8-K
Verastem, Inc. (VSTM)
8-K
2021-05-26
For: 2021-05-26
View Original
Added on
April 07, 2026
UNITED STATESSECURITIES 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): May 26, 2021
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 | | TradingSymbol(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. Other Events
On May 26, 2021, Verastem, Inc. posted its corporate presentation, a copy of which is furnished hereto as Exhibit 99.1.
Item 9.01. Financial Statements and Exhibits
| <br><br> | ||
|---|---|---|
| Exhibit No. | Description | |
| 99.1 | Corporate Presentation, dated May 26, 2021 | |
| 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.
| | | |
|---|---|---|
| | VERASTEM, INC. | |
| | | |
| Dated: May 26, 2021 | By: | /s/ Brian M. Stuglik |
| | | Brian M. Stuglik |
| | | Chief Executive Officer |
Exhibit 99.1
| Corporate Presentation<br>May 2021<br>NASDAQ: VSTM |
|---|
| 2<br>This presentation includes forward-looking statements about, among other things, Verastem Oncology’s<br>programs and product candidates, including anticipated regulatory submissions, approvals, performance and<br>potential benefits of Verastem Oncology’s product candidates, that are subject to substantial risks and<br>uncertainties that could cause actual results to differ materially from those expressed or implied by such<br>statements. Applicable risks and uncertainties include the risks and uncertainties, among other things,<br>regarding: the success in the development and potential commercialization of our product candidates,<br>including defactinib in combination with VS-6766; the occurrence of adverse safety events and/or unexpected<br>concerns that may arise from additional data or analysis or result in unmanageable safety profiles as<br>compared to their levels of efficacy; or our ability to obtain, maintain and enforce patent and other intellectual<br>property protection for our product candidates<br>Additional information regarding these factors can be found in Verastem Oncology’s Annual Report on Form<br>10-K for the fiscal year ended December 31, 2020 and in any subsequent filings with the SEC, including in the<br>sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors that May Affect<br>Future Results,” as well as in our subsequent reports on Form 8-K, all of which are filed with the U.S.<br>Securities and Exchange Commission (SEC) and available at www.sec.gov and www.verastem.com.<br>The forward-looking statements in this presentation speak only as of the original date of this presentation, and<br>we undertake no obligation to update or revise any of these statements.<br>Safe Harbor Statement |
| --- |
| 3<br>We are a<br>biopharmaceutical<br>company<br>committed to<br>developing and<br>commercializing<br>new medicines for<br>patients battling<br>cancer<br>VS-6766 (RAF/MEKi) and defactinib (FAKi) are clinically<br>active against RAS mutant cancers<br>30% of all human cancers are driven by mutations in RAS family<br>of genes; VS-6766 combinations broadly applicable across a<br>variety of tumor types, with preclinical synergy shown with an<br>extensive number of agents including KRAS G12C inhibitors<br>Monetization of COPIKTRA® (duvelisib) provides funding until at<br>least 2024<br>Cash Balance of $127.1 million, as of Mar. 31, 2021<br>Debt reduced from approx. $185M to $28M (2019-2020)<br>Annual operating expense forecast of approximately $50 million<br>New lead clinical program<br>has best-in-class potential<br>Significant downstream<br>market opportunity and<br>blockbuster potential<br>Strong balance sheet<br>Rapid development paths<br>to market<br>Validating clinical results achieved in KRAS mutant<br>low-grade serous ovarian cancer (LGSOC), strong signal in<br>KRAS mutant G12V NSCLC; registration-directed trials initiated<br>in 4Q 2020; FDA Breakthrough Therapy Designation in LGSOC<br>Well Positioned to Capitalize on<br>Growth Opportunities |
| --- |
| 4<br>Verastem Oncology Strategic Transformation<br>November 2020: Initiated registration-directed ph. 2 study in<br>LGSOC<br>September 2020: Divested global rights to Copiktra to Secura Bio<br>February 2020: PIPE financing based on data for new clinical<br>program<br>January 2020: In-licensed global rights to VS-6766, best-in-class<br>RAF/MEK inhibitor, from Chugai<br>December 2020: Initiated registration-directed ph. 2 study in<br>NSCLC |
