8-K
Verastem, Inc. (VSTM)
8-K
2022-10-04
For: 2022-10-04
View Original
Added on
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): October 4, 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 October 4, 2022, Verastem, Inc. 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 9.01. Financial Statements and Exhibits
| | ||
|---|---|---|
| | ||
| Exhibit No. | Description | |
| 99.1 | | Corporate Presentation, dated October 4, 2022 |
| 104 | | Cover Page Interactive Data File (formatted in Inline XBRL) |
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.
| | | |
|---|---|---|
| | VERASTEM, INC. | |
| | | |
| Dated: October 4, 2022 | By: | /s/ Brian M. Stuglik |
| | | Brian M. Stuglik |
| | | Chief Executive Officer |
Exhibit 99.1
| Corporate Presentation<br>October 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. |
| --- |
| 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/MEK clamp) and defactinib (FAK inhibitor) are clinically<br>active against 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>across RAS pathway<br>-<br>driven cancers<br>based on preclinical data<br>Up to $150 million of non<br>-<br>dilutive funding available from new credit facility<br>Cash balance of $94.3 million as of June 30, 2022 & $110.4 million as of<br>August 31, 2022<br>Company ended Quarter 2 2022 with $19.6 million non<br>-<br>GAAP operating<br>expenses<br>Lead clinical program has<br>best<br>-<br>in<br>-<br>class potential<br>Patent Update<br>Strong balance sheet<br>Rapid development path to<br>market<br>FDA Breakthrough Therapy Designation in LGSOC;<br>Registration<br>-<br>directed trial initiated in 4Q 2020 in low<br>-<br>grade serous<br>ovarian cancer (LGSOC)<br>* Q2 2022 GAAP operating expenses<br>-<br>$21.4M minus Q2 2022 stock compensation<br>-<br>$1.8M = $19.6M Q2 2022 non<br>-<br>GAAP operating expenses<br>Recently issued intermittent dosing IP for both VS<br>-<br>6766 alone and VS<br>-<br>6766 + defactinib extends patent coverage up to 2038 and 2040<br>Significant downstream<br>market opportunity and<br>blockbuster potential |
| --- |
| 4<br>Key VSTM Milestones 2021<br>-<br>2022<br>LGSOC<br>NSCLC<br>1H2021<br>2H2021<br>1H2022<br>RAMP 201<br>Amended to Include<br>KRAS wt patients in<br>Selection Phase<br>RAMP 201 Target enrollment of<br>Selection Phase Complete<br>Initiated enrollment of Expansion Phase<br>RAMP 202 Complete 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>4Q2022<br>Additional<br>Indications*<br>Initiate combo study of VS<br>-<br>6766 +<br>cetuximab in KRAS mt CRC<br>RAMP 201 Selection Phase Update*<br>RAMP 201 Complete enrollment of<br>Expansion Phase<br>Translational data from FRAME<br>LGSOC cohort presented at AACR<br>Initiate RAMP 204 (VS<br>-<br>6766 + adagrasib)<br>in KRAS G12C (Mirati)<br>Initiate RAMP 203 (VS<br>-<br>6766 + sotorasib)<br>in KRAS G12C (Amgen)<br>Top<br>-<br>Line Data from RAMP 202 Selection<br>Phase<br>Top<br>-<br>Line Data from VS<br>-<br>6766 +<br>everolimus in KRAS mt<br>Initiate combo study of VS<br>-<br>6766 +<br>abemaciclib and fulvestrant in ER+ breast<br>cancer<br>Initial readout of RAMP 203 data<br>*Next RAMP 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 VS<br>-<br>6766 +<br>defactinib in RAS pathway<br>-<br>driven<br>gynecological cancers<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>✓<br>RAMP 202 Amended to include BRAF<br>mt cohorts<br>✓<br>✓<br>PanCAN Agreement Executed<br>✓<br>RAMP 201 FDA Meeting<br>✓<br>✓<br>Initiate combo study of VS<br>-<br>6766 +<br>gemcitabine/nab<br>-<br>paclitaxel + defactinib in<br>metastatic pancreatic cancer<br>RAMP 201 Second Interim Update<br>✓<br>✓ |
