VS<br>-<br>6766 +/<br>-<br>defactinib<br>RAMP 202<br>R/R NSCLC (KRAS non<br>-<br>G12V mt)<br>VS<br>-<br>6766 + defactinib<br>RAMP 202<br>R/R NSCLC (BRAF mt)<br>VS<br>-<br>6766 + defactinib<br>RAMP 202<br>R/R NSCLC (KRAS G12C mt)<br>VS<br>-<br>6766 + sotorasib<br>RAMP 203<br>R/R NSCLC (KRAS G12C mt)<br>3<br>VS<br>-<br>6766 + adagrasib<br>RAMP 204<br>R/R NSCLC (KRAS mt)<br>VS<br>-<br>6766 + everolimus (mTORi)<br>IST<br>R/R NSCLC (KRAS mt)<br>4<br>VS<br>-<br>6766 + defactinib<br>FRAME<br>Robust Clinical Program Targeting the RAS Pathway in Gynecologic Oncology<br>& Non<br>-<br>Small Cell Lung Cancer<br>1<br>FDA Breakthrough Therapy Designation<br>2<br>Registration<br>-<br>directed trial<br>3<br>In Startup<br>4<br>Preclinical studies underway, ph. 2 investigator<br>-<br>sponsored trials in preparation |
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| 9<br>VS<br>-<br>6766 is a unique RAF/MEK Clamp which induces inactive complexes of<br>MEK with ARAF, BRAF & CRAF<br>Contrasting mechanism of action vs. trametinib<br>Deborah Morrison unpublished<br>RTK<br>RAS<br>RAF<br>MEK<br>ERK<br>Tumor Growth<br>Growth factors<br>+ VS<br>-<br>6766<br>Improved ERK<br>blockade<br>Feedback<br>reactivation<br>is blocked;<br>Sustained<br>inhibition<br>Formation of<br>inactive RAF/MEK<br>complex to block<br>ARAF, BRAF & CRAF<br>signaling<br>RTK<br>RAS<br>RAF<br>MEK<br>ERK<br>Tumor Growth<br>KSR<br>Growth factors<br>+ Trametinib<br>Feedback<br>reactivation<br>of RAF<br>maintains<br>pMEK;<br>Adaptive<br>resistance<br>DMSO Tram VS<br>-<br>6766<br>DMSO Tram VS<br>-<br>6766 |
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| 10<br>VS<br>-<br>6766 inhibits cell proliferation across multiple MAPK pathway alterations<br>and multiple solid tumor indications<br>SW1463<br>MIAPACA2<br>H358<br>H1373<br>SW837<br>H2122<br>H2030<br>SW1573<br>HPAC<br>ASPC1<br>HPAFII<br>SNU-C2B<br>LS513<br>LS 180<br>SKLU1<br>A427<br>SNU-C2A<br>H441<br>SW403<br>SK-CO-1<br>SW620<br>PANC0327<br>H2291<br>SNG-M<br>SW480<br>H2444<br>CAPAN2<br>CFPAC1<br>NCI-H747<br>HCT 116<br>DLD-1<br>T84<br>HCT-15<br>Calu-6<br>HT-29<br>WM-266-4<br>SW1417<br>A-375<br>C32<br>SK-MEL-5<br>IGR-1<br>Colo-205<br>A2058<br>HS852.T<br>RKO<br>NCI-H2087<br>RL95-2<br>GAK<br>SK-MEL-2<br>HEC-151<br>HS940.T<br>HMCB<br>SW48<br>AN3 CA<br>5637<br>0.01<br>0.1<br>1<br>10<br>VS-6766 IC50<br>(3D proliferation assay)<br>VS-6766 IC50 (<br><br><br>KRAS G12V<br>KRAS G13D<br>KRAS G12D<br>BRAF V600E<br>KRAS G12C<br>Indication<br>NSCLC<br>Panc<br>CRC<br>Indication:<br>KRAS/BRAF/NRAS/NF1 status:<br>Melanoma<br>NF1 mt<br>NRAS mt<br>KRAS Q61K<br>BRAF class 2 mt<br>KRAS G12C<br>KRAS G12D<br>KRAS G12V<br>Other<br>KRAS mt<br>BRAF mt<br>NRAS<br>mt<br>ARAF mt<br>ERK2 mt<br>Endometrial<br>Bladder<br>Other<br>mt<br>Reference: Pachter<br>RAS<br>-<br>Targeted Drug Discovery<br>,<br>Sep 2021 3D proliferation assay |
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| 11<br>Vertical Blockade: Establishing VS<br>-<br>6766 as the backbone of therapy for RAS<br>pathway<br>-<br>driven tumors<br>▪<br>Current Challenges<br>•<br>Blocking any single target in the pathway is insufficient for maximum depth and<br>duration of anti<br>-<br>tumor efficacy<br>•<br>e.g., SHP2i, KRAS<br>-<br>G12Ci, RAFi, MEKi, ERKi<br>•<br>Vertical blockade concept is now well established<br>•<br>Necessary to block more than 1 target in the pathway<br>•<br>Many of these agents (e.g., SHP2i, MEKi) have poor tolerability as monotherapy<br>and in combination<br>▪<br>Solutions offered by VS<br>-<br>6766<br>•<br>Vertical blockade (RAF and MEK blockade) in a single drug<br>•<br>Potential best<br>-<br>in<br>-<br>class tolerability with recommended twice weekly dosing<br>regimen<br>•<br>Should enable tolerable combinations<br>•<br>Compelling synergy data (preclinical) for VS<br>-<br>6766 combinations (e.g., with<br>KRAS<br>-<br>G12C inhibitors) supporting clinical combinations<br>RTK<br>Growth factors<br>EGFRi<br>FGFRi<br>G12Ci<br>RAFi<br>MEKi<br>ERKi<br>VS<br>-<br>6766<br>SHP2i<br>SOS1i<br>RAS<br>RAF<br>MEK<br>ERK<br>Tumor Growth<br>References:<br>1<br>Chen,<br>Mol Cancer Res<br>2018;<br>2<br>Banerji, BTOG Dublin, Jan 23, 2019 |
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| 12<br>Parallel Pathway Inhibition: Establishing VS<br>-<br>6766 as the backbone of therapy<br>for RAS pathway<br>-<br>driven tumors<br>▪<br>Current Challenges<br>•<br>Blocking Ras pathway can be circumvented through<br>parallel pathways<br>•<br>e.g., PI3K/AKT/mTOR, FAK, RhoA, YAP<br>•<br>Combinations of MEKi + AKTi have shown poor<br>tolerability<br>▪<br>Solutions offered with VS<br>-<br>6766<br>•<br>Good tolerability with twice weekly VS<br>-<br>6766 opens<br>up intermittent dosing options for combinations<br>•<br>Compelling preclinical synergy data with VS<br>-<br>6766 in<br>combination with FAK inhibition and with AKT<br>pathway inhibition (e.g., everolimus)<br>•<br>RP2D established for VS<br>-<br>6766 + defactinib and for<br>VS<br>-<br>6766 + mTORi (everolimus) with twice weekly<br>regimen<br>β<br>α<br>Integrin<br>FAK<br>Extracellular Matrix<br>P<br>PI3K<br>AKTi<br>mTORi<br>FAKi<br>SRC<br>AKT<br>RTK<br>Growth factors<br>G12Ci<br>RAFi<br>MEKi<br>ERKi<br>VS<br>-<br>6766<br>RAS<br>RAF<br>MEK<br>ERK<br>SHP2i<br>SOS1i<br>Tumor Growth<br>EGFRi<br>FGFRi<br>RhoA, YAP, etc.<br>mTOR<br>References:<br>1<br>Chen,<br>Mol Cancer Res<br>2018;<br>2<br>Banerji, BTOG Dublin, Jan 23, 2019 |
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| VS<br>-<br>6766 +/<br>-<br>Defactinib in Low<br>-<br>Grade Serous Ovarian Cancer |
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| 14<br>Favorable Tolerability Profile with Novel Intermittent Dosing Regimen<br>VS<br>-<br>6766 monotherapy<br>Daily at MTD<br>N=6<br>28<br>-<br>day cycle<br>RP2D<br>VS<br>-<br>6766 monotherapy<br>4mg twice weekly<br>N=26<br>28<br>-<br>day cycle<br>RP2D<br>(VS<br>-<br>6766 3.2mg twice weekly +<br>defactinib 200mg twice daily)<br>N=38<br>21 days of 28<br>-<br>day cycle<br>Treatment Related Adverse Event<br>Grade ≥3<br>Grade ≥3<br>Grade ≥3<br>Rash<br>3 (50%)<br>5 (19%)<br>2 (5%)<br>CK elevation (Creatine phosphokinase)<br>1 (17%)<br>2 (8%)<br>2 (5%)<br>1<br>Chenard<br>-<br>Poirier,<br>et al<br>.. ASCO 2017<br>References: Banerji, Q4 2020 report; Data on file<br>RP2D: recommended phase 2 dosing<br>Summary of Adverse Events Grade<br>≥ 3<br>Occurring in ≥ 5% of patients<br>Summary of FRAME Safety Profile<br>Most Adverse Events (AE) were Grade 1/2<br>Few patients have discontinued due to AEs in the study |
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| 15<br>Favorable Tolerability Profile at Recommended Phase 2 dose for VS<br>-<br>6766 plus<br>defactinib combination regimen<br>Treatment Related Adverse<br>Events Details*<br>(≥10% patients in cohort<br>3.2mg 6766 and Def 200mg<br>)<br>VS<br>-<br>6766 4mg<br>Twice Weekly<br>(4 wks of<br>every 4 wks)<br>1<br>n=22<br>VS<br>-<br>6766 3.2mg Twice<br>Weekly<br>Def 200mg BID<br>(3 wks of<br>every 4 wks)<br>2<br>n=38<br>Gr1/2<br>Gr3/4<br>Gr1/2<br>Gr3/4<br>Rash<br>15<br>5<br>32<br>2<br>CK Elevation<br>13<br>2<br>19<br>2<br>AST Elevation<br>1<br>13<br>Hyperbilirubinemia<br>14<br>1<br>Visual Disturbance<br>13<br>9<br>ALT Elevation<br>2<br>5<br>Diarrhoea<br>6<br>1<br>14<br>1<br>Fatigue<br>5<br>1<br>8<br>1<br>Oral Mucositis^<br>7<br>1<br>11<br>Nausea<br>5<br>5<br>Vomiting<br>2<br>4<br>Peripheral Edema<br>9<br>10<br>Paronychia<br>3<br>4<br>Thrombocytopenia<br>6<br>Pruritus<br>3<br>0<br>5<br>Summary of FRAME Safety Profile<br><br>Most Adverse Events (AE) were Grade 1/2<br><br>Few patients have discontinued due to AEs<br>in the study<br>RP2D<br><br>VS<br>-<br>6766 3.2 mg<br>oral twice wkly (3<br>wks of every 4 wks)<br><br>Defactinib 200 mg<br>oral BID<br>(3 wks of every 4 wks)<br>*AEs were graded by NCI CTC v4; highest grade only recorded for each<br>patient; AEs presented in ≥10% Patient (cohort 3.2mg 6766 and Def<br>200mg) data preliminary and subject to change;<br>^also includes glossitis/mouth ulcers<br>References:<br>1<br>Data on file VS<br>-<br>6766 Investigator’s Brochure;<br>2<br>Banerji, Q4 2020 report |