| --- |
| VS-6766 RAF/MEK<br>Inhibitor Program<br>Overview |
| --- |
| 6<br> Unique dual RAF/MEK targeting mechanism of action<br> Best-in-class safety & tolerability profile relative to marketed MEK inhibitors, with potential for<br>combinability with agents from multiple target classes<br> Novel intermittent dosing schedule; convenient oral regimen<br> Clear signals of clinical activity in various RAS-driven cancers, including in patients whose<br>tumors previously progressed on other MEK inhibitors<br> Strong preclinical and clinical synergy data in combination with other agents targeting RAS<br>pathway and parallel pathways<br>VS-6766 is a differentiated, best-in-class asset<br>potentially applicable across multiple patient<br>populations |
| --- |
| 7<br>VS-6766<br>High Priority Registration Indications<br>Registration-Directed Trials Initiated in 4Q20<br> LGSOC1,2<br> KRASG12V NSCLC1,2<br>Additional Indication Opportunities<br> Pancreatic1,2 (10 pt cohort initiated)<br> KRAS mt endometrioid1 (10 pts initiated)<br> Uveal Melanoma2 (IST initiated)<br> Melanoma1,2<br> Colorectal1<br>Mutation Opportunities<br> KRAS mutations1,2<br> BRAF & NRAS mutations1,2<br> NF1 mutations<br> GNAQ mutations2<br>High Priority Lead Indications with Multiple Growth<br>Opportunities<br>1 Supported by clinical data<br>2 Supported by preclinical data<br>Other VS-6766 Combinations<br> Everolimus1,2<br> KRAS G12C inhibitor2<br> SHP2 or SOS1 inhibitor2<br> CDK4/6 inhibitor2<br> EGFR inhibitor2<br> Anti-PD-11 |
| --- |
| 8<br>Robust Pipeline Targeting the RAS Pathway and<br>Multiple Growth Opportunities<br>RAMP 201 study = NCT04625270<br>RAMP 202 study = NCT04620330<br>FRAME study = NCT03875820<br>*Pre-clinical studies ongoing in multiple KRAS mutant tumors<br>FDA Breakthrough Therapy Designation for VS-6766 + defactinib |
| --- |
| 9<br> VS-6766 inhibits both MEK &<br>RAF kinase activities<br> MEK inhibitors paradoxically<br>induce MEK phosphorylation<br>(pMEK) by relieving<br>ERK-dependent feedback<br>inhibition of RAF<br>VS-6766 is a Unique Small Molecule RAF/MEK<br>Inhibitor<br>Reference: Ishii et al., Cancer Res, 2013; Lito et al., Cancer Cell, 2014; Blasco, R. B. et al. Cancer Cell (2011); Sanclemente, M. et al. Cancer Cell (2018)<br>VS-6766 PD0325901<br> By inhibiting RAF<br>phosphorylation of MEK,<br>VS-6766 has advantage of<br>not inducing pMEK<br> VS-6766 inhibits ERK<br>signaling more completely;<br>may confer enhanced<br>therapeutic activity<br>RTK<br>Growth factors<br>RAS<br>RAF<br>MEK<br>ERK<br>Tumor<br>Growth |
| --- |
| 10<br>▪ Current Challenges<br>o Blocking any single target in the pathway is insufficient for maximum<br>depth and duration of anti-tumor efficacy<br>• e.g.,, SHP2i, KRAS-G12Ci, RAFi, MEKi, ERKi<br>o Vertical inhibition concept is now well established<br>• Necessary to block more than 1 target in the pathway<br>o Many of these agents (e.g., SHP2i, MEKi) have poor tolerability as<br>monotherapy and in combination<br>▪ Solutions offered by VS-6766<br>o Vertical inhibition (RAF and MEK blockade) in a single drug<br>o Best-in-class tolerability with established twice weekly dosing regimen<br>• Should enable tolerable combinations<br>o Compelling synergy data (preclinical) emerging for VS-6766<br>combinations (e.g., with KRAS-G12C inhibitors)<br>Vertical Blockade: Establishing VS-6766 as the backbone of<br>therapy for RAS pathway-driven tumors<br>RTK<br>Growth factors<br>EGFRi<br>FGFRi<br>G12Ci<br>RAFi<br>MEKi<br>ERKi<br>VS-6766<br>SHP2i<br>SOS1i<br>RAS<br>RAF<br>MEK<br>ERK<br>Tumor Growth<br>References: 1 Chen, Mol Cancer Res 2018; 2 Banerji, BTOG Dublin, Jan 23, 2019 |
| --- |