| --- |
| 5<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 RAF/MEK clamp 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 |
| --- |
| 6<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>VS<br>-<br>6766 + defactinib<br>FRAME<br>R/<br>R endometrioid<br>cancer<br>(RAS/RAF mt)<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 (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>Pancreatic Ductal Adenocarcinoma<br>VS<br>-<br>6766 + gemcitabine/nab<br>-<br>paclitaxel + defactinib<br>RAMP 205<br>R/R NSCLC (KRAS mt)<br>VS<br>-<br>6766 + everolimus (mTORi)<br>IST<br>R/R Colorectal Cancer<br>VS<br>-<br>6766 + cetuximab (EGFRi)<br>IST<br>ER+ Breast Cancer<br>VS<br>-<br>6766 +<br>abemaciclib<br>+<br>fulvestrant<br>IST<br>Robust Clinical Program: VS<br>-<br>6766 in multiple combinations across RAS/MAPK<br>pathway<br>-<br>driven tumors<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 |
| --- |
| 7<br>Key Financial Statistics<br>Cash, cash equivalents & investments<br>$94.3M ($110.4M as of August 31, 2022)<br>Non<br>-<br>GAAP Operating Expenses<br>$19.6M<br>Shares Outstanding<br>187.6M<br>(210.0M as of August 31, 2022)<br>As of and for the quarter ended June 30, 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>* Q2 2022 GAAP operating expenses<br>-<br>$21.4M minus Q2 2022 stock compensation<br>-<br>$1.8M = $19.6M Q2 2022 non<br>-<br>GAAP operating expenses |
| --- |
| VS<br>-<br>6766 RAF/MEK Clamp Program<br>Overview |
| --- |
| 9<br>Broad Development Opportunities Across Multiple RAS/MAPK Pathway<br>-<br>Driven Cancers<br>VS<br>-<br>6766<br>High Priority Registration Indication<br>Registration<br>-<br>Directed Trial Initiated in 4Q20<br><br>LGSOC<br>1,2<br>(RAMP 201)<br>Key Signal Finding<br><br>VS<br>-<br>6766 + G12Ci KRAS G12C mt NSCLC<br>2<br>(RAMP<br>203<br>-<br>sotorasib) & (RAMP 204<br>-<br>adagrasib)<br><br>BRAF mt (V600E & non V600E) NSCLC<br>1,2<br>(RAMP<br>202)<br><br>Pancreatic<br>2<br><br>RAS/RAF mt endometrioid<br>1<br><br>Uveal Melanoma<br>2<br><br>VS<br>-<br>6766 + everolimus KRAS mt NSCLC<br>1,2<br><br>VS<br>-<br>6766 + cetuximab KRAS mt CRC<br>2<br><br>VS<br>-<br>6766 +<br>abemaciclib<br>and<br>fulvestrant<br>in ER+ breast<br>cancer<br>Rational Combinations<br><br>G12Ci<br>1,2<br><br>G12Di<br>2<br><br>Anti<br>-<br>EGFR<br>2<br><br>Everolimus<br>1,2<br><br>CDK4/6 inhibitor<br>2<br><br>Anti<br>-<br>PD<br>-<br>1<br>1,2<br><br>Chemotherapy<br>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><br>Thyroid<br>1,2<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 |
| --- |
| 10<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 MEK, BRAF &<br>CRAF by trapping these<br>molecules 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 |
| --- |
| 11<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>DMSO Tram VS<br>-<br>6766<br>DMSO Tram VS<br>-<br>6766<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 |
| --- |