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| 16<br>70% of LGSOC tumors driven by mutations in the RAS pathway<br>LGSOC is a type of ovarian cancer that disproportionately<br>affects younger women<br>Patients often experience significant pain and suffering from<br>their disease over time<br>A slow growing cancer, that has a median survival of<br>almost 10 years, so patients remain in treatment for a long<br>time (10<br>-<br>yr prevalence<br>~80,000 worldwide, ~6,000 US)<br>Most prior research has focused on high grade serous ovarian cancer<br>(HGSOC). However, LGSOC is clinically, histologically and molecularly<br>unique from HGSOC with limited treatments available<br>1,000 to 2,000 patients in the U.S. and 15,000 to 30,000<br>worldwide diagnosed with LGSOC each year<br>~30% of LGSOC Patients Have KRAS mt<br>~70% of LGSOC Shows RAS Pathway<br>-<br>Associated mts<br>References: AACR Project GENIE Cohort v9.0<br>-<br>public and Verastem unpublished analysis<br>Reference: Monk, Randall, Grisham, The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Canc<br>er,<br>Am Soc Clin Oncol Educ Book; 2019;<br>Slomovitz, Gourley, Carey, Malpica, Shih, Huntsman, Fader., Grisham et al, Low<br>-<br>Grade serous ovarian cancer: State of the Science<br>; Gynecol Oncol; 2020. Grisham, Iyer, Low<br>-<br>Grade<br>Serous Ovarian Cancer: Current Treatment Paradigms and Future Directions; Curr Treat Options Oncology; 2018.<br>KRAS mutant<br>,<br>30%<br>NRAS, BRAF,<br>ARAF mutant<br>,<br>20%<br>Other RAS<br>-<br>associated<br>gene mutations<br>,<br>20%<br>Non<br>-<br>RAS<br>-<br>associated<br>,<br>30% |
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| 17<br>LGSOC: Limited Treatment Options with High Unmet Need<br>References:<br>1<br>NCCN guidelines v1.2022<br>2<br>No standard sequencing of<br>drugs for recurrence disease<br>Low<br>-<br>Grade Ovarian Cancer<br>–<br>Treatment Algorithm<br>1<br>Observe only<br>Carbo<br>-<br>Pt + Paclitaxel<br>+<br>hormonal (2b)<br>OR Chemo + Beva for Stage II<br>-<br>IV (2a)<br>OR<br>Hormonal Tx (2b)<br><br>Clinical trial (2a)<br><br>Chemotherapy (Pt<br>-<br>based combination or<br>monotherapy) (2a)<br><br>Hormonal Tx (2a)<br><br>Trametinib (2a)<br><br>Binimetinib (2b)<br>Recurrence Therapy<br>2<br>Stage IC<br>Stage II<br>-<br>IV<br>Stage IA<br>-<br>IB<br>Therapy<br>Response Rate<br>ORR<br>Median PFS<br>Months (95% CI)<br>Discontinuation<br>Rate due to AEs<br>Standard of<br>Care<br>1<br>6%<br>7.2 (5.6<br>-<br>9.9)<br>12 %<br>Trametinib<br>1<br>26%*<br>13.0 (9.9<br>-<br>15.0)<br>35%<br>Standard of<br>Care<br>2<br>13%<br>10.6 (9.2 to 14.5)<br>17%<br>Binimetinib<br>2<br>16%<br>9.1 (7.3<br>-<br>11.3)<br>31%<br>1<br>Study GOG 281 trial Gershenson et al., Lancet 2022<br>2<br>MILO Study Monk et al., J Clin Oncol 2020.<br>Standard of Care = letrozole, tamoxifen, chemotherapy<br>PFS = Progression free survival<br>CI = confidence interval<br>* Not confirmed by central review<br>Recent Clinical Trials in Recurrent LGSOC |
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| 18<br>VS<br>-<br>6766 in Combination with Defactinib Shows Promising ORR with<br>Durability in Refractory LGSOC with Expanded Number of Patients (n=24)<br>Reference: Banerjee et al., ESMO Sept 2021<br>Data cut off April 2021<br>PFS: Progression free survival<br>NR: Not reached<br>•<br>Overall response rate (ORR) = 46% (11 confirmed PRs/24)<br>o<br>KRAS mutant ORR = 64% (7 confirmed PRs/11)<br>o<br>KRAS wild<br>-<br>type ORR = 44% (4 confirmed PRs/9)<br>o<br>KRAS status undetermined (1 unconfirmed PR/4)<br>•<br>Response too early to determine for 2 pts on study for<br><br>5<br>months<br>•<br>Responses in patients previously treated with MEKi<br>•<br>54% (13/24) patients still on treatment<br>•<br>1 patient discontinuing for adverse events as of April 2021<br>•<br>Median PFS 23 months (95% CI 10.6<br>-<br>NR)<br>across all LGSOC<br>0<br>2<br>4<br>6<br>8<br>10<br>12<br>14<br>16<br>18<br>20<br>22<br>24<br>26<br>28<br>30<br>32<br>34<br>36<br>38<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>20<br>Response by RECIST<br>Time (cycles)<br>Response<br>(% change from baseline)<br>FRA101001 - KRAS G12V<br>FRA101002 - KRAS G12A<br>FRA101009 - KRAS G12D<br>FRA101012 - KRAS WT<br>FRA101007 - KRAS WT<br>FRA101014 - KRAS G12D<br>FRA101015 - KRAS WT<br>FRA101019 - KRAS G12D<br>FRA101024 - KRAS WT<br>FRA101025 - KRAS WT<br>FRA102010 - KRAS WT<br>FRA101028 - undocumented<br>FRA101032 - KRAS D33E, I24N<br>FRA101033 - KRAS G12D<br>FRA101035 - KRAS G12D<br>FRA101037 - KRAS WT<br>FRA101038 - KRAS WT<br>Continuing on treatment<br>FRA101039 - KRAS WT<br>FRA103001 - KRAS G12V<br>FRA104001- KRAS D57-T58ins<br>FRA103002 - undocumented<br>FRA101042 - KRAS G12D<br>FRA103003 - KRAS WT<br>FRA102018 - KRAS WT<br>FRA101007<br>FRA101014<br>FRA101042<br>FRA101012<br>FRA103003<br>FRA101032<br>FRA103002<br>FRA101038<br>FRA102018<br>FRA101015<br>FRA102010<br>FRA101019<br>FRA101024<br>FRA101028<br>FRA101039<br>FRA101025<br>FRA101037<br>FRA103001<br>FRA101035<br>FRA101033<br>FRA104001<br>FRA101009<br>FRA101001<br>FRA101002<br>-80<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>Best Response<br>(% change from baseline)<br>Undocumented<br> KRAS wt<br>KRAS wt<br>KRAS G12D<br> KRAS wt<br>KRAS D33E, I24N<br>Undocumented<br>Prior MEK inhibitor<br>*<br>*<br> KRAS G12A<br> KRAS G12V<br> KRAS G12D<br>KRAS G12V<br>*<br>KRAS wt<br> KRAS G12D<br>Confirmed partial response<br>Unconfirmed partial response<br> KRAS wt<br>KRAS wt<br>*<br>*<br>Best response by RECIST<br>KRAS wt<br> KRAS G12D<br>KRAS wt<br>KRAS wt<br> KRAS G12D<br>KRAS D57-T58ins<br>*<br>*<br>*<br>*<br>*<br>*<br>Still on treatment<br>*<br>KRAS G12D<br>Undocumented<br>*<br>*<br>Undocumented<br>Stable disease<br>FRA101007<br>FRA101014<br>FRA101042<br>FRA101012<br>FRA103003<br>FRA101032<br>FRA103002<br>FRA101038<br>FRA102018<br>FRA101015<br>FRA102010<br>FRA101019<br>FRA101024<br>FRA101028<br>FRA101039<br>FRA101025<br>FRA101037<br>FRA103001<br>FRA101035<br>FRA101033<br>FRA104001<br>FRA101009<br>FRA101001<br>FRA101002<br>-80<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>Best Response<br>(% change from baseline)<br>Undocumented<br> KRAS wt<br>KRAS wt<br>KRAS G12D<br> KRAS wt<br>KRAS D33E, I24N<br>Undocumented<br>Prior MEK inhibitor<br>*<br>*<br> KRAS G12A<br> KRAS G12V<br> KRAS G12D<br>KRAS G12V<br>*<br>KRAS wt<br> KRAS G12D<br>Confirmed partial response<br>Unconfirmed partial response<br> KRAS wt<br>KRAS wt<br>*<br>*<br>Best response by RECIST<br>KRAS wt<br> KRAS G12D<br>KRAS wt<br>KRAS wt<br> KRAS G12D<br>KRAS D57-T58ins<br>*<br>*<br>*<br>*<br>*<br>*<br>Still on treatment<br>*<br>KRAS G12D<br>Undocumented<br>*<br>*<br>Undocumented<br>Stable disease |
