8-K
Verastem, Inc. (VSTM)
8-K
2022-01-11
For: 2022-01-11
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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): January 11, 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:
| | | | | |
|---|---|---|---|---|
| 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 January 11, 2022, Verastem, Inc. posted its corporate presentation on its website, a copy of which is furnished hereto as Exhibit 99.1.
Item 8.01. Other Events
On January 11, 2022, Verastem, Inc. issued a press release outlining key 2022 strategic priorities and upcoming catalysts for advancing VS-6766 as a backbone of therapy for RAS pathway-driven cancers. A copy of the press release is filed hereto as Exhibit 99.2.
Item 9.01. Financial Statements and Exhibits
| <br><br> | ||
|---|---|---|
| Exhibit No. | Description | |
| 99.1 | Corporate Presentation, dated January 11, 2022 | |
| 99.2 | | Press Release, dated January 11, 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: January 11, 2022 | By: | /s/ Brian M. Stuglik |
| | | Brian M. Stuglik |
| | | Chief Executive Officer |
Exhibit 99.1
| Corporate Presentation<br>January 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 in combination with VS<br>-<br>6766; the occurrence of<br>adverse safety events and/or unexpected concerns that may arise from additional data or analysis or result in<br>unmanageable safety profiles as compared to their levels of efficacy; or our ability to obtain, maintain and enforce patent<br>and other intellectual property protection for our product candidates.<br>Additional information regarding these factors can be found in Verastem Oncology’s Annual Report on Form 10<br>-<br>K for<br>the fiscal year ended December 31, 2020 and in any subsequent filings with the SEC, including in the sections thereof<br>captioned “Risk Factors” and “Forward<br>-<br>Looking Information and Factors that May Affect Future Results,” as well as in<br>our subsequent reports on Form 8<br>-<br>K, all of which are filed with the U.S. Securities and Exchange Commission (SEC)<br>and available at www.sec.gov and 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>Cash Balance of $103.4 million, as of September 30, 2021<br>Debt reduced from approx. $185M to $0M (2019<br>-<br>2021)<br>Annual operating expense of approximately $55<br>-<br>60 million for 2021<br>New lead clinical program<br>has 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 achieved in low<br>-<br>grade serous ovarian cancer<br>(LGSOC), strong signal in KRAS G12V mutant NSCLC; registration<br>-<br>directed trials initiated in 4Q 2020 | |
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| 4<br>Key VSTM Milestones 2021<br>-<br>2022<br>LGSOC<br>NSCLC<br>Corporate<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>Retired<br>Outstanding Debt<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 Top<br>-<br>Line<br>Data from Selection<br>Phase<br>RAMP<br>-<br>201 Complete<br>enrollment of<br>Expansion Phase<br>Translational data<br>from FRAME<br>LGSOC cohort<br>presented<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>Initiate combo study<br>of VS<br>-<br>6766 +<br>pembrolizumab in<br>BRAF mt melanoma<br>*Investigator<br>-<br>sponsored research | |
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| VS<br>-<br>6766 RAF/MEK Inhibitor<br>Program Overview | |
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| 6<br>VS<br>-<br>6766 is a differentiated, best<br>-<br>in<br>-<br>class asset potentially applicable across<br>multiple patient populations<br>•<br>Unique dual RAF/MEK targeting mechanism of action<br>•<br>Best<br>-<br>in<br>-<br>class safety & tolerability profile relative to marketed MEK inhibitors, with potential for combinability with<br>agents from multiple target classes<br>•<br>Novel intermittent dosing schedule; convenient oral regimen<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>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>Pancreatic<br>1,2<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>Anti<br>-<br>EGFR<br>2<br><br>SOS1 or SHP2 inhibitor<br>2<br><br>CDK4/6 inhibitor<br>2<br><br>Anti<br>-<br>PD<br>-<br>1<br>1,2<br><br>G12Ci<br>1,2<br><br>Everolimus<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>Robust Pipeline Targeting the RAS Pathway and Multiple Growth<br>Opportunities<br>RAMP 201 study = NCT04625270<br>RAMP 202 study = NCT04620330<br>RAMP 203 study = NCT05074810<br>FRAME study = NCT03875820<br>1<br>Registration<br>-<br>directed trial<br>*Pre<br>-<br>clinical studies ongoing in multiple KRAS mutant tumors<br>FDA Breakthrough Therapy Designation for VS<br>-<br>6766 + defactinib<br>Clinical Collaboration Initiated with<br>Clinical Collaboration Initiated with<br>LGSOC VS<br>-<br>6766 +/<br>-<br>defactinib<br>KRAS G12V NSCLC VS<br>-<br>6766 +/<br>-<br>defactinib<br>RAMP 203 KRAS G12C NSCLC VS<br>-<br>6766 + LUMAKRAS<br>TM<br>(sotorasib)<br>RAMP 204 KRAS G12C NSCLC VS<br>-<br>6766 + adagrasib<br>KRAS mt NSCLC | VS<br>-<br>6766 + everolimus (mTORi) |