| 12<br>VS<br>-<br>6766 Inhibits Cell Proliferation Across Multiple RAS/MAPK Pathway<br>Alterations and Multiple Solid Tumor Histologies<br>Reference: Adapted from Pachter<br>RAS<br>-<br>Targeted Drug Discovery<br>,<br>Sep 2021 3D proliferation assay<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>PSN1<br>KP2<br>HUP-T3<br>H2009<br>H1573<br>SW1116<br>A549<br>LS123<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>NCI-H2087<br>GAK<br>SK-MEL-2<br>HEC-151<br>H1573<br>DLD-1<br>HS940.T<br>H1373<br>HMCB<br>HCT 116<br>RKO<br>SW48<br>AN3 CA<br>RL95-2<br>LS513<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 G12D<br>BRAF V600E<br>KRAS G12C<br>Indication<br>NSCLC<br>Panc<br>CRC<br>Indication:<br>MAPK pathway lateration:<br>Melanoma<br>NF1 mt<br>NRAS mt<br>KRAS G12R<br>BRAF class 2 mt<br>KRAS G12C<br>KRAS G12D<br>KRAS G12V<br>Other KRAS mt<br>BRAF mt<br>NRAS mt<br>ARAF mt<br>RAF1 mt<br>Endometrial<br>Bladder<br>NF1 mt<br>KRAS G12S<br>KRAS G13D<br>KRAS Q61K<br>KRAS G12A<br>ERK2 mt<br>Other mt |
| --- |
| 13<br>Vertical Blockade: Establishing VS<br>-<br>6766 as the Backbone of Therapy for<br>RAS/MAPK 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 |
| --- |
| 14<br>Parallel Pathway Inhibition: Establishing VS<br>-<br>6766 as the Backbone of Therapy<br>for RAS/MAPK 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 several key anti<br>-<br>cancer agents<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 |
| --- |
| 15<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 |
| --- |
| 16<br>Favorable Tolerability Profile at Recommended Phase 2 Dose for VS<br>-<br>6766<br>plus 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 |
| --- |
| VS<br>-<br>6766 +/<br>-<br>Defactinib in<br>Low<br>-<br>Grade Serous Ovarian Cancer |
| --- |
| 18<br>70% of LGSOC Tumors Driven by Mutations in the RAS/MAPK 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% |
| --- |
| 19<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 |
| --- |
| 20<br>VS<br>-<br>6766 in Combination with<br>Defactinib<br>(FRAME) 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 |
| --- |
| 21<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 (<br>wt<br>)<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) |
| --- |
| 22<br>RAMP 201 Update<br>-<br>October 2022<br>•<br>Full enrollment based on the study protocol on<br>track and expected by the end of the year<br>•<br>FDA meeting 4Q<br>-<br>22 to align on regulatory path<br>forward and go forward regimen<br>•<br>Completed second planned interim analysis<br>•<br>Encouraging efficacy results include independently<br>confirmed responses<br>•<br>Enrollment continues towards completion of all<br>four cohorts<br>•<br>No new safety signals, continued favorable safety<br>profile<br>•<br>Majority of patients remain on treatment<br>Next Steps<br>Update |
| --- |
| 23<br>LGSOC Market Opportunity Larger or Comparable to Other High Unmet<br>Need 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 |
| --- |
| VS<br>-<br>6766 +/<br>-<br>Defactinib in NSCLC |
| --- |
| 25<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/<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>▪<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>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 |
| --- |
| 26<br>RAMP 202: Phase 2 Trial of VS<br>-<br>6766 +/<br>-<br>Defactinib in Advanced NSCLC Primary<br>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>Criteria to continue to expansion phase<br>not met<br>Selection Phase<br>Expansion Phase<br>Completed Enrollment<br>Defactinib + VS<br>-<br>6766<br>1<br>KRAS mt non<br>-<br>G12V<br>N=40, maximum<br>Criteria to continue to expansion phase<br>not met<br>Completed Enrollment |
| --- |