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| 19<br>RAMP 201 Registration<br>-<br>directed Phase 2 Trial of VS<br>-<br>6766 +/<br>-<br>Defactinib in<br>Recurrent LGSOC<br>-<br>KRAS Mutant (mt) and Wild Type (wt): adaptive design<br>modified based on interim analysis findings<br>*Dosing: Defactinib + VS<br>-<br>6766 combo: Defactinib 200mg PO BID: 21/28 days + VS<br>-<br>6766 3.2mg PO 2x/wk 21/28 days; VS<br>-<br>6766 monothera<br>py: VS6766 4.0 mg PO 2x/wk 21/28 days<br>**Expansion Phase<br>–<br>final sample size to be adjusted based on adaptive design<br>Defactinib + VS<br>-<br>6766<br>KRAS<br>-<br>mt<br>(n=16)<br>VS<br>-<br>6766 Mono<br>KRAS<br>-<br>mt<br>(n=16)<br>E<br>ach cohort<br>expanded<br>to ~36 patients (~20 additional patients)**<br>Go<br>-<br>forward treatment regimen to be selected once data sufficiently mature **<br>Selection Phase*<br>Expansion Phase**<br>Defactinib + VS<br>-<br>6766<br>KRAS<br>-<br>wt<br>(n=16)<br>VS<br>-<br>6766 Mono<br>KRAS<br>-<br>wt<br>(n=16)<br>Now Enrolling<br>E<br>xpansion P<br>hase<br>Primary Endpoint:<br>Objective Response Rate<br>(blinded independent review)<br>Evaluation of:<br>1)<br>In KRAS mt patients<br>2)<br>All patients (KRAS mt & wt)<br><br>Recurrent LGSOC<br><br>Prior<br>chemotherapy<br><br>Measurable disease<br>(RECIST 1.1)<br><br>Prior MEKi allowed<br>Completed Enrollment<br>Defactinib + VS<br>-<br>6766<br>KRAS<br>-<br>mt<br>(n=36)<br>VS<br>-<br>6766 Mono<br>KRAS<br>-<br>mt<br>(n=36)<br>Defactinib + VS<br>-<br>6766<br>KRAS<br>-<br>wt<br>(n=36)<br>VS<br>-<br>6766 Mono<br>KRAS<br>-<br>wt<br>(n=36) |
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| 20<br>RAMP<br>-<br>201Selection Phase: Interim Analysis Findings<br>-<br>June 2022<br>•<br>All four cohorts from Selection Phase will be<br>enrolled for Expansion Phase (add ~ 20<br>patients/cohort)<br>•<br>Fully enroll all four Expansion Phase cohorts in<br>2H 2022<br>•<br>Select go<br>-<br>forward treatment regimen, timing<br>driven by data maturity<br>•<br>Next update to be provided once go<br>-<br>forward<br>treatment regimen determined<br>•<br>Support continued evaluation of both VS<br>-<br>6766<br>monotherapy and VS<br>-<br>6766 + defactinib<br>combination therapy treatment arms<br>•<br>Encouraging efficacy results include confirmed<br>responses in:<br>•<br>Monotherapy and combo therapy<br>•<br>KRAS mt and KRAS wt tumors<br>•<br>No addl. safety signals to date, continued favorable<br>safety profile for both monotherapy and<br>combination treatment arms (~ 6% of patients<br>discontinuing due to AEs)<br>•<br>Substantial majority (~ 80%) of patients remain on<br>study treatment<br>Next Steps<br>Findings |
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| 21<br>LGSOC market opportunity larger or comparable to other high unmet need<br>KRAS opportunities<br>NSCLC KRAS G12C<br>3<br>Pancreatic<br>3<br>LGSOC<br>3<br>Endometrioid<br>3<br>Metastatic uveal<br>melanoma<br>3<br>~6K<br>patients US<br>1<br>~80K<br>patients WW<br>1<br>Patient<br>-<br>months of Therapy Per Year<br>2<br>(across all 2L+ patients)<br>1<br>References<br>:<br>Monk, Randall, Grisham, The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer, Am Soc<br>Cli<br>n Oncol Educ Book;<br>2019; Slomovitz, Gourley, Carey, Malpica, Shih, Huntsman, Fader., Grisham et al, Low<br>-<br>Grade serous ovarian cancer: State of the S<br>cience; Gynecol Oncol; 2020. Grisham,<br>Iyer, Low<br>-<br>Grade Serous Ovarian Cancer: Current Treatment Paradigms and Future Directions; Curr Treat Options Oncology; 2018; Glo<br>bocan 2020<br>2<br>Patient<br>-<br>months of Therapy metric calculated by multiplying relevant incidence/prevalence rate times estimated duration of thera<br>py; represents US market opportunity only;<br>patient population estimates from Globocan 2020, American Cancer Society 2021, AACR Genie Cohort V9.0 public, and scientific<br>pub<br>lications. Duration of therapy<br>estimates from clinical studies and clinician experience. Patient<br>-<br>months on therapy is for 2<br>nd<br>-<br>line+ patients<br>3<br>NSCLC KRAS G12C 2<br>nd<br>line patients (incidence); Pancreatic RAS/RAF mutant 2<br>nd<br>-<br>line patients (incidence); LGSOC KRAS mutant and wild<br>-<br>type patients (prevalence);<br>Endometrioid RAS/RAF mutant 2<br>nd<br>-<br>line patients (incidence); Uveal melanoma RAS/RAF mutant 2nd<br>-<br>line patients (incidence)<br>Prevalence<br> -<br> 50,000<br> 100,000<br> 150,000<br>~4k<br>~2k<br>wild<br>type<br>KRAS<br>mutation |
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| VS<br>-<br>6766 +/<br>-<br>Defactinib in NSCLC |
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| 23<br>High Unmet Need in Refractory mt NSCLC Adenocarcinoma<br>Advanced or Metastatic NSCL Cancer<br>Recommend Histologic and Molecular Subtyping<br>5<br>Appropriate targeted<br>agent<br>Chemotherapy<br><br>Docetaxel<br><br>Gemcitabine<br><br>Pemetrexed<br>Prior PD<br>-<br>(L)1<br>No Prior PD<br>-<br>(L)1<br>PD<br>-<br>(L)1<br>Chemo<br><br>PD<br>-<br>(L)1<br>PD<br>-<br>(L)1 single agent<br>or<br>PD<br>-<br>(L)1 + chemo<br>Chemotherapy or clinical trials<br>EGFR/ALK/ROS1/BRAF/KR<br>AS<br>-<br>G12C (targeted)<br>Non<br>-<br>targeted<br>PD<br>-<br>(L)1<br><br>1%<br>Non<br>-<br>Targeted<br>PD<br>-<br>(L)1<br><br>1%<br>▪<br>SOC in recurrent disease is<br>chemotherapy<br>▪<br>Pre<br>-<br>PD<br>-<br>(L)1<br>era, chemotherapy<br>response rate ~10% in recurrent<br>disease; 12w PFS of 30<br>–<br>45%<br>Recurrence<br>Recurrence<br>Verastem Clinical Trials:<br>•<br>RAMP 202:<br>•<br>KRAS G12V<br>—<br>VS<br>-<br>6766 monotherapy & VS<br>-<br>6766 + Defactinib<br>•<br>Other KRAS mutations<br>—<br>VS<br>-<br>6766 + Defactinib<br>•<br>BRAF V600E and BRAF non<br>-<br>V600E<br>—<br>VS<br>-<br>6766 + Defactinib<br>•<br>RAMP 203<br>—<br>KRAS G12C: VS<br>-<br>6766 + sotorasib<br>•<br>RAMP 204<br>—<br>KRAS G12C: VS<br>-<br>6766 + adagrasib<br>NSCLC Adenocarcinoma<br>3<br>0<br>5<br>10<br>15<br>% of Patients<br>KRAS Mutation<br>BRAF Mutation<br>US Annual Incidence<br>1,2<br>: 92K<br>WW Annual Incidence<br>1,2<br>: 836K<br>References:<br>1<br>Globocan, 2018<br>2<br>https://www.ncbi.nlm.nih.gov/books/NBK519578/<br>3<br>TCGA PanCancer Atlas (cBioPortal analysis)<br>4<br>www.thelancet.com Vol 389 January 21, 2017<br>5<br>Adapted from NCCN Non<br>-<br>small cell lung cancer guidelines Version 3.2020<br>6<br>Clinical Cancer Research DOI 10.1158/1078<br>-<br>0432.CCR<br>-<br>18<br>-<br>2062<br>KRAS Mutations Represent 25% of Lung Cancer Adenocarcinoma<br>& BRAF Represent 2<br>-<br>4% (EGFR 17%, ALK 7%)<br>4,6 |
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| 24<br>VS<br>-<br>6766 Inhibits CRAF<br>-<br>The key driver of KRAS G12V mt NSCLC<br>References: Ishii et al.<br>Cancer Res<br>(2013),<br>Blasco, R. B. et al.<br>Cancer Cell<br>(2011),<br>Lito, P. et al.<br>Cancer Cell<br>(2014),<br>Sanclemente, M. et al.<br>Cancer Cell<br>(2018)<br>A Precision Approach to KRAS G12V Driven NSCLC<br>CRAF, but not BRAF, ablation improves survival of mice with KRAS G12V induced lung cancer<br>in<br>vivo<br><br>KRAS G12V signals mainly through<br>RAF/MEK in contrast to other variants, such<br>as KRAS<br>-<br>G12D, which signal more through<br>PI3K/AKT<br><br>KRAS G12V models are especially<br>dependent on CRAF<br>KRAS G12V<br>CRAF<br>PI3K<br>MEK/ERK<br>AKT/mTOR<br>Tumor Growth<br>CRAF Drives KRAS G12V mt NSCLC<br>1<br>+83%<br><br>OS<br>CRAF KO Shows Strong<br>Efficacy<br>BRAF KO Has No Effect<br>BRAF |
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| 25<br>VS<br>-<br>6766 +/<br>-<br>FAKi induces significant tumor regression in KRAS G12V mt<br>NSCLC in vivo model, with clear differentiation from trametinib<br>Doses Tested<br>Trametinib: 0.1 mg/kg QD (5 days/week)<br>VS<br>-<br>6766: 0.1 mg/kg QD (5 days/week)<br>FAKi: 50 mg/kg BID (5 days/week)<br>KRAS G12V mutant; Tp53 KO NSCLC<br>•<br>VS<br>-<br>6766 monotherapy caused tumor regression<br>•<br>VS<br>-<br>6766 + FAKi showed stronger regression<br>•<br>No significant anti<br>-<br>tumor effect of trametinib at same dose level<br>Reference: Coma et al. AACR 2021<br>Vehicle<br>Trametinib<br>VS-6766<br>FAKi<br>VS-6766 + FAKi<br>0<br>2<br>4<br>6<br>8<br>10<br>20<br>40<br>60<br>80<br>Tumor volume fold change<br>(mean)<br>4 weeks of treatment<br>Statistics: Mann<br>-<br>Whitney test<br>Collaboration with Mariano Barbacid |