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| 9<br>VS<br>-<br>6766 is a Unique Small Molecule RAF/MEK Clamp<br>VS<br>-<br>6766 (RAF/MEKi)<br>Mirdametinib (MEKi)<br><br>VS<br>-<br>6766 inhibits both MEK &<br>RAF kinase activities by<br>trapping them in inactive<br>complexes<br><br>MEK inhibitors paradoxically<br>induce MEK phosphorylation<br>(pMEK) by relieving<br>ERK<br>-<br>dependent feedback<br>inhibition of RAF<br><br>By inhibiting RAF<br>phosphorylation of MEK,<br>VS<br>-<br>6766 has advantage of not<br>inducing pMEK<br><br>VS<br>-<br>6766 inhibits ERK signaling<br>more completely;<br>may confer enhanced<br>therapeutic activity<br>References<br>:<br>Ishii et al.,<br>Cancer Res<br>, 2013; Lito et al.,<br>Cancer Cell<br>, 2014 | |
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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>Best<br>-<br>in<br>-<br>class tolerability with established twice weekly dosing 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>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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| 17<br>LGSOC: Limited Treatment Options with High Unmet Need<br>References:<br>1<br>NCCN guidelines<br>Low<br>-<br>Grade Ovarian Cancer<br>–<br>Treatment Algorithm<br>1<br>Observe only<br>Pt Chemo Combo:<br>Carbo<br>-<br>Pt + Paclitaxel (preferred)<br>+ Beva for Stage II<br>-<br>IV (incl maintenance Beva)<br>OR Hormonal Tx (2B)<br><br>Pt<br>-<br>Chemo combo<br>+/<br>-<br>Beva<br><br>Trametinib<br><br>Fulvestrant<br>Recurrence<br><br>Taxane or<br>gemcitabine, or<br>doxorubicine, or<br>topotecan +/<br>-<br>Beva<br><br>Trametinib<br><br>Fulvestrant<br>Pt<br>-<br>Sensitive<br>Pt<br>-<br>Resistance<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%<br>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>Gershenson, et al. ESMO 2019.<br>2<br>Monk et al., J Clin Oncol 2020.<br>Standard of Care = letrozole, tamoxifen, chemotherapy<br>PFS = Progression free survival<br>CI = confidence interval | |
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| 18<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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| 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)<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>Expand each cohort to ~36 patients<br>(~20 additional patients)**.<br>Total Expected Patients: to ~144<br>patients<br>**<br>..<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 expansion<br>phase<br>Primary Endpoint:<br>Objective Response Rate<br>(blinded independent review)<br>Hierarchical evaluation of:<br>1)<br>In KRAS mt patients<br>2)<br>All patients (KRAS mt & wt)<br>Registration<br>-<br>directed Study: FDA Supportive of Development Strategy, Adaptive Design and Inclusion of KRAS wt LGSOC<br>Commenced in Nov. 2020<br>with estimated Primary Completion Date for the Expansion Phase of June 2023 (NCT04625270)<br><br>Recurrent LGSOC<br><br>Prior<br>chemotherapy<br><br>Measurable disease<br>(RECIST 1.1)<br><br>Prior MEKi allowed | |
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| 20<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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| 22<br>High Unmet Need in Refractory KRAS mt NSCLC Adenocarcinoma<br>0<br>5<br>10<br>15<br>G12C<br>G12V<br>G12D<br>G12A<br>G13C<br>G12S<br>G13D<br>% of Patients<br>KRAS Mutation<br>Advanced or Metastatic NSCL Cancer<br>Recommend Histologic and Molecular Subtyping<br>5<br>Appropriate<br>targeted 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<br>/KRAS<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>NSCLC Adenocarcinoma<br>3<br>US Annual Incidence<br>1,2<br>: 92K<br>WW Annual Incidence<br>1,2<br>: 836K<br>KRAS Mutations Represent 25% of Lung Cancer<br>Adenocarcinoma (EGFR 17%, ALK 7%)<br>4<br><br>SOC in recurrent disease is chemotherapy<br><br>Pre<br>-<br>PD<br>-<br>(L)1<br>era, chemotherapy response rate ~10% in recurrent<br>disease; 12w PFS of 30<br>–<br>45%<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>Recurrence<br>Recurrence | |
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| 23<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>BRAF<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 | |