| 27<br>RAMP 202 Results<br>–<br>August 2022<br>•<br>Results of Part A of RAMP 202 trial in KRAS<br>-<br>G12V mt NSCLC show VS<br>-<br>6766<br>±<br>defactinib did<br>not meet criteria to continue to expansion<br>phase<br>•<br>Continue to analyze the results of the trial and<br>integrate the findings into our development<br>plans moving forward<br>•<br>Continuing VS<br>-<br>6766 development in NSCLC<br>with other combinations:<br>o<br>Sotorasib<br>o<br>Adagrasib<br>o<br>Everolimus<br>•<br>The confirmed ORR was 11% (2/19) in KRAS<br>G12V mt NSCLC patients treated with VS<br>-<br>6766 +<br>defactinib with a disease control rate of 37%<br>•<br>The ORR in non<br>-<br>G12V KRAS mt patients treated<br>with VS<br>-<br>6766 + defactinib was 5% (2/37) with a<br>disease control rate of 54%<br>o<br>No subtype was identified for further clinical<br>evaluation of VS<br>-<br>6766 + defactinib in this trial<br>Next Steps<br>Findings |
| --- |
| 28<br>RAMP 202: VS<br>-<br>6766 + Defactinib in 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>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>Initial Phase<br>Analysis |
| --- |
| 29<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 |
| --- |
| 30<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 |
| --- |
| 31<br><br>Patients must have<br>known G12C KRAS<br>mutation determined<br>using<br>validated test<br><br>Treatment with at least<br>1 but no more than 3<br>prior systemic regimens,<br>for Stage 3B<br>-<br>C or 4<br>NSCLC*<br><br>Patient may have<br>previously received<br>adjuvant chemotherapy<br>for earlier<br>-<br>stage disease<br><br>Measurable disease<br>according to RECIST 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 who<br>Progressed on KRAS<br>G12C Inhibitor<br>Treatment<br>Stage 1<br>: ~20 patients<br>Stage 2<br>: expand<br>Collaboration with Amgen<br>*may include patients with or without prior<br>G12C therapy<br>*H<br>as advanced to Cohort 2:<br>4mg VS<br>-<br>6766/960mg sotorasib |
| --- |
| 32<br>RAMP 204: Phase 1/2 Trial of VS<br>-<br>6766 + Adagrasib in KRAS G12C<br>-<br>mutated<br>Advanced NSCLC<br><br>Patients must have a<br>KRAS G12C<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 must have<br>received prior<br>therapy with a KRAS<br>G12C inhibitor and<br>experience<br>progressive disease<br><br>Measurable disease<br>according to RECIST<br>1.1<br><br>ECOG performance<br>status ≤ 1<br>Part A: Dose Evaluation<br>(3+3 DLT Assessment)<br>Part B: Dose Expansion<br>(Primary endpoint ORR)<br>Stage 1<br>: 19 patients<br>(including Part A<br>patients) treated<br>with RP2D<br>Stage 2<br>: expand to<br>55 patients<br>RP2D<br>Selection<br>VS<br>-<br>6766 + Adagrasib<br>Dose Finding Cohorts<br>(N= 3<br>-<br>6 pts)<br>Collaboration with Mirati Therapeutics |
| --- |
| Future Opportunities: VS<br>-<br>6766 as<br>Backbone of RAS Therapy |
| --- |
| 34<br>High Unmet Needs in RAS/MAPK Pathway<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% |
| --- |
| 35<br>Preclinical Synergy of VS<br>-<br>6766 in Combination with Promising Agents for<br>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>VS<br>-<br>6766 + G12Ci (sotorasib)<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 (adagrasib)<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>Vertical MAPK Pathway Inhibition<br>Parallel Pathway Inhibition<br>KP4<br>Panc 04.03<br>Panc 08.13<br>AsPC-1<br>HPAF-II<br>HPAC<br>LS 180<br>LS513<br>SNU-C2B<br>SNU-C2A<br>Gp2D<br>A427<br>SK-LU-1<br>0<br>20<br>40<br>60<br>VS-6766 + MRTX1133<br>Combined Synergy Score<br>Indication<br>NSCLC<br>CRC<br>Synergy<br>Antagonism<br>Indication<br>Panc<br>VS<br>-<br>6766 + SHP2i (RMC<br>-<br>4550)<br>VS<br>-<br>6766 + SOS1i (BI<br>-<br>3406)<br>VS<br>-<br>6766 + CDK4/6i (Palbociclib)<br>VS<br>-<br>6766 + pan<br>-<br>HERi (Afatinib)<br>VS<br>-<br>6766 + G12Di (MRTX1133) |