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| 26<br>Case Study: Response to VS<br>-<br>6766 + defactinib in a patient with KRAS G12V<br>mutant NSCLC<br>Reference: Krebs et al. AACR 2021<br>May 2019: Diagnosed with NSCLC<br>June 2019<br>-<br>Sept 2019: Treated with<br>first line Carboplatin + Pemetrexed +<br>Pembrolizumab<br>Oct 2019: Progression, palliative RT to<br>right hip<br>Nov 2019<br>–<br>present: On treatment in<br>FRAME study VS<br>-<br>6766 + Defactinib<br>VS<br>-<br>6766 + Defactinib |
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| 27<br>Strong Signal Identified in KRAS G12V NSCLC<br><br>Preclinical evidence suggests combination with Defactinib may improve efficacy in KRAS G12V mt NSCLC<br><br>Activity of VS<br>-<br>6766 as a single agent and in combo with Defactinib in KRAS G12V mt NSCLC<br>VS<br>-<br>6766<br>±<br>Defactinib Has Shown a 57% ORR in KRAS G12V mt NSCLC in Integrated Analysis<br>References:<br>1<br>Guo, et al<br>Lancet Oncology 2020<br>2<br>Krebs, AACR April 2021(March 18, 2021 cutoff)<br>Best Response by RECIST in KRAS G12V mt NSCLC<br>Time on Treatment for KRAS G12V mt NSCLC<br>NSCLC (57% ORR; N=7)<br>Weeks on treatment<br>0<br>10<br>20<br>30<br>40<br>50<br>60<br>70<br>Mono<br>Combo<br>Mono<br>Mono<br>Mono<br>Combo<br>Mono<br>180<br>200<br>220<br>216<br>216<br>70<br>70<br>58<br>58<br>20<br>20<br>19<br>19<br>18<br>18<br>14<br>14<br>Time on Treatment (weeks)<br>Continuing on treatment<br>Time on Treatment<br>24<br>Mono:<br> VS-6766 monotherapy<br>Combo:<br> VS-6766 + Defactinib<br>*<br>*<br>4.0 mg VS-6766/200 mg defactinib<br>+<br>+ |
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| 28<br>RAMP 202: Registration<br>-<br>directed Phase 2 Trial of VS<br>-<br>6766 +/<br>-<br>Defactinib in<br>advanced NSCLC Primary Cohort: KRAS G12V mt NSCLC<br>References:<br>1<br>Defactinib 200 mg PO BID (21/28 days) + VS<br>-<br>6766 3.2 mg PO 2x/wk (21/28 days)<br>2<br>VS<br>-<br>6766 4.0 mg PO 2x/wk (21/28 days)<br><br>Advanced NSCLC<br><br>1<br>-<br>2 prior regimens<br><br>1 prior platinum<br>-<br>containing chemo;<br><br>Prior CPI unless<br>contraindicated<br><br>Measurable disease<br>(RECIST 1.1)<br><br>Appropriate approved<br>therapy for other<br>relevant mutations<br><br>No prior MEKi, no<br>prior KRAS<br>-<br>specific<br>targeted therapy<br><br>No untreated CNS<br>metastases<br><br>ECOG OS 0<br>-<br>1<br>Defactinib + VS<br>-<br>6766<br>1<br>KRAS mt G12V<br>N=16<br>VS<br>-<br>6766<br>2<br>KRAS mt G12V<br>N=16<br>KRAS Mutant<br>–<br>G12V<br>Selected Regimen based on ORR<br>Selection Phase<br>Expansion Phase<br>Final G12V sample<br>size to be discussed with<br>FDA<br>Completed Enrollment |
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| 29<br>RAMP 202: Additional Cohorts of VS<br>-<br>6766 + Defactinib in KRAS non<br>-<br>G12V<br>mt & BRAF mt NSCLC<br>References:<br>1<br>Defactinib 200 mg PO BID (21/28 days) + VS<br>-<br>6766 3.2 mg PO 2x/wk (21/28 days)<br><br>Advanced NSCLC<br><br>1<br>-<br>2 prior regimens<br><br>1 prior platinum<br>-<br>containing chemo;<br><br>Prior CPI unless<br>contraindicated<br><br>Measurable disease<br>(RECIST 1.1)<br><br>Appropriate approved<br>therapy for other<br>relevant mutations<br><br>No prior KRAS<br>-<br>specific<br>targeted therapy<br><br>No prior MEKi, (except<br>for BRAF mtV600E)<br><br>No untreated CNS<br>metastases<br><br>ECOG OS 0<br>-<br>1<br>Initial Phase<br>Analysis<br>Defactinib + VS<br>-<br>6766<br>1<br>KRAS mt non<br>-<br>G12V<br>N=40, maximum<br>KRAS Mutant<br>–<br>non<br>-<br>G12V<br><br>Exploratory mutation<br>-<br>specific<br>cohort analyses for ORR<br><br>Non<br>-<br>G12V Cohort<br>Expansion TBD based<br>on results of<br>exploratory analysis<br>Defactinib + VS<br>-<br>6766<br>1<br>BRAF mt V600E<br>N=15<br>Defactinib + VS<br>-<br>6766<br>1<br>BRAF mt non<br>-<br>V600E<br>N=15<br>BRAF Mutant<br><br>Mutation<br>-<br>specific cohort analyses<br>for ORR<br><br>BRAF Cohorts<br>Expansion TBD based<br>on results of analysis<br>Completed Enrollment |
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| 30<br>Preclinical synergy of VS<br>-<br>6766 + G12C inhibitors in KRAS G12C mt models<br>Synergy of VS<br>-<br>6766 + G12C inhibitors across<br>G12C mutant NSCLC, CRC & Pancreatic cancer cell lines<br>Doses Tested<br>Trametinib: 0.3 mg/kg QD<br>VS<br>-<br>6766: 0.3 mg/kg QD<br>FAKi: 50 mg/kg BID<br>Sotorasib: 30 mg/kg QD<br>Response @ Day 10<br>VS<br>-<br>6766 & FAKi potentiate sotorasib efficacy in KRAS G12C mutant<br>NSCLC in vivo; Tumor regression in all mice with triple combination<br>VS<br>-<br>6766 + sotorasib yields deeper and more sustained inhibition<br>of ERK signaling pathway<br>H2122 KRAS G12C mutant NSCLC<br>Sotorasib<br>VS<br>-<br>6766<br>4h<br>48h<br>p<br>-<br>ERK<br>Actin<br>Total ERK<br>ND: not determined<br>-<br>-<br>+<br>-<br>-<br>+<br>+<br>+<br>-<br>-<br>+<br>-<br>-<br>+<br>+<br>+<br>H2122 KRAS G12C mutant NSCLC<br>Concentrations Tested<br>Sotorasib: 100 nM<br>VS<br>-<br>6766: 100 nM<br>Reference: Coma et al., AACR 2021<br>Combined Synergy Score<br>Cell line<br>Indication<br>Sensitivity to<br>G12C inhibitors<br>VS<br>-<br>6766 +<br>sotorasib<br>VS<br>-<br>6766 +<br>adagrasib<br>H2122<br>NSCLC<br>Moderately sensitive<br>44.7<br>44.6<br>H1373<br>NSCLC<br>Sensitive<br>10.0<br>3.4<br>SW1573<br>NSCLC<br>Insensitive<br>8.6<br>12.0<br>H358<br>NSCLC<br>Sensitive<br>6.9<br>5.4<br>H2030<br>NSCLC<br>Moderately sensitive<br>5.1<br>ND<br>SW837<br>CRC<br>Sensitive<br>16.1<br>18.5<br>MIAPACA2<br>Panc<br>Sensitive<br>2.3<br>5.3 |
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| 31<br>Acquired resistance mechanisms to KRAS G12Ci treatment in patients<br>further support combination of KRAS G12Ci with VS<br>-<br>6766<br>Summary of Putative Mechanisms of Acquired<br>Resistance to Adagrasib Treatment<br>•<br>Mechanisms of acquired resistance to KRAS G12Ci<br>adagrasib treatment in patients recently reported<br>1,2<br>•<br>The main resistance alterations occurred in<br>•<br>RTK mts or amplifications<br>•<br>KRAS mts or amplification<br>•<br>NRAS mt<br>•<br>BRAF V600E mt, BRAF or CRAF fusions<br>•<br>MAP2K1 (MEK1) mt/deletion<br>•<br>VS<br>-<br>6766 has shown activity against these KRAS,<br>NRAS, BRAF and CRAF modifications<br>Reference: Andrew Aguirre, unpublished<br>Reference:<br>1<br>Awad MM et al., N Engl J Med 2021; 384: 2382<br>-<br>93;<br>2<br>Tanaka et al., Cancer Discov 2021;11:1<br>–<br>10 |
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| 32<br><br>Patients must have<br>known G12C KRAS<br>mutation determined<br>using<br>validated test<br><br>Treatment with at<br>least 1 but no more<br>than 3 prior systemic<br>regimens, for Stage<br>3B<br>-<br>C or 4 NSCLC<br><br>Patient may have<br>previously received<br>adjuvant<br>chemotherapy for<br>earlier<br>-<br>stage disease<br><br>Measurable disease<br>according to RECIST<br>1.1<br><br>ECOG performance<br>status ≤ 1<br>RAMP 203: Phase 1/2 Trial of VS<br>-<br>6766 + LUMAKRAS<br>TM<br>(sotorasib) in<br>KRAS G12C<br>-<br>mutated advanced NSCLC<br>RP2D<br>Selection<br>Part A: Dose Evaluation<br>(3+3 DLT Assessment)<br>Part B: Dose Expansion at RP2D<br>(Primary endpoint ORR)<br>Cohort 1<br>Patients without Prior<br>KRAS G12C Inhibitor<br>Treatment<br>Stage 1<br>: ~20 patients<br>Stage 2<br>: expand<br>VS<br>-<br>6766 + Sotorasib<br>Dose Finding Cohorts<br>(N= 3<br>-<br>6 pts)<br>Cohort 2<br>Patients whose NSCLC<br>Progressed on KRAS<br>G12C Inhibitor<br>Treatment<br>Stage 1<br>: ~20 patients<br>Stage 2<br>: expand |