| 11<br>▪ Current Challenges<br>o Blocking Ras pathway can be circumvented through<br>parallel pathways<br>• e.g. PI3K/AKT/mTOR, FAK, RhoA, YAP<br>o Combinations of MEKi + AKTi have shown poor<br>tolerability<br>▪ Solutions offered with VS-6766<br>o Good tolerability with twice weekly VS-6766 opens<br>up intermittent dosing options for combinations<br>o Compelling preclinical synergy data with VS-6766 in<br>combination with FAK inhibition and with AKT<br>pathway inhibition (e.g. everolimus)<br>o RP2D established for VS-6766 + defactinib and for<br>VS-6766 + mTORi (everolimus) with twice weekly<br>regimen (Udai Banerji, 3Q20)<br>Parallel Pathway Blockade: Establishing VS-6766 as the<br>backbone of therapy for RAS pathway-driven tumors<br>β α<br>Integrin<br>FAK<br>Extracellular Matrix<br>P<br>PI3K<br>AKTi<br>mTORi<br>FAKi<br>SRC<br>AKT<br>mTOR<br>RTK<br>Growth factors<br>G12Ci<br>RAFi<br>MEKi<br>ERKi<br>VS-6766<br>RAS<br>RAF<br>MEK<br>ERK<br>SHP2i<br>SOS1i<br>Tumor Growth<br>References: 1 Chen, Mol Cancer Res 2018; 2 Banerji, BTOG Dublin, Jan 23, 2019<br>EGFRi<br>FGFRi<br>RhoA, YAP, etc. |
| --- |
| VS-6766 +/- Defactinib in<br>Low-Grade Serous<br>Ovarian Cancer |
| --- |
| 13<br>Favorable Tolerability Profile with Novel Intermittent<br>Dosing Regimen<br>VS-6766 monotherapy<br>Daily at MTD<br>N=6<br>28-day cycle<br>RP2D<br>VS-6766 monotherapy<br>4mg twice weekly<br>N=26<br>28-day cycle<br>RP2D<br>(VS-6766 3.2mg twice weekly<br>+ defactinib 200mg twice<br>daily)<br>N=38<br>21 days of 28-day cycle<br>Treatment Related Adverse Event Grade ≥3 Grade ≥3 Grade ≥3<br>Rash 3 (50%) 5 (19%) 2 (5%)<br>CK elevation (Creatine phosphokinase) 1 (17%) 2 (8%) 2 (5%)<br>1 Chenard-Poirier, et al. ASCO 2017<br>References: Banerji, Q4 2020 report; Data on file<br>RP2D: recommended phase 2 dosing<br>Summary of Adverse Events Grade ≥ 3 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 |
| --- |
| 14<br>Treatment Related Adverse<br>Events Details*<br>(≥10% patients in cohort<br>3.2mg 6766 and Def 200mg)<br>VS-6766 4mg<br>Twice Weekly<br>(4 wks of<br>every 4 wks)1<br>n=22<br>VS-6766 3.2mg Twice<br>Weekly<br>Def 200mg BID<br>(3 wks of<br>every 4 wks)2<br>n=38<br>Gr1/2 Gr3/4 Gr1/2 Gr3/4<br>Rash 15 5 32 2<br>CK Elevation 13 2 19 2<br>AST Elevation 1 13<br>Hyperbilirubinemia 14 1<br>Visual Disturbance 13 9<br>ALT Elevation 2 5<br>Diarrhoea 6 1 14 1<br>Fatigue 5 1 8 1<br>Oral Mucositis^ 7 1 11<br>Nausea 5 5<br>Vomiting 2 4<br>Peripheral Edema 9 10<br>Paronychia 3 4<br>Thrombocytopenia 6<br>Pruritus 3 0 5<br>Favorable Tolerability Profile at Recommended Phase 2 dose for VS-6766<br>plus defactinib combination regimen<br>*AEs were graded by NCI CTC v4; highest grade only recorded for each patient; AEs<br>presented in ≥10% Patient (cohort 3.2mg 6766 and Def 200mg) data preliminary<br>and subject to change;<br>^also includes glossitis/mouth ulcers<br>References: 1 Data on file VS-6766 Investigator’s Brochure; 2Banerji, Q4 2020 report<br>Summary of FRAME Safety Profile<br> Most Adverse Events (AE) were Grade<br>1/2<br> Few patients have discontinued due to<br>AEs in the study<br>RP2D<br> VS-6766 3.2 mg oral twice wkly<br>(3 wks of every 4 wks)<br> Defactinib 200 mg oral BID<br>(3 wks of every 4 wks) |
| --- |
| 15<br>VS-6766 in Combination with Defactinib Shows<br>Robust ORR with Durability in Refractory LGSOC<br>with Expanded Number of Patients (n=17)<br>0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30<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 (months)<br>R<br>e<br>s<br>p<br>o<br>n<br>s<br>e<br>(<br>%<br><br>c<br>h<br>a<br>n<br>g<br>e<br><br>f<br>r<br>o<br>m<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br>)<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 - G12V<br>FRA101019 - KRAS G12D<br>FRA101024 - KRAS WT<br>FRA101025 - KRAS WT<br>FRA102010 - KRAS G12D<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>• KRAS-G12 mutations ORR = 56% (5/9); data still maturing<br>• Current ORR = 41% (7/17); data still maturing<br>• 9/17 (53%) still on study1<br>• 3 pts on treatment for ~2 yrs or more<br>1 Data cutoff date August 17, 2020<br>0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34<br>FRA101015<br>FRA101012<br>FRA101038<br>FRA101037<br>FRA101035<br>FRA101007<br>FRA102010<br>FRA101033<br>FRA101032<br>FRA101028<br>FRA101024<br>FRA101025<br>FRA101019<br>FRA101014<br>FRA101009<br>FRA101001<br>FRA101002<br>Time on Treatment (months)<br>*<br>*<br>*<br>*<br>*<br>#<br>*<br>*<br>* #<br>*<br>G12A<br>G12V<br>G12D<br>G12D<br>G12D<br>WT<br>WT<br>Undocumented<br>D33E, I24N<br>G12D<br>G12D<br>WT<br>G12D<br>WT<br>WT<br>WT<br>G12V<br>Time on Treatment<br><br><br><br><br><br><br><br>Previous MEK inhibitor treatment<br>Continuing on treatment *<br>Approaching PR #<br>Time to response <br>Partial Response<br>Stable Disease<br>+<br>+<br>+<br>+<br>+<br>+ At 4.0 mg VS-6766 |