| --- |
| 36<br>VS<br>-<br>6766 + Everolimus Clinical Data Presented at ASCO<br>•<br>Well<br>-<br>tolerated RP2D established for VS<br>-<br>6766 +<br>everolimus with intermittent dosing of both<br>agents (twice weekly; 3 wks on/1 wk off)<br>o<br>No DLTs reported<br>at RP2D<br>•<br>VS<br>-<br>6766 + everolimus combo induced PRs in<br>patients with various RAS mutations in<br>NSCLC, LGSOC and thyroid cancers<br>•<br>Both LGSOC pts showed PRs with 69% and<br>79% reduction and have been on treatment for<br>≥3 years with treatment ongoing<br>•<br>KRAS mutant NSCLC expansion cohort is<br>currently ongoing<br>–<br>expanding to 20 pts<br>o<br>Currently 2 PRs/11<br>o<br>Median progression free interval of 6.25<br>months in heavily pre<br>-<br>treated patients<br>NRAS Q61K<br>Anaplastic<br>thyroid cancer<br>(lung metastasis)<br>VS<br>-<br>6766 + Everolimus<br>Pre<br>-<br>treatment<br>KRAS G13A<br>NSCLC<br>KRAS G12D<br>LGSOC<br>(liver metastasis)<br>Reference: Minchom et al., ASCO 2022 |
| --- |
| 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 |
| --- |
| 38<br>VS<br>-<br>6766 Patent Exclusivity<br>Composition of Matter<br>Method of Making<br>Sept 2032<br>Dosing Protocol<br>May 2038<br>Combination w/ Defactinib<br>2041<br>-<br>2042 if issued<br>Feb 2027 + 5 yrs (PTE) = 2032<br>Sept 2040<br>Methods of Treating<br>PTE<br>2041<br>-<br>2042 if issued<br>Combinations |
| --- |
| Backup Slides |
| --- |
| 40<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 |
| --- |
| 41<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 |
| --- |
| 42<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 |
| --- |
| 43<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>+ |
| --- |
| 44<br>VS<br>-<br>6766 Monotherapy Has Shown Clinical Activity in Several RAS/RAF<br>Mutant Cancer Indications, Including NSCLC and Gynecologic Cancers<br>Confirmed responses especially in patients with KRAS G12V mutation<br>Guo et al., Lancet Oncology 2020<br>KRAS G12R |
| --- |
| 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 |
| --- |
| 46<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 |
| --- |
| 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 +<br>Defactinib<br>Combination (FRAME) (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 |
| --- |
| 48<br>Target exposures for preclinical tumor regression &<br>pERK<br>inhibition in human<br>subjects are covered by twice weekly dosing of 3.2 mg VS<br>-<br>6766, 3 wks on/1 wk off<br><br>Modeling<br>of<br>PK<br>for<br>3<br>..<br>2<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>3<br>..<br>2<br>mg<br>single<br>dose<br>PK<br>data<br>(study<br>CCR<br>3808<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>and<br>IC<br>50<br>against<br>human<br>PBMC<br>pERK<br>activity<br>References: Martinez<br>-<br>Garcia et al., Clin Cancer Res 2012; Coma et al. AACR 2021<br>C<br>av<br>for tumor regression from KRAS<br>G12V mt NSCLC GEMM model<br>IC<br>50<br>for<br>pERK<br>inhibition in PBMCs of<br>orally dosed subjects |
| --- |
| 49<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 |
| --- |
| 50<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 |
| --- |
| 51<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 |
| --- |
| THANK YOU |
| --- |