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| Future Opportunities: VS<br>-<br>6766 as<br>Backbone of RAS Therapy |
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| 34<br>High Unmet Needs in RAS/RAF/MEK/ERK<br>-<br>Driven Cancers<br>NSCLC<br>Incidence<br>3,5<br>:<br>194K<br>Colorectal<br>Incidence<br>5<br>:<br>148K<br>Pancreatic<br>Incidence<br>5<br>:<br>58K<br>Uterine<br>Endometrioid<br>Incidence<br>4,5<br>: 59K<br>Melanoma<br>Incidence<br>5<br>:<br>108K<br>Multiple Myeloma<br>Incidence<br>5<br>:<br>32K<br>Melanoma<br>Incidence<br>5<br>:<br>108K<br>Colorectal<br>Incidence<br>7<br>:<br>148K<br>Papillary Thyroid<br>Incidence<br>5,6<br>:<br>42K<br>Ovarian<br>Incidence<br>5<br>:<br>22K<br>Incidence References:<br>1<br>Reference for RAS mt frequencies<br>–<br>Cox et al.<br>Nature Reviews<br>13: 828, 2014;<br>2<br>Reference for BRAF mt frequencies<br>–<br>Turski et al.<br>Mol Cancer Ther<br>15: 533, 2016<br>3<br>85% of lung cancer is NSCLC (Lu et. al.<br>Cancer Manag Res.<br>2019)<br>;<br>4<br>90% of all uterine cancers are of the endometrial type (ACS)<br>;<br>5<br>Cancer Statistics 2020, Siegel et. al.<br>CA<br>Cancer J Clin<br>2020;70:7<br>-<br>30<br>;<br>6<br>8 out of 10 thyroid cancers are of the papillary type (ACS)<br>7<br>CbioPortal<br>References:<br>McCormick F Clin Cancer Res 15April2015;<br>6<br>Adderley H et al. EBioMedicine 01Mar2019; Papke B et al. Science 17Mar2017; Ryan M et al.<br>Nature Reviews Clinical<br>Oncology<br>01Oct2018; NIH cancer.gov/research/key<br>-<br>initiatives/ras<br>KRAS<br>-<br>mutant<br>Cancers<br>1<br>31%<br>45%<br>98%<br>21%<br>NRAS<br>-<br>mutant<br>Cancers<br>1<br>28%<br>BRAF<br>-<br>mutant<br>Cancers<br>2<br>60%<br>10%<br>30<br>–<br>80%<br>20%<br>5%<br>Challenges with conventional approaches<br><br>Modest progress; limited number of approved therapies<br><br>Single agent therapies (e.g., MEK inhibitors) associated with resistance<br><br>Tolerable combination regimens with MEK inhibitors have been challenging<br><br>Current RAS inhibitors in development address only a minority of all RAS mutated<br>cancers<br>Breadth of potential opportunity<br><br>30% of all human cancers are driven by<br>mutations of the RAS family of genes<br>6<br>Established prognostic significance<br><br>Patients with mutations of the RAS family have<br>an overall worse prognosis<br>NSCLC<br>Incidence<br>3,7<br>:<br>194K<br>7% |
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| 35<br>Vertical Blockade: Preclinical synergy in combination with promising agents<br>for clinical investigation<br>H2122<br>SW837<br>H1373<br>SW1573<br>H358<br>H2030<br>MIAPACA2<br>0<br>10<br>20<br>30<br>40<br>50<br>VS-6766 + AMG 510<br>Combined Synergy Score<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>Indication<br>CRC<br>H2122<br>H1373<br>MIAPACA2<br>H358<br>SW1573<br>HPAC<br>ASPC1<br>A427<br>HPAFII<br>SKLU1<br>PANC0327<br>H2291<br>CFPAC1<br>H2444<br>CAPAN2<br>H441<br>-20<br>0<br>20<br>40<br>VS-6766 + Afatinib<br>Combined Synergy Score<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>80% (4/5)<br>100% (6/6)<br>100% (5/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>H2122<br>SW1573<br>H1373<br>MIAPACA2<br>H358<br>ASPC1<br>HPAFII<br>A427<br>HPAC<br>SKLU1<br>CAPAN2<br>CFPAC1<br>H2291<br>PANC0327<br>H2444<br>H441<br>-20<br>-10<br>0<br>10<br>20<br>30<br>40<br>VS-6766 + LY-3214996<br>Combined Synergy Score<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>100% (5/5)<br>66% (4/6)<br>60% (3/5)<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>Indication<br>VS<br>-<br>6766 + pan<br>-<br>HERi (Afatinib)<br>VS<br>-<br>6766 + ERK1/2i (LY3214996)<br>VS<br>-<br>6766 + SHP2i (RMC<br>-<br>4550)<br>H2122<br>MIAPACA2<br>H358<br>H1373<br>SW1573<br>A427<br>HPAC<br>HPAFII<br>SKLU1<br>ASPC1<br>PANC0327<br>CFPAC1<br>H2444<br>H2291<br>CAPAN2<br>H441<br>-20<br>0<br>20<br>40<br>VS-6766 + BI-3406<br>Combined Synergy Score<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>100% (5/5)<br>83% (5/6)<br>60% (3/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>VS<br>-<br>6766 + SOS1i (BI<br>-<br>3406)<br>Reference: Coma et al., AACR 2021<br>VS<br>-<br>6766 + G12Ci (AMG 510)<br>H2122<br>SW837<br>H1373<br>SW1573<br>H358<br>H2030<br>MIAPACA2<br>0<br>10<br>20<br>30<br>40<br>50<br>VS-6766 + AMG 510<br>Combined Synergy Score<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>Indication<br>CRC<br>H2122<br>SW837<br>SW1573<br>H358<br>MIAPACA2<br>H1373<br>0<br>10<br>20<br>30<br>40<br>50<br>VS-6766 + MRTX849<br>Combined Synergy Score<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>Indication<br>CRC<br>VS<br>-<br>6766 + G12Ci (MRTX849) |
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| 36<br>Parallel Pathway Inhibition: Preclinical synergy in combination with promising<br>agents for clinical investigation<br>Reference: Coma et al., RAS<br>-<br>Targeted Drug<br>Discovery, Feb 2021<br>H2122<br>MIAPACA2<br>H1373<br>H358<br>SW1573<br>A427<br>HPAC<br>ASPC1<br>HPAFII<br>SKLU1<br>CFPAC1<br>CAPAN2<br>H2291<br>PANC0327<br>H441<br>H2444<br>-20<br>-10<br>0<br>10<br>20<br>30<br>40<br>VS-6766 + Palbociclib<br>Combined Synergy Score<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>100% (5/5)<br>50% (3/6)<br>100% (5/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>VS<br>-<br>6766 + mTORi (Everolimus)<br>VS<br>-<br>6766 + CDK4/6i (Palbociclib)<br>SW1573<br>H1373<br>H358<br>MIAPACA2<br>H2122<br>A427<br>SKLU1<br>HPAFII<br>ASPC1<br>HPAC<br>H2291<br>H2444<br>CAPAN2<br>H441<br>PANC0327<br>CFPAC1<br>-40<br>-20<br>0<br>20<br>40<br>VS-6766 + M2698<br>Combined Synergy Score<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>80% (4/5)<br>66% (4/6)<br>80% (4/5)<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>Indication |
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| 37<br>Combination of VS<br>-<br>6766 with anti<br>-<br>EGFR mAb induces tumor regression in a<br>KRAS mt Colorectal PDX model<br>•<br>VS<br>-<br>6766 + anti<br>-<br>EGFR (panitumumab)<br>induces tumor regression in a KRAS G12V<br>mt CRC patient<br>-<br>derived xenograft model<br>•<br>G12Ci + anti<br>-<br>EGFR (sotorasib +<br>panitumumab and adagrasib + cetuximab)<br>have shown partial responses in KRAS G12C<br>mt CRC (Fakih et al. ESMO 2021; Weiss et al.<br>ESMO 2021)<br>•<br>These data support clinical testing of<br>VS<br>-<br>6766 + anti<br>-<br>EGFR (cetuximab) for<br>treatment of KRAS mt CRC<br>(NCT05200442)<br>Vehicle<br>VS<br>-<br>6766<br>Panitumumab (anti<br>-<br>EGFR)<br>Panitumumab + VS<br>-<br>6766<br>Collaboration with Marwan Fakih, City of Hope<br>Pachter, RAS Development Summit, 2021 |
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| 38<br>Clinical Program Targeting the RAS Pathway in Additional Indications<br>1<br>Investigator<br>-<br>sponsored trial<br>2<br>In preparation/planning<br>INDICATION<br>REGIMEN<br>STUDY<br>NAME<br>PRECLINICAL<br>PHASE 1<br>PHASE 2<br>PHASE 3<br>R/R pancreatic cancer<br>1<br>VS<br>-<br>6766 + defactinib<br>FRAME<br>Metastatic uveal melanoma<br>1<br>VS<br>-<br>6766 + defactinib<br>IST<br>ER+ breast cancer<br>1,2<br>VS<br>-<br>6766 + abemaciclib +<br>fulvestrant<br>IST<br>KRAS mt colorectal cancer<br>1<br>VS<br>-<br>6766 + cetuximab<br>IST<br>BRAF mt (non<br>-<br>V600E) Papillary<br>& anaplastic thyroid cancer<br>1,2<br>VS<br>-<br>6766<br>IST<br>Metastatic Castrate<br>-<br>resistant<br>Prostate Cancer<br>1,2<br>VS<br>-<br>6766 (+/<br>-<br>darolutamide)<br>IST<br>BRAF mt melanoma<br>1,2<br>VS<br>-<br>6766 + pembrolizumab<br>IST |
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| Corporate |