| --- |
| 16<br>In an updated Dec. 2020 read-out (n=24), ORR data<br>has continued to strengthen, in both KRAS mt and<br>KRAS wt patients, with a consistent safety profile<br> Overall response rate (ORR) is 52% (11 of 21 response evaluable patients)<br>▪ KRAS mutant ORR at 70% (7 of 10 response evaluable patients)<br>▪ KRAS wild-type ORR at 44% (4 of 9 response evaluable patients)<br>▪ KRAS status undetermined ORR at 0% (0 of 2 response evaluable patients)<br> As reported previously, the most common side effects seen in the study were rash,<br>creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC<br>Grade 1/2 and all were reversible<br> Additional data is anticipated to be shared at a medical meeting in 2H 2021 |
| --- |
| 17<br> 31-35% discontinuation rate with MEK<br>inhibitors due to AEs<br> Few discontinuations in the FRAME study<br>due to AEs<br>Low-Grade Ovarian Cancer – Treatment Algorithm1<br>Observe only<br>Pt Chemo Combo:<br>Carbo-Pt + Paclitaxel (preferred)<br>+ Beva for Stage II-IV (incl maintenance Beva)<br>OR Hormonal Tx (2B)<br> Pt-Chemo combo +/-<br>Beva<br> Trametinib<br> Fulvestrant<br>Recurrence<br> Taxane or<br>gemcitabine, or<br>doxorubicine, or<br>topotecan +/- Beva<br> Trametinib<br> Fulvestrant<br>LGSOC: Limited Treatment Options with High Unmet<br>Need<br>1 NCCN guidelines<br>2 Gershenson, et al. ESMO 2019.<br>3 Farley, et al. Lancet Oncology, 2013.<br>4 Grisham, Monk, Banerjee, et al. IGCS 2019.<br>Pt-Sensitive Pt-Resistance<br>Limited Response Rates<br>for Available Treatments:<br>0%<br>5%<br>10%<br>15%<br>20%<br>25%<br>30% Stage IC Stage II-IV Stage IA-IB<br><10%2<br>14%2 15%3<br>26%2<br>24%4 |
| --- |
| 18<br>KRAS wt patients represent 70% of the LGSOC<br>patient population<br>LGSOC is a type of ovarian cancer that disproportionately<br>affects younger women<br>Patients often experience significant pain and suffering<br>from their disease over time<br>A slow growing cancer, that has a median survival<br>of almost 10 years, so patients remain in treatment<br>for a long time (10-yr prevalence ~80,000<br>worldwide, ~6,000 US)<br>Source: Monk, Randall, Grisham, The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer, Am Soc Clin Oncol Educ Book; 2019; Slomovitz, Gourley,<br>Carey, Malpica, Shih, Huntsman, Fader., Grisham et al, Low-Grade serous ovarian cancer: State of the Science; Gynecol Oncol; 2020. Grisham, Iyer, Low-Grade Serous Ovarian Cancer: Current<br>Treatment Paradigms and Future Directions; Curr Treat Options Oncology; 2018.<br>Most prior research has focused on high grade serous ovarian<br>cancer (HGSOC). However, LGSOC is clinically, histologically and<br>molecularly unique from HGSOC with limited treatments available<br>1,000 to 2,000 patients in the U.S. and 15,000 to<br>30,000 worldwide diagnosed with LGSOC each year<br>KRAS mutant,<br>30%<br>NRAS,<br>BRAF, ARAF<br>mutant, 20%<br>Other RAS-<br>associated gene<br>mutations,<br>20%<br>Non-RAS-<br>associated,<br>30%<br>~30% of LGSOC Patients Have KRAS mt<br>~70% of LGSOC Shows RAS Pathway-Associated mts<br>Source: AACR Project GENIE Cohort v9.0-public and Verastem unpublished analysis |
| --- |
| 19<br>RAMP 201: KRAS Mutated (mt) and Wild Type (wt), Phase 2,<br>Recurrent LGSOC Adaptive Design for Potential Accelerated<br>Approval<br>*Dosing: Defactinib + VS-6766 combo: Defactinib 200mg PO BID: 21/28 days + VS-6766 3.2mg PO 2x/wk 21/28 days; VS-6766 monotherapy: VS6766 4.0 mg PO 2x/wk 21/28 days<br>**Expansion Phase – final sample size to be adjusted based on adaptive design<br> Recurrent<br>LGSOC<br> Measurable<br>disease (RECIST<br>1.1)<br> Prior MEKi<br>allowed<br> Approximately 64<br>patients<br>Primary Endpoint ORR<br>Hierarchical evaluation of:<br>1) In KRAS mt patients<br>2) All patients (KRASmt & wt)<br>Defactinib+VS-6766<br>KRAS-mt<br>(n=16)<br>VS-6766 Mono<br>KRAS-mt<br>(n=16)<br>Selected Regimen based on ORR<br>Add ~20-30 patients with KRAS mt<br>Add ~20-40 patients with KRAS wt<br>Total Expected Range of Patients:<br>104- 134<br>Selection Phase*<br>Expansion Phase**<br>Defactinib+VS-6766<br>KRAS-wt<br>(n=16)<br>VS-6766 Mono<br>KRAS-wt<br>(n=16)<br>FDA Was Supportive of Development Strategy, Adaptive Design, and Addition of KRAS wt to Selection Phase<br>Registration-directed Study Commenced in Nov. 2020 with estimated Primary Completion Date for the Expansion<br>Phase of June 2023 (clinicaltrials.gov)<br>New cohorts added via<br>protocol amendment |