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| 24<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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| 25<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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| 26<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 a Confirmed 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>Mono<br>Mono<br>Mono<br>Mono<br>Combo<br>Mono<br>Combo<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>4.0 mg VS-6766/200 mg defactinib<br>Best response by RECIST<br>0<br>-8<br>-38<br>-46<br>-68<br>-70<br>0<br>Mono:<br> VS-6766 monotherapy<br>Combo:<br> VS-6766 + Defactinib<br>Continuing on treatment<br>*<br>*<br>+<br>+<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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| 27<br>RAMP 202: Registration<br>-<br>directed Phase 2 Trial of VS<br>-<br>6766+/<br>-<br>Defactinib in<br>KRAS Mutant (mt), G12V Enriched Advanced 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>This Registration<br>-<br>directed Phase 2 Study commenced December 2020 with an estimated Primary<br>Completion Date for the Expansion Phase of March 2023<br>(NCT04620330)<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>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>Final G12V sample<br>size to be discussed<br>with FDA<br><br>Non<br>-<br>G12V Cohorts<br>TBD based on results<br>of exploratory analysis | |
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| 28<br>Preclinical synergy of VS<br>-<br>6766 + G12C inhibitors in KRAS G12C mt models<br>Synergy of VS<br>-<br>6766 + G12C inhibitor AMG 510 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>AMG 510: 30 mg/kg QD<br>-100<br>0<br>100<br>200<br>300<br>400<br>Response at Day 10<br>Response<br>(% change from baseline)<br>Vehicle<br>VS-6766 0.3mg/kg QD<br>AMG 510 30mg/kg QD<br>VS-6766 + AMG 510<br>VS-4718 50mg/kg BID<br>VS-6766 + VS-4718<br>AMG 510 + VS-4718<br>VS-6766 + AMG 510 + VS-4718<br>Trametinib 0.3mg/kg QD<br>Trametinib + AMG 510<br>Vehicle<br>Trametinib<br>10 PR<br>VS-6766<br>FAKi<br>AMG510<br>AMG510 + Trametinib<br>AMG510 + VS-6766<br>AMG510 + FAKi<br>VS-6766 + FAKi<br>AMG510 + VS-6766 + FAKi<br>-30<br>20<br>1 SD<br>2 SD<br>1 SD<br>1 SD<br>1 SD<br>1 PR<br>8 SD<br>2 PR<br>4 SD<br>3 PR<br>2 SD<br>4 PR<br>Response @ Day 10<br>VS<br>-<br>6766 & FAKi potentiate AMG 510 efficacy in KRAS G12C mutant<br>NSCLC in vivo; Tumor regression in all mice with triple combination<br>VS<br>-<br>6766 + AMG 510 yields deeper and more sustained inhibition<br>of ERK signaling pathway<br>H2122 KRAS G12C mutant NSCLC<br>AMG 510<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>AMG 510: 100 nM<br>VS<br>-<br>6766: 100 nM<br>Combined Synergy Score<br>Cell line<br>Indication<br>Sensitivity to G12C<br>inhibitors<br>VS<br>-<br>6766 +<br>AMG 510<br>VS<br>-<br>6766 +<br>MRTX849<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<br>0<br>5<br>10<br>15<br>20<br>25<br>30<br>0<br>500<br>1000<br>1500<br>2000<br>Tumor growth<br>Days after cell inoculation<br>Tumor volume<br>(mm<br>3<br> +/- SEM)<br>Vehicle<br>AMG510<br>AMG510 + FAKi<br>AMG510 + VS-6766<br>AMG510 + VS-6766 + FAKi<br>VS-6766<br>Reference: Coma et al., AACR 2021 | |
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| 29<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 is expected to be effective against these<br>KRAS, NRAS, BRAF and CRAF modifications<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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| 30<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>Part A (Dose Evaluation) portion of study expected to be initiated in 1Q 2022 (<br>NCT05074810<br>)<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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| 32<br>Vertical Blockade: Preclinical synergy in combination with several promising<br>targets<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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| 33<br>Parallel Pathway Inhibition: Two synergistic combinations already progressed<br>to clinical stage<br>Reference: Coma et al., RAS<br>-<br>Targeted Drug<br>Discovery, Feb 2021<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>MIAPACA2<br>H358<br>H1373<br>SW1573<br>H2122<br>HPAC<br>A427<br>ASPC1<br>HPAFII<br>SKLU1<br>CFPAC1<br>H2291<br>H441<br>H2444<br>PANC0327<br>CAPAN2<br>-20<br>-10<br>0<br>10<br>20<br>VS-6766 + Defactinib<br>Combined Synergy Score<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>40% (2/5)<br>83% (5/6)<br>20% (1/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<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>VS<br>-<br>6766 + p70S6K/AKTi (M2698)<br>VS<br>-<br>6766 + FAKi (Defactinib)<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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| Corporate | |
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| 35<br>Key Financial Statistics<br>Cash, cash equivalents & investments<br>$103.4M<br>Shares fully<br>diluted<br>196.9M<br>Insider ownership (outstanding / vested)<br>8.1% / 5.1%<br>As of September 30, 2021<br>*<br>The 2018 Notes have an initial conversion rate of 139.5771 shares of Common Stock per $1,000 which translates to an initial c<br>on<br>version price of $7.16 per share of Common Stock. | |
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| Backup Slides | |
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| 37<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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| 38<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>105K<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>Ovarian<br>Incidence<br>5<br>:<br>22K<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>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>35<br>–<br>60%<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 | |
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| 39<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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| 40<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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| 41<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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| 42<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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| 43<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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| 44<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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| 45<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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| 46<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 for treatment of<br>KRAS mt CRC<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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| 47<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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| 48<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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| 49<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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| 50<br>LGSOC Market Opportunity<br>–<br>Reference Calculations<br>NSCLC KRAS<br>G12C<br>3<br>Pancreatic<br>3<br>LGSOC<br>1<br>Endometrioid<br>3<br>Metastatic uveal<br>melanoma<br>3<br>Patient<br>-<br>months of Therapy<br>Per Year<br>(across all 2L+ patients)<br>2<br>Average months on<br>Therapy<br>(per patient)<br>2<br>Number of Patients (2L+)<br>2<br> -<br> 10,000<br> 20,000<br> 30,000<br> 40,000<br>1<br>Prevalence used for LGSOC patient population estimate. 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<br>Educ Book; 2019; Slomovitz, Gourley, Carey, Malpica, Shih, Huntsman, Fader., Grisham et al, Low<br>-<br>Grade serous ovarian cancer: Sta<br>te of the Science; Gynecol Oncol; 2020. Grisham, Iyer, Low<br>-<br>Grade Serous Ovarian<br>Cancer: Current Treatment Paradigms and Future Directions; Curr Treat Options Oncology; 2018; Globocan 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; patient population estimates from Globocan<br>2020, American Cancer Society 2021, AACR Genie Cohort 9.0 public, and scientific publications. Duration of therapy estimates<br>fr<br>om clinical studies and clinician experience. Number of patients and months on<br>therapy are for 2<br>nd<br>-<br>line+<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); Endometrioid RAS/RAF mutant 2<br>nd<br>-<br>line patients (incidence); Uveal melanoma RAS/RAF mutant 2nd<br>-<br>line<br>patients (incidence)<br> -<br> 5.00<br> 10.00<br> 15.00<br> -<br> 50,000<br> 100,000<br> 150,000 | |
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| 51<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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| 52<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 Outlines Key 2022 Strategic Priorities and Upcoming Catalysts for Advancing VS-6766 as a Backbone of Therapy for RAS Pathway-Driven Cancers
Report Selection Phase (Part A) Results from RAMP 201 and RAMP 202 Evaluating VS-6766 Alone and in Combination with Defactinib in Low-Grade Serous Ovarian Cancer (LGSOC) and KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC), Respectively
Report Preliminary Data from Phase 1/2 Trial Evaluating LUMAKRAS™ (sotorasib) and VS-6766 and Initiate Phase 1/2 Trial Evaluating adagrasib and VS-6766*;* Both in KRAS G12C-Mutant Non-Small Cell Lung Cancer
Expand Ongoing Investigator-Initiated Trial Program to Explore Combination Potential with VS-6766 in Additional Areas of High Unmet Need; Data Read-Outs Expected Throughout 2022
BOSTON – January 11, 2022 – Verastem Oncology (Nasdaq:VSTM), a biopharmaceutical company committed to advancing new medicines for patients battling cancer, today outlined key strategic priorities and upcoming catalysts to support its lead compound VS-6766 in 2022. 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. VS-6766 is currently in late-stage development.
“Building on the Breakthrough Therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer, the significant progress of our RAMP program in both low-grade serous ovarian cancer and KRAS G12V-mutant non-small cell lung cancer, our clinical collaborations in KRAS G12C-mutant non-small cell lung cancer as well as our ongoing investigator-initiated trials program, we expect to see tremendous progress on behalf of patients in 2022,” said Brian Stuglik, CEO of Verastem Oncology. “We plan to efficiently advance our development strategy, report multiple data readouts and further highlight the differentiated potential of VS-6766 across tumor types and mutations.”
2022 Strategic Priorities
Gynecologic Oncology Program
| ● | Fully enroll Part B of the RAMP 201 trial (LGSOC VS-6766 +/- defactinib). |
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| ● | Expand development program into other RAS pathway-driven gynecologic cancers. |
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Non-Small Cell Lung Cancer (NSCLC) Program
| ● | Select regimen for Part B of the RAMP 202 trial (KRAS G12V NSCLC VS-6766 +/- defactinib) |
|---|---|
| ● | Initiate and complete dose-finding portions of RAMP 203 (KRAS G12C NSCLC VS-6766 + LUMAKRAS^TM^(sotorasib)) and RAMP 204 (KRAS G12C NSCLC VS-6766 + adagrasib) combination trials. |
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| ● | Provide signal read-out of investigator-sponsored trial of VS-6766 and everolimus in KRAS- mutant NSCLC. |
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Other Programs
| ● | Expand investigator-initiated trial program to include signal-finding studies in other tumor types, including melanoma, breast and colorectal cancers. |
|---|---|
| ● | Expand clinical combinations with VS-6766. |
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Anticipated 2022 Development Milestones and Catalysts
1Q-2022
| ● | Having completed target enrollment (n=64) in the selection phase (Part A) of the Phase 2 RAMP 201 trial (LGSOC VS-6766 +/- defactinib), the enrollment phase (Part B) is now ongoing with both treatment arms currently advancing. |
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| ● | Complete enrollment in the selection phase (Part A) of the Phase 2 RAMP 202 trial (KRAS G12V NSCLC VS-6766 +/- defactinib). |
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| ● | Initiate RAMP 203 trial (KRAS G12C NSCLC VS-6766 + LUMAKRAS^TM^(sotorasib)) with Amgen. |
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Q2-2022
| ● | Report topline results from Part A of the RAMP 201 trial (LGSOC VS-6766 +/- defactinib), following discussions with regulatory authorities. |
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| ● | Initiate RAMP 204 trial (KRAS G12C VS-6766 + adagrasib) with Mirati. |
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| ● | Present topline results of investigator-initiated trial of VS-6766 and everolimus in KRAS-mutant NSCLC. |
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| ● | Present investigator-initiated FRAME LGSOC translational data. |
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2H-2022
| ● | Complete enrollment in the RAMP 201 trial (LGSOC VS-6766 +/- defactinib). |
|---|---|
| ● | Report topline results from RAMP 202 trial (KRAS G12V NSCLC VS-6766 +/- defactinib) and initiate the expansion phase (Part B), following discussions with regulatory authorities. |
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| ● | Report initial readout of the RAMP 203 trial (KRAS G12C NSCLC VS-6766 + LUMAKRAS^TM^(sotorasib)) with Amgen. |
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“We are pleased with the progress of our scientific collaborations and the high level of interest of leading investigators to advance the preclinical synergy data towards clinical evaluation of VS-6766 in combinations across multiple tumor types, including melanoma, colorectal and breast cancers,” said Louis Denis, CMO of Verastem Oncology. “These clinical research efforts complement our company-sponsored development program and help to expediently advance our efforts to address an even broader scope of significant unmet medical needs.”
About VS-6766
VS-6766 (formerly known as CH5126766 and RO5126766) 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. VS-6766 is currently in late-stage development.
In contrast to other 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 U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK inhibitor VS-6766, with defactinib, its FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.^1^
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. Verastem Oncology has also established clinical collaborations with Amgen and Mirati 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 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 compound. 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 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, 2020 as filed with the Securities and Exchange Commission (SEC) on March 18, 2021 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.
^1^ Verastem Oncology Press Release. Verastem Oncology Receives Breakthrough Therapy Designation for VS-6766 with Defactinib in Recurrent Low-Grade Serous Ovarian Cancer. May 24, 2021. Available at: https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-breakthrough-therapy-designation-vs. Accessed October 2021.
Investors: Ajay Munshi Vice President, Corporate Development +1 781-469-1579 amunshi@verastem.com
Sherri Spear Argot Partners +1 212-600-1902 sherri@argotpartners.com
Media: Lisa Buffington Corporate Communications +1 781-292-4205 lbuffington@verastem.com