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| 40<br>Key Financial Statistics<br>Cash, cash equivalents & investments<br>$106M<br>Non<br>-<br>GAAP Operating Expenses<br>$18M<br>Shares Outstanding<br>186M<br>As of and for the quarter ended March 31, 2022<br>Oxford Finance LLC Credit Facility<br>Loan Tranches<br>Event<br>A<br>$25M<br>At closing<br>B<br>$15M<br>COPIKTRA PTCL approval in U.S. or $50M equity proceeds<br>C<br>$25M<br>LGSOC accelerated or full approval<br>D<br>$35M<br>$50M product revenue on six months trailing basis<br>E<br>$50M<br>Lender discretion<br>Total<br>$150M<br>Interest rate:<br>floating rate, which is subject to a floor and a cap; 5% final payment charge, and loan subject to 1<br>-<br>3% early payment fee<br>Term:<br>5 Years; Interest only two years initially, extendable up to four years based on achievement of milestones<br>Financial covenants:<br>None<br>* Q1 2022 GAAP operating expenses<br>-<br>$19.6M minus Q1 2022 stock compensation<br>-<br>$1.6M = $18.0M Q1 2022 non<br>-<br>GAAP operating expenses |
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| Backup Slides |
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| 42<br>Verastem Oncology Strategic Transformation<br>Q1 2021: LGSOC study updated to include KRAS wild type patients<br>Q4 2020:<br>Initiated registration<br>-<br>directed ph. 2 study in LGSOC<br>Initiated registration<br>-<br>directed ph. 2 study in NSCLC<br>Q3 2020: Divested global rights to Copiktra to Secura Bio<br>Q1 2020: In<br>-<br>licensed global rights to VS<br>-<br>6766, best<br>-<br>in<br>-<br>class RAF/MEK inhibitor, from Chugai<br>PIPE financing based on data for new clinical program<br>Q2 2021: FDA Breakthrough Therapy Designation granted for VS<br>-<br>6766 + Defactinib in<br>LGSOC<br>Q3 2021: Remaining outstanding debt retired<br>VS<br>-<br>6766 + sotorasib Collaboration agreement with Amgen<br>Q4 2021:<br>VS<br>-<br>6766 + adagrasib Collaboration agreement with Mirati |
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| 43<br>KRAS G12V and G12D Represent ~50% of KRAS Mutations across Human<br>Cancers<br>21.40% G12V<br>25.30% G12D<br>5.10% G12A<br>13.30% G12C<br>2.70% Q61H<br>32.20% Others<br>Pancreatic Adenocarcinoma<br>1<br>G12D<br>G12V<br>G12R<br>Q61H<br>Q61R<br>G12A<br>G12C<br>0<br>10<br>20<br>30<br>Pancreatic Cancer<br>KRAS Mutation<br>% of patients<br>Uterine Endometrioid Carcinoma<br>1<br>G12D<br>G12V<br>G13D<br>G12A<br>G12C<br>G13C<br>Q61H<br>0<br>2<br>4<br>6<br>8<br>10<br>Uterine Endometrioid Carcinoma<br>KRAS Mutation<br>% of patients<br>References:<br>1<br>TCGA PanCancer Atlas (cBioPortal analysis)<br>2<br>90% of all uterine cancers are of the endometrial type (ACS)<br>3<br>Cancer Statistics 2020 (Siegel et al. CA Cancer J Clin 2020; 70:7<br>-<br>30)<br>Annual Incidence<br>3<br>:<br>58K<br>Annual Incidence<br>2<br>,<br>3<br>:<br>59K<br>% frequency in a total of 780 cancer patients<br>with KRAS mutations<br>1 |
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| 44<br>VS<br>-<br>6766 and FAK inhibitor combination leads to<br>more robust anti<br>-<br>tumor efficacy in vivo<br>KRAS<br>mt<br>Ovarian TOV<br>-<br>21G<br>in vivo<br>Model<br>1<br>KRAS<br>mt<br>NSCLC H358<br>in vivo<br>Model<br>2<br>0<br>5<br>10<br>15<br>0<br>100<br>200<br>300<br>400<br>500<br>Tumor growth<br>VS-4718 + CH5126766<br>Days on treatment<br>Tumor volume<br>(mm<br>3<br> +/- SEM)<br>Vehicle<br>Trametinib 1.5 mg/kg QD<br>FAKi 50 mg/kg BID<br>VS-6766 1.5 mg/kg QD<br>VS-6766 + FAKi<br>0<br>5<br>10<br>15<br>20<br>0<br>200<br>400<br>600<br>Tumor growth<br>Days on treatment<br>Tumor volume<br>(mm<br>3<br> +/- SEM)<br>Vehicle<br>Trametinib 0.3 mg/kg QD<br>FAKi 50 mg/kg BID<br>VS-6766 0.3 mg/kg QD<br>VS-6766 + FAKi<br>References:<br>1<br>Coma AACR 2021;<br>2<br>Krebs AACR 2021 |
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| 45<br>Overcoming Key Resistance Mechanisms to MEK Inhibitors<br>•<br>MEK inhibition induces<br>compensatory activation of<br>pFAK preclinically and clinically<br>Pre dose<br>Post VS-6766<br>Post combination<br>0<br>50<br>100<br>150<br>p-FAK<br>H-Score<br>o<br>Trametinib induced<br>↑<br>pFAK (Y397)<br>preclinically in KRAS mt NSCLC cell lines<br>o<br>Also observed in patients<br>•<br>VS<br>-<br>6766 induced<br>↑<br>pFAK (Y397) as a<br>potential resistance mechanism in<br>the majority of patients<br>•<br>Combination with defactinib<br>reduced this compensatory pFAK<br>signal<br>= Feedback<br>Reactivation<br>References:<br>Banerji, BTOG Dublin, Jan 23, 2019<br>Banerji, AACR VM 1, April 27, 2020, CT143 |
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| 46<br>Pharmacokinetic Profiles of VS<br>-<br>6766 + Defactinib in Combination Similar to<br>that seen in Single Agent Studies<br>Cohort<br>Dose<br>(mg)<br>N<br>Subject<br>AUC<br>0<br>-<br>24h<br>(h*ng/mL)<br>C<br>max<br>(ng/mL)<br>1<br>3.2<br>(with 200mg VS)<br>3<br>Mean<br>6179<br>354<br>CV%<br>32.1<br>30.4<br>2a<br>4<br>(with 200mg VS)<br>5<br>Mean<br>5353<br>289<br>CV%<br>15.8<br>16.0<br>2b<br>3.2<br>(with 400mg<br>VS)<br>1<br>FRA101<br>-<br>007<br>3302<br>229<br>VS<br>-<br>6766<br>Cohort<br>Dose (mg)<br>N<br>Subject<br>AUClast<br>(h*ng/mL)<br>Cmax<br>(ng/mL)<br>1<br>200<br>(with 3.2mg RO)<br>3<br>Mean<br>2071<br>273<br>CV%<br>103<br>80<br>2a<br>200<br>(with 4mg RO)<br>5<br>Mean<br>2252<br>318<br>CV%<br>124<br>117<br>2b<br>400<br>(with 3.2mg RO)<br>3<br>Mean<br>2807<br>360<br>CV%<br>31<br>32<br>Defactinib<br>Reference: Banerji, AACR VM 1, April 27, 2020, CT143 |
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| 47<br>0<br>10<br>20<br>30<br>40<br>50<br>60<br>70<br>FRA101017<br>FRA102005<br>FRA101043<br>FRA101040<br>FRA101034<br>FRA101018<br>FRA102016<br>FRA101026<br>FRA101020<br>FRA101036<br>FRA102004<br>FRA101010<br>FRA102008<br>FRA102006<br>FRA102007<br>FRA101041<br>FRA102017<br>FRA102002<br>FRA102009<br>FRA101031<br>Time on Treatment (weeks)<br>Unconfirmed PR<br>Partial response<br>Stable disease<br>Progression disease<br>Time on Treatment<br>G12D<br>Q61H<br>G12C<br>G12D<br>G12A<br>G12V<br>G12D<br>G12C<br>G12D<br>G12C<br>G12D<br>G12C<br>G12D<br>G12V<br>*<br><br>Time to response<br>*<br>*<br>G12A<br>G12C<br>G12D<br>Continuing on treatment<br>*<br>#<br>#<br>G12C<br>G12D<br>G12C<br>NSCLC Responses with VS<br>-<br>6766 + Defactinib Combination (n=20)<br>Confirmed responses in 2/2 patients with KRAS G12V mt NSCLC<br>Tumor reduction in 4/6 patients with KRAS G12C mt NSCLC<br>Data cut off March 5, 2021<br>•<br>ORR = 15% (3/20)<br>•<br>ORR in G12V mt = 100% (2/2)<br>•<br>DCR =65% (13/20)<br>•<br>3/20 (15%) still on study<br>•<br>7 pts on treatment ≥ 24 weeks<br>Reference: Krebs et al. AACR 2021<br>FRA101040<br>FRA101034<br>FRA101026<br>FRA101017<br>FRA101018<br>FRA101043<br>FRA102008<br>FRA101020<br>FRA102007<br>FRA102017<br>FRA102004<br>FRA102006<br>FRA102002<br>FRA102009<br>FRA101036<br>FRA101041<br>FRA101010<br>FRA101031<br>-80<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>20<br>30<br>40<br>50<br>60<br>Best Response<br>(% change from baseline)<br> G12C<br> G12D<br> G12A<br> G12D<br> G12D<br> Q61H<br> G12C<br> G12A<br> G12C<br>*<br> G12C<br> G12V<br> G12C<br> G12V<br> G12D<br>Continuing on treatment<br>*<br>Partial response<br>Stable disease<br>Best response by RECIST in KRAS mt NSCLC<br>Progressive disease<br>*<br>*<br> G12D<br> G12D<br> G12C<br>#<br>#<br>Unconfirmed PR<br> G12D<br>KRAS mt<br>FRA101040<br>FRA101034<br>FRA101026<br>FRA101017<br>FRA101018<br>FRA101043<br>FRA102008<br>FRA101020<br>FRA102007<br>FRA102017<br>FRA102004<br>FRA102006<br>FRA102002<br>FRA102009<br>FRA101036<br>FRA101041<br>FRA101010<br>FRA101031<br>-80<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>20<br>30<br>40<br>50<br>60<br>Best Response<br>(% change from baseline)<br> G12C<br> G12D<br> G12A<br> G12D<br> G12D<br> Q61H<br> G12C<br> G12A<br> G12C<br>*<br> G12C<br> G12V<br> G12C<br> G12V<br> G12D<br>Continuing on treatment<br>*<br>Partial response<br>Stable disease<br>Best response by RECIST in KRAS mt NSCLC<br>Progressive disease<br>*<br>*<br> G12D<br> G12D<br> G12C<br>#<br>#<br>Unconfirmed PR<br> G12D<br>KRAS mt |
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| 48<br>Target exposure for preclinical tumor regression is covered by twice weekly<br>dosing of 4 mg VS<br>-<br>6766 3 wks on/1 wk off<br><br>Modeling<br>of<br>PK<br>for<br>4<br>mg<br>VS<br>-<br>6766<br>2<br>/wk,<br>3<br>wks<br>on/<br>1<br>wk<br>off,<br>based<br>on<br>4<br>mg<br>single<br>dose<br>PK<br>data<br>(study<br>NO<br>21895<br>)<br><br>Relationship<br>to<br>average<br>exposure<br>for<br>tumor<br>regression<br>in<br>KRAS<br>G<br>12<br>V<br>mt<br>NSCLC<br>mouse<br>model<br>C<br>av<br>for tumor regression from<br>KRAS G12V mt NSCLC GEMM model<br>References: Martinez<br>-<br>Garcia et al., Clin Cancer Res 2012; Coma et al. AACR 2021 |
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| 49<br>Status: Combination of VS<br>-<br>6766 with Everolimus (mTOR inhibitor)<br>•<br>Synergy of VS<br>-<br>6766 + everolimus observed broadly<br>across cancer cell lines with various KRAS mutation<br>variants<br>•<br>A well<br>-<br>tolerated RP2D for VS<br>-<br>6766 + everolimus has been<br>established with intermittent dosing of both agents (twice<br>weekly; 3 wks on/1 wk off)<br>•<br>KRAS mutant NSCLC expansion cohort is currently ongoing<br>with VS<br>-<br>6766 + everolimus<br>VS<br>-<br>6766 + Everolimus<br>SW1573<br>H1373<br>H358<br>MIAPACA2<br>H2122<br>A427<br>SKLU1<br>HPAFII<br>ASPC1<br>HPAC<br>H2291<br>H2444<br>CAPAN2<br>H441<br>PANC0327<br>CFPAC1<br>-40<br>-20<br>0<br>20<br>40<br>VS-6766 + M2698<br>Combined Synergy Score<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>80% (4/5)<br>66% (4/6)<br>80% (4/5)<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>Indication<br>Reference: Coma et al., RAS<br>-<br>Targeted Drug Discovery, Feb 2021 |
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| 50<br>VS<br>-<br>6766 monotherapy has shown clinical activity in several cancer<br>indications, including NSCLC<br>Best Response<br>Guo et al., Lancet Oncology 2020 |
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| 51<br>VS<br>-<br>6766 upregulates MHC Class I antigens on tumor cells: a mechanism for<br>potentiation of I/O efficacy<br>Cell Line<br>Tumor type<br>RAS/RAF mutation<br>status<br>A549<br>Lung<br>KRASmt G12S<br>TOV21g<br>Ovarian<br>KRASmt G13C<br>SKMEL5<br>Melanoma<br>BRAFmt V600E<br>IGR<br>-<br>1<br>Melanoma<br>BRAFmt V600E<br>WM115<br>Melanoma<br>BRAFmt V600E<br>A549<br>TOV21g<br>SKMEL5<br>IGR1<br>WM115<br>0<br>2<br>4<br>6<br>B2M<br>Relative mRNA Levels<br>DMSO<br>VS-6766<br>KRAS mt<br>BRAF mt<br>A549<br>TOV21g<br>SKMEL5<br>IGR1<br>WM115<br>0<br>2<br>4<br>6<br>8<br>HLA-A<br>Relative mRNA Levels<br>DMSO<br>VS-6766<br>KRAS mt<br>BRAF mt<br>A549<br>TOV21g<br>SKMEL5<br>IGR1<br>WM115<br>0<br>2<br>4<br>6<br>TAP-1<br>Relative mRNA Levels<br>DMSO<br>VS-6766<br>KRAS mt<br>BRAF mt<br>A549<br>TOV21g<br>SKMEL5<br>IGR1<br>WM115<br>0.0<br>0.5<br>1.0<br>1.5<br>2.0<br>2.5<br>TAP-2<br>Relative mRNA Levels<br>DMSO<br>VS-6766<br>KRAS mt<br>BRAF mt<br>VS<br>-<br>6766 @ 1 µM (except SKMEL5 and IGR<br>-<br>1, 300 nM)<br>Reference: Pachter, RAS<br>-<br>Targeted Drug Development, Sept 2020 |
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| 52<br>VS<br>-<br>6766 enhances tumor growth inhibition when combined with anti<br>-<br>PD<br>-<br>1<br>in the CT26 KRAS (G12D) syngeneic model<br>Reference: Pachter, RAS<br>-<br>Targeted Drug Development, Sept 2020<br>-100<br>0<br>100<br>200<br>300<br>400<br>Response at Day 13<br>% Change in Tumor Volume<br>Vehicle<br>VS-6766<br>anti-PD-1<br>VS-6766 + anti-PD-1<br>20<br>40<br>60<br>80<br>100<br>0<br>20<br>40<br>60<br>80<br>100<br>Survival<br>Time<br>Percent survival<br>VS-6766 + anti-PD-1<br>anti-PD-1 3 mg/kg 2xW x 4 doses<br>VS-6766 0.5 mg/kg QD x 28 days<br>Vehicle<br>Day 11,<br>Last dose<br>anti<br>-<br>PD<br>-<br>1<br>Day 28,<br>Last dose<br>VS<br>-<br>6766<br>0<br>10<br>20<br>30<br>40<br>50<br>60<br>70<br>80<br>90<br>100<br>0<br>20<br>40<br>60<br>80<br>100<br>Survival<br>Days after first dose<br>Percent survival<br>VS-6766 + anti-PD-1<br>anti-PD-1 3 mg/kg 2xW x 4 doses<br>VS-6766 0.5 mg/kg QD x 28 days<br>Vehicle<br>Tumor re<br>-<br>challenge in tumor<br>-<br>free mice showed immune<br>memory with increased<br>memory T cells<br>0<br>2<br>4<br>6<br>8<br>10<br>12<br>14<br>16<br>18<br>20<br>22<br>24<br>26<br>0<br>200<br>400<br>600<br>800<br>1000<br>1200<br>Tumor growth<br>Days after first dose<br>Tumor volume<br>(mm<br>3<br> +/- SEM)<br>Vehicle<br>VS-6766 0.5 mg/kg QD<br>anti-PD-1 3 mg/kg 2xW<br>VS-6766 + anti-PD-1 |
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| 53<br>Strong Patent Protection<br>•<br>COM for VS<br>-<br>6766 to 2027 & defactinib to 2028, Hatch Waxman should extend to 2032<br>•<br>VS<br>-<br>6766 intermittent dosing regimen until 2038 if granted<br>•<br>FAK/MEK combination to 2035<br>•<br>VS<br>-<br>6766/defactinib combination until 2040 if granted<br>•<br>Method of manufacture for VS<br>-<br>6766 to 2032<br>•<br>Other activity related to patent protection is ongoing and will continue into the future |
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| 54<br>Experienced Senior Management Team<br>Brian Stuglik<br>Chief Executive Officer<br>Cathy Carew<br>Chief Organizational<br>Effectiveness Officer<br>Louis Denis, M.D.<br>Chief Medical Officer<br><br>Principal<br>–<br>HR Collaborative<br><br>Ironwood, ActiveBiotics, Dynogen,<br>Tufts Health Plan<br><br>CMO, Asana BioSciences<br><br>Boehringer<br>-<br>Ingelheim, Pfizer<br><br>Global VP & Chief Marketing<br>Officer<br>–<br>Lilly Oncology<br><br>Founding Member<br>–<br>Proventus<br>Health Solutions<br>Daniel Paterson<br>President and Chief Operating<br>Officer<br>Jonathan Pachter,<br>Ph.D.<br>Chief Scientific Officer<br><br>CEO<br>–<br>The DNA Repair Co. (now<br>On<br>-<br>Q<br>-<br>ity)<br><br>PharMetrics (now IMS), Axion<br><br>Head of Cancer Biology<br>–<br>OSI<br>(now Astellas)<br><br>Schering<br>-<br>Plough<br>Rob Gagnon<br>Chief Business and<br>Financial Officer<br><br>CFO<br>–<br>Harvard Bioscience, Clean<br>Harbors<br><br>VP of Finance<br>–<br>Biogen Idec<br>Hagop Youssoufian,<br>MSc, M.D.<br>Head of Medical Strategy<br><br>CMO, BIND Therapeutics, EVP,<br>Progenics,<br><br>CMO & EVP, Ziopharm Oncology,<br>SVP, Imclone |
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| THANK YOU |
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Exhibit 99.2
Verastem Oncology Provides Update on RAMP 201 Study Evaluating VS-6766 ± Defactinib in Low-Grade Serous Ovarian Cancer
Interim Analysis Findings Support Continued Evaluation of Both Monotherapy and Combination Therapy
Encouraging Efficacy Results Include Independently Confirmed Responses in Both KRAS Mutant and KRAS Wild-Type Tumors with No New Safety Signals Observed
Substantial Majority (~80%) of Patients Remain on Therapy; Timing of Go Forward Treatment Regimen Selection Driven by Data Maturity
BOSTON – June 06, 2022 – Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for people living with cancer, today announced an update from an interim analysis of its international Phase 2 RAMP 201 trial evaluating VS-6766 ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC), regardless of KRAS status.
Verastem recently completed a planned interim analysis of its RAMP 201 trial with the goal of selecting a go forward treatment regimen of either VS-6766 monotherapy or VS-6766 in combination with defactinib. The analysis indicated encouraging efficacy results with confirmed responses by independent review in patients treated with VS-6766 monotherapy and patients treated with VS-6766 in combination with defactinib. The findings also include confirmed responses by independent review in both KRAS mutant and KRAS wild-type LGSOC. To date, there have been no additional safety signals with a continued favorable safety profile in both the monotherapy and combination treatment arms with approximately 6% of patients discontinuing due to adverse events.
With a substantial majority (approximately 80%) of patients remaining on study treatment with a median duration of follow-up of four months, the Company has concluded that the data from the interim analysis are not mature enough to make a final decision on the go forward treatment regimen at this time and the trial will continue with all four cohorts (VS-6766 ± defactinib in KRAS mutant and KRAS wild type patient populations).
“We are encouraged by the positive anti-tumor activity that we have seen to date in the RAMP 201 trial in patients with both KRAS mutant and KRAS wild-type tumors. We look forward to evaluating a more mature data set and expect to provide an update on progress once the go forward treatment regimen has been determined,” said Brian Stuglik, Chief Executive Officer, Verastem Oncology. “This interim analysis adds to our optimism about the potential for VS-6766 with or without defactinib and our commitment to advancing the first new treatment specifically developed and approved for women with low-grade serous ovarian cancer where a high medical need remains.”
The Company plans to complete enrollment of all four cohorts of the trial in the second half of this year. Each cohort is expected to have approximately 36 patients for a total of 144 patients.
Both VS-6766 and defactinib are in late-stage development and the combination has received Breakthrough Therapy Designation by the U.S. Food and Drug Administration for the treatment of all patients with recurrent low-grade serous ovarian cancer regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.
About the VS-6766/Defactinib Combination
VS-6766 is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS pathway inhibition. In contrast to currently available MEK inhibitors, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The combination of VS-6766 and FAK inhibitor, defactinib provides RAF/MEK vertical blockade and FAK parallel inhibition to overcome key resistance mechanisms. Both VS-6766 and defactinib are in late-stage development.
Verastem Oncology is conducting Phase 2 registration-directed trials of VS-6766 alone and with defactinib in patients with recurrent LGSOC and in patients with recurrent KRAS G12V-mutant NSCLC as part of its RAMP (Raf And Mek Program) clinical trials, RAMP 201 and RAMP 202, respectively (www.ramp201study.com and www.ramp202study.com). Verastem Oncology has also established clinical collaborations with Amgen, Inc. and Mirati Therapeutics, Inc. to evaluate LUMAKRAS™ (sotorasib) and adagrasib in combination with VS-6766 in KRAS G12C-mutant NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively.
About Low-Grade Serous Ovarian Cancer
Low-grade serous ovarian cancer is a highly recurrent, chemotherapy-resistant cancer, associated with slow tumor growth and high mortality rate.^1^ Approximately 6,000 women in the U.S. and 80,000 worldwide are living with this disease. Mutations in the KRAS gene are present in 35-57% cases of LGSOC.^2^ LGSOC is most often diagnosed in women between the ages of 45-55 years and has a median survival of approximately ten years.^2^ The majority of patients experience severe pain and complications as the disease progresses. Chemotherapy is the standard of care for this disease, with limited treatment options currently available.^2^
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a development-stage biopharmaceutical company committed to the development and commercialization of new medicines to improve the lives of patients diagnosed with cancer. Our pipeline is focused on novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition and focal adhesion kinase (FAK) inhibition. For more information, please visit www.verastem.com.
Forward-Looking Statements Notice
This press release includes forward-looking statements about Verastem Oncology’s strategy, future plans and prospects, including statements related to the potential clinical value of various of its clinical trials, the timing of commencing and completing trials, including topline data reports, and potential for additional development programs involving Verastem Oncology’s lead compounds VS-6766 and
defactinib. The words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," “can,” “promising” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement.
Applicable risks and uncertainties include the risks and uncertainties, among other things, regarding: the success in the development and potential commercialization of our product candidates, including VS-6766 in combination with other compounds, including defactinib, LUMAKRAS^TM^ and others; the occurrence of adverse safety events and/or unexpected concerns that may arise from additional data or analysis or result in unmanageable safety profiles as compared to their levels of efficacy; our ability to obtain, maintain and enforce patent and other intellectual property protection for our product candidates; the scope, timing, and outcome of any legal proceedings; decisions by regulatory authorities regarding labeling and other matters that could affect the availability or commercial potential of our product candidates; whether preclinical testing of our product candidates and preliminary or interim data from clinical trials will be predictive of the results or success of ongoing or later clinical trials; that the timing, scope and rate of reimbursement for our product candidates is uncertain; that third-party payors (including government agencies) may not reimburse; that there may be competitive developments affecting our product candidates; that data may not be available when expected; that enrollment of clinical trials may take longer than expected; that our product candidates will experience manufacturing or supply interruptions or failures; that we will be unable to successfully initiate or complete the clinical development and eventual commercialization of our product candidates; that the development and commercialization of our product candidates will take longer or cost more than planned; that we or Chugai Pharmaceutical Co., Ltd. will fail to fully perform under the VS-6766 license agreement; that we or our other collaboration partners may fail to perform under our collaboration agreements; that we may not have sufficient cash to fund our contemplated operations; that we may be unable to obtain adequate financing in the future through product licensing, co-promotional arrangements, public or private equity, debt financing or otherwise; that Secura Bio, Inc. will achieve the milestones that result in payments to us under our asset purchase agreement with Secura Bio, Inc.; that we will be unable to execute on our partnering strategies for VS-6766 in combination with other compounds; that we will not pursue or submit regulatory filings for our product candidates; and that our product candidates will not receive regulatory approval, become commercially successful products, or result in new treatment options being offered to patients.
Other risks and uncertainties include those identified under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2021 as filed with the Securities and Exchange Commission (SEC) on March 28, 2022 and in any subsequent filings with the SEC. The forward-looking statements contained in this press release reflect Verastem Oncology’s views as of the date hereof, and the Company does not assume and specifically disclaims any obligation to update any forward-looking statements whether as a result of new information, future events or otherwise, except as required by law.
References:
^1^ Grisham R. Low grade serous carcinoma of the ovary. Oncology. 2016; 30(7):650-652. Available at: https://www.cancernetwork.com/view/low-grade-serous-carcinoma-ovary. Accessed February 8, 2022
^2^ Slomovitz B, Gourley C, Carey S. M, Malpica A, Shih I, Huntsman D, et al. Low-Grade serous ovarian cancer: State of the Science. Gynecol Oncol. 2020;156(3):715-725. https://doi.org/10.1016/j.ygyno.2019.12.033.
Investors: Ajay Munshi Vice President, Corporate Development +1 781-469-1579 amunshi@verastem.com
Nate LiaBraaten Argot Partners +1 212-600-1902 nate@argotpartners.com
Media: Lisa Buffington Corporate Communications +1 781-292-4205 lbuffington@verastem.com