| --- |
| 20<br>NSCLC KRAS G12C3<br>Pancreatic3<br>LGSOC3<br>Endometrioid3<br>Metastatic uveal<br>melanoma3<br>~4k ~2k<br>wild<br>type<br>kras<br>mutation<br>~6K<br>patients US1<br>~80K<br>patients WW1<br>Patient-months of Therapy Per Year2 (across all 2L+ patients)<br>1 Source: Monk, Randall, Grisham, The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer, Am Soc Clin Oncol Educ Book; 2019; Slomovitz, Gourley, Carey,<br>Malpica, Shih, Huntsman, Fader., Grisham et al, Low-Grade serous ovarian cancer: State of the Science; Gynecol Oncol; 2020. Grisham, Iyer, Low-Grade Serous Ovarian Cancer: Current Treatment<br>Paradigms and Future Directions; Curr Treat Options Oncology; 2018; Globocan 2020<br>2 Patient-months of Therapy metric calculated by multiplying relevant incidence/prevalence rate times estimated duration of therapy; represents US market opportunity only; patient population estimates from<br>Globocan 2020, American Cancer Society 2021, AACR Genie Cohort V9.0 public, and scientific publications. Duration of therapy estimates from clinical studies and clinician experience. Patient-months on<br>therapy is for 2nd-line+ patients<br>3 NSCLC KRAS G12C 2nd line patients (incidence); Pancreatic RAS/RAF mutant 2nd-line patients (incidence); LGSOC KRAS mutant and wild-type patients (prevalence); Endometrioid RAS/RAF mutant 2nd-<br>line patients (incidence); Uveal melanoma RAS/RAF mutant 2nd-line patients (incidence)<br>LGSOC market opportunity larger or comparable to<br>other high unmet need KRAS opportunities<br>Prevalence<br> - 50,000 100,000 150,000 |
| --- |
| VS-6766 +/- Defactinib in<br>NSCLC |
| --- |
| 22<br>0<br>5<br>10<br>15<br>G12C G12V G12D G12A G13C G12S G13D<br>% of Patients<br>KRAS Mutation<br>Advanced or Metastatic NSCL Cancer<br>Recommend Histologic and Molecular Subtyping5<br>Appropriate<br>targeted agent<br>Chemotherapy<br> Docetaxel<br> Gemcitabine<br> Pemetrexed<br>Prior PD-(L)1 No Prior PD-(L)1<br>PD-(L)1<br>Chemo PD-(L)1<br>PD-(L)1 single agent<br>or<br>PD-(L)1 + chemo<br>Chemotherapy or clinical trials<br>EGFR/ALK/ROS1/B<br>RAF (targeted)<br>Non-targeted<br>PD-(L)1 1%<br>Non-Targeted<br>PD-(L)1 1%<br>NSCLC Adenocarcinoma3<br>US Annual Incidence1,2: 92K<br>WW Annual Incidence1,2: 836K<br>KRAS Mutations Represent 25% of Lung<br>Cancer Adenocarcinoma (EGFR 17%, ALK 7%)4 SOC in recurrent disease is chemotherapy<br> Pre-PD-(L)1 era, chemotherapy response rate ~10% in recurrent<br>disease; 12w PFS of 30–45%<br>High Unmet Need in Refractory KRASm NSCLC<br>Adenocarcinoma<br>1 Globocan, 2018<br>2 https://www.ncbi.nlm.nih.gov/books/NBK519578/<br>3 TCGA PanCancer Atlas (cBioPortal analysis)<br>4 www.thelancet.com Vol 389 January 21, 2017<br>5 Adapted from NCCN Non-small cell lung cancer guidelines Version 3.2020<br>Recurrence<br>Recurrence |
| --- |
| 23<br>A Precision Approach to KRAS-G12V Driven NSCLC<br>VS-6766 Inhibits CRAF - The key driver of KRAS-G12V<br>mutant NSCLC<br>Source: Ishii et al. Cancer Res (2013), Blasco, R. B. et al. Cancer Cell (2011), Lito, P. et al. Cancer Cell (2014), Sanclemente, M. et al.<br>Cancer Cell (2018)<br>CRAF, but not BRAF, ablation improves survival of mice with KRASG12V induced lung<br>cancer in vivo<br>CRAF Drives KRASG12V NSCLC1,3<br>CRAF KO vs. WT<br>BRAF KO vs. WT<br>+83% OS<br> KRASG12V signals mainly through<br>RAF/MEK in contrast to other variants,<br>such as KRAS-G12D, which signal more<br>through PI3K/AKT<br> KRASG12V models are especially<br>dependent on CRAF<br>KRASG12V<br>CRAF BRAF PI3K<br>MEK/ERK AKT/mTOR<br>Tumor Growth |
| --- |
| 24<br>VS-6766 +/- 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-6766: 0.1 mg/kg QD (5 days/week)<br>FAKi: 50 mg/kg BID (5 days/week)<br>KRAS G12V mutant; Trp53 KO NSCLC<br>• VS-6766 monotherapy caused tumor regression<br>• VS-6766 + FAKi showed stronger regression<br>• No significant anti-tumor effect of trametinib at same dose level<br>Source: Coma et al. AACR 2021 |
| --- |
| 25<br>Case Study: Response to VS-6766 + defactinib in a<br>patient with KRAS G12V mutant NSCLC<br>Source: Krebs et al. AACR 2021<br>May 2019: Diagnosed with NSCLC<br>June 2019 - Sept 2019: Treated<br>with first line Carboplatin +<br>Pemetrexed + Pembrolizumab<br>Oct 2019: Progression, palliative<br>RT to right hip<br>Nov 2019 – present: On treatment<br>in FRAME study VS-6766 +<br>Defactinib<br>VS-6766 + Defactinib |
| --- |
| 26<br> Preclinical evidence suggests combination with Defactinib may improve efficacy in KRASG12V<br> Activity of VS-6766 as a single agent and in combo with Defactinib in KRASG12V<br>VS-6766 ± Defactinib Has a Confirmed 57% ORR in KRASG12V NSCLC in Integrated Analysis<br>Strong Signal Identified in KRASG12V<br>to Be Further Validated<br>Source: 1 Guo, et al Lancet Oncology 2020 2 Banerji, AACR VM 1, April 27, 2020, CT143<br>*On Treatment<br>Best Response by RECIST in KRASG12V NSCLC Time on Treatment for KRASG12V NSCLC<br>0% 0%<br>-8%<br>-38% -38%<br>-61%<br>-68%<br>-80%<br>-70%<br>-60%<br>-50%<br>-40%<br>-30%<br>-20%<br>-10%<br>0%<br>10%<br>Mono Mono Mono Combo Mono Combo Mono<br>Best Response<br>(% Change from Baseline)<br>All Confirmed Responses<br>NSCLC (57% ORR; N=7)<br>Mono = VS-6766<br>Monotherapy1<br>Combo = VS-6766 +<br>Defactinib2<br>*<br>*<br>+<br>7<br>17<br>18<br>18<br>18<br>58<br>0 5 10 15 20 25 30 35 40 45 50 55 60<br>Mono<br>Mono<br>Combo<br>Mono<br>Combo<br>Mono<br>Mono<br>Weeks on Treatment<br>215<br>214<br>*<br>*<br>+ 4.0 mg VS-6766/200 mg defactinib |
| --- |
| 27<br>NSCLC Clinical Strategy: KRAS Mutant (mt), Enriched G12V,<br>Phase 2, Recurrent NSCLC for Potential Accelerated Approval<br>1 Defactinib 200 mg PO BID (21/28 days) + VS-6766 3.2 mg PO 2x/wk (21/28 days)<br>2 VS-6766 4.0 mg PO 2x/wk (21/28 days)<br>This Registration-directed Phase 2 Study commenced December 2020 with an estimated Primary<br>Completion Date for the Expansion Phase of March 2023 (clinicaltrials.gov)<br> Recurrent NSCLC<br> 1-2 prior regimens<br> 1 prior platinum-<br>containing chemo;<br> Prior CPI unless<br>contraindicated<br> Measurable disease<br>(RECIST 1.1)<br> Appropriate approved<br>therapy for other<br>relevant mutations<br> No prior MEKi, no prior<br>KRAS-specific targeted<br>therapy<br> No untreated CNS<br>metastases<br> ECOG OS 0-1<br>Defactinib+VS-67661<br>KRAS mt G12V<br>N=16<br>VS-67662<br>KRAS mt G12V<br>N=16<br>KRAS Mutant – G12V<br>Selected Regimen based on ORR<br>Selection Phase Expansion Phase<br>Defactinib+VS-67661<br>KRAS mt non-G12V<br>N=25, maximum<br>KRAS Mutant – non-G12V<br> Exploratory mutation-specific cohort<br>analyses for ORR<br> Final G12V sample<br>size to be discussed<br>with FDA<br> Non-G12V Cohorts<br>TBD based on results<br>of exploratory analysis |
| --- |
| Future Opportunities:<br>VS-6766 as Backbone of<br>RAS Therapy |
| --- |
| 29<br>29<br>H<br>2<br>1<br>2<br>2<br>S<br>W<br>8<br>3<br>7<br>H<br>1<br>3<br>7<br>3<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>3<br>5<br>8<br>H<br>2<br>0<br>3<br>0<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>0<br>10<br>20<br>30<br>40<br>50<br>VS-6766 + AMG 510<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>Indication<br>CRC<br>Vertical Blockade: Preclinical synergy in combination with<br>several promising targets<br>H<br>2<br>1<br>2<br>2<br>H<br>1<br>3<br>7<br>3<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>3<br>5<br>8<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>P<br>A<br>C<br>A<br>S<br>P<br>C<br>1<br>A<br>4<br>2<br>7<br>H<br>P<br>A<br>F<br>I<br>I<br>S<br>K<br>L<br>U<br>1<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>H<br>2<br>2<br>9<br>1<br>C<br>F<br>P<br>A<br>C<br>1<br>H<br>2<br>4<br>4<br>4<br>C<br>A<br>P<br>A<br>N<br>2<br>H<br>4<br>4<br>1<br>-20<br>0<br>20<br>40<br>VS-6766 + Afatinib<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>80% (4/5) 100% (6/6) 100% (5/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>H<br>2<br>1<br>2<br>2<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>1<br>3<br>7<br>3<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>3<br>5<br>8<br>A<br>S<br>P<br>C<br>1<br>H<br>P<br>A<br>F<br>I<br>I<br>A<br>4<br>2<br>7<br>H<br>P<br>A<br>C<br>S<br>K<br>L<br>U<br>1<br>C<br>A<br>P<br>A<br>N<br>2<br>C<br>F<br>P<br>A<br>C<br>1<br>H<br>2<br>2<br>9<br>1<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>H<br>2<br>4<br>4<br>4<br>H<br>4<br>4<br>1<br>-20<br>-10<br>0<br>10<br>20<br>30<br>40<br>VS-6766 + LY-3214996<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>100% (5/5) 66% (4/6) 60% (3/5)<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>Indication<br>VS-6766 + pan-HERi (Afatinib)<br>VS-6766 + ERK1/2i (LY3214996)<br>VS-6766 + SHP2i (RMC-4550)<br>H<br>2<br>1<br>2<br>2<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>3<br>5<br>8<br>H<br>1<br>3<br>7<br>3<br>S<br>W<br>1<br>5<br>7<br>3<br>A<br>4<br>2<br>7<br>H<br>P<br>A<br>C<br>H<br>P<br>A<br>F<br>I<br>I<br>S<br>K<br>L<br>U<br>1<br>A<br>S<br>P<br>C<br>1<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>C<br>F<br>P<br>A<br>C<br>1<br>H<br>2<br>4<br>4<br>4<br>H<br>2<br>2<br>9<br>1<br>C<br>A<br>P<br>A<br>N<br>2<br>H<br>4<br>4<br>1<br>-20<br>0<br>20<br>40<br>VS-6766 + BI-3406<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>100% (5/5) 83% (5/6) 60% (3/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>VS-6766 + SOS1i (BI-3406)<br>Presented at RAS-Targeted Drug Discovery<br>(February 23-25, 2021)<br>VS-6766 + G12Ci (AMG 510)<br>H<br>2<br>1<br>2<br>2<br>S<br>W<br>8<br>3<br>7<br>H<br>1<br>3<br>7<br>3<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>3<br>5<br>8<br>H<br>2<br>0<br>3<br>0<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>0<br>10<br>20<br>30<br>40<br>50<br>VS-6766 + AMG 510<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>Indication<br>CRC<br>H<br>2<br>1<br>2<br>2<br>S<br>W<br>8<br>3<br>7<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>3<br>5<br>8<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>1<br>3<br>7<br>3<br>0<br>10<br>20<br>30<br>40<br>50<br>VS-6766 + MRTX849<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>Indication<br>CRC<br>VS-6766 + G12Ci (MRTX849) |
| --- |
| 30<br>30 Synergy of VS-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-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>R<br>e<br>s<br>p<br>o<br>n<br>s<br>e<br>(<br>%<br><br>c<br>h<br>a<br>n<br>g<br>e<br><br>f<br>r<br>o<br>m<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br>)<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 8 SD<br>2 PR 4 SD<br>3 PR 2 SD<br>4 PR<br>Response @ Day 10<br>VS-6766 & FAKi potentiate AMG 510 efficacy in KRAS G12C mutant<br>NSCLC in vivo; Tumor regression in all mice with triple combination<br>VS-6766 + AMG 510 yields deeper and more sustained inhibition<br>of ERK signaling pathway H2122 KRAS G12C mutant NSCLC<br>AMG 510<br>VS-6766<br>4h 48h<br>p-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-6766: 100 nM<br>Combined Synergy Score<br>Cell line Indication Sensitivity to G12C<br>inhibitors<br>VS-6766 +<br>AMG 510<br>VS-6766 +<br>MRTX849<br>H2122 NSCLC Moderately sensitive 44.7 44.6<br>H1373 NSCLC Sensitive 10.0 3.4<br>SW1573 NSCLC Insensitive 8.6 12.0<br>H358 NSCLC Sensitive 6.9 5.4<br>H2030 NSCLC Moderately sensitive 5.1 ND<br>SW837 CRC Sensitive 16.1 18.5<br>MIAPACA2 Panc Sensitive 2.3 5.3<br>0 5 10 15 20 25 30<br>0<br>500<br>1000<br>1500<br>2000<br>Tumor growth<br>Days after cell inoculation<br>T<br>u<br>m<br>o<br>r<br><br>v<br>o<br>l<br>u<br>m<br>e<br>(<br>m<br>m<br>3<br><br>+<br>/<br>-<br><br>S<br>E<br>M<br>)<br>Vehicle<br>AMG510<br>AMG510 + FAKi<br>AMG510 + VS-6766<br>AMG510 + VS-6766 + FAKi<br>VS-6766<br>Preclinical synergy of VS-6766 + G12C inhibitors in KRAS G12C mt models<br>Presented at RAS-Targeted Drug Discovery (February 23-25, 2021) |
| --- |
| 31<br>31<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>1<br>3<br>7<br>3<br>H<br>3<br>5<br>8<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>2<br>1<br>2<br>2<br>A<br>4<br>2<br>7<br>S<br>K<br>L<br>U<br>1<br>H<br>P<br>A<br>F<br>I<br>I<br>A<br>S<br>P<br>C<br>1<br>H<br>P<br>A<br>C<br>H<br>2<br>2<br>9<br>1<br>H<br>2<br>4<br>4<br>4<br>C<br>A<br>P<br>A<br>N<br>2<br>H<br>4<br>4<br>1<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>C<br>F<br>P<br>A<br>C<br>1<br>-40<br>-20<br>0<br>20<br>40<br>VS-6766 + M2698<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>80% (4/5) 66% (4/6) 80% (4/5)<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>Indication<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>3<br>5<br>8<br>H<br>1<br>3<br>7<br>3<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>2<br>1<br>2<br>2<br>H<br>P<br>A<br>C<br>A<br>4<br>2<br>7<br>A<br>S<br>P<br>C<br>1<br>H<br>P<br>A<br>F<br>I<br>I<br>S<br>K<br>L<br>U<br>1<br>C<br>F<br>P<br>A<br>C<br>1<br>H<br>2<br>2<br>9<br>1<br>H<br>4<br>4<br>1<br>H<br>2<br>4<br>4<br>4<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>C<br>A<br>P<br>A<br>N<br>2<br>-20<br>-10<br>0<br>10<br>20<br>VS-6766 + Defactinib<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>40% (2/5) 83% (5/6) 20% (1/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>Parallel Pathway Blockade: Two synergistic combinations<br>already progressed to clinical stage<br>H<br>2<br>1<br>2<br>2<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>1<br>3<br>7<br>3<br>H<br>3<br>5<br>8<br>S<br>W<br>1<br>5<br>7<br>3<br>A<br>4<br>2<br>7<br>H<br>P<br>A<br>C<br>A<br>S<br>P<br>C<br>1<br>H<br>P<br>A<br>F<br>I<br>I<br>S<br>K<br>L<br>U<br>1<br>C<br>F<br>P<br>A<br>C<br>1<br>C<br>A<br>P<br>A<br>N<br>2<br>H<br>2<br>2<br>9<br>1<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>H<br>4<br>4<br>1<br>H<br>2<br>4<br>4<br>4<br>-20<br>-10<br>0<br>10<br>20<br>30<br>40<br>VS-6766 + Palbociclib<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>100% (5/5) 50% (3/6) 100% (5/5)<br>Indication<br>NSCLC<br>PDAC<br>Synergy<br>Antagonism<br>VS-6766 + mTORi (Everolimus)<br>VS-6766 + CDK4/6i (Palbociclib)<br>VS-6766 + p70S6K/AKTi (M2698)<br>VS-6766 + FAKi (Defactinib)<br>Presented at RAS-Targeted Drug Discovery<br>(February 23-25, 2021) S<br>W<br>1<br>5<br>7<br>3<br>H<br>1<br>3<br>7<br>3<br>H<br>3<br>5<br>8<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>2<br>1<br>2<br>2<br>A<br>4<br>2<br>7<br>S<br>K<br>L<br>U<br>1<br>H<br>P<br>A<br>F<br>I<br>I<br>A<br>S<br>P<br>C<br>1<br>H<br>P<br>A<br>C<br>H<br>2<br>2<br>9<br>1<br>H<br>2<br>4<br>4<br>4<br>C<br>A<br>P<br>A<br>N<br>2<br>H<br>4<br>4<br>1<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>C<br>F<br>P<br>A<br>C<br>1<br>-40<br>-20<br>0<br>20<br>40<br>VS-6766 + M2698<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>80% (4/5) 66% (4/6) 80% (4/5)<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>Indication |
| --- |
| 32<br>Key VSTM Milestones 2020-2022<br>LGSOC<br>NSCLC<br>Corporate<br>1H2020 2H2020 1H2021 2H2021 1H2022<br>VS-6766 In-<br>Licensed from<br>Chugai<br>Copiktra divested<br>to Secura Bio<br>RAMP-201<br>Amended to Include<br>KRAS wt patients in<br>Selection Phase<br>RAMP-201 Study<br>Initiated<br>RAMP-202 Study<br>Initiated<br>RAMP-201 Top-Line<br>Data from Selection<br>Phase & Initiate<br>Expansion Phase<br>RAMP-202 Top-Line<br>Data from Selection<br>Phase & Initiate<br>Expansion Phase<br>PIPE Financing for<br>New Clinical<br>Program<br>Updated data from<br>FRAME NSCLC<br>cohort<br>Updated data<br>from FRAME<br>LGSOC cohort FDA Breakthrough<br>Therapy<br>Designation |
| --- |
| Corporate |
| --- |
| 34<br>Key Financial Statistics<br>Cash, cash equivalents & investments as of 3/31/2021 $127.1M<br>Shares fully diluted as of 3/31/2021 195.8M<br>5.00% Convertible Senior Notes Due 2048 (2018 Notes) as of 3/31/2021 $0.3M*<br>5.00% Convertible Senior Notes Due 2048 (2020 Notes) as of 3/31/2021 $28.0M**<br>Insider ownership (outstanding / vested) as of 3/31/2021 8.7% / 4.9%<br>As of March 31, 2021<br>* The 2018 Notes have an initial conversion rate of 139.5771 shares of Common Stock per $1,000 which translates to an initial conversion price of $7.16 per share of<br>Common Stock.<br>** The 2020 Notes have an initial conversion rate of 307.6923 shares of Common Stock per $1,000 which translates to an initial conversion price of $3.25 per share of<br>Common Stock. |
| --- |
| Backup Slides<br>www.verastem.com |
| --- |
| 36<br>NSCLC<br>Incidence3,5:<br>194K<br>Colorectal<br>Incidence5:<br>105K<br>Pancreatic<br>Incidence5:<br>58K<br>Uterine<br>Endometrioid<br>Incidence4,5: 59K<br>Melanoma<br>Incidence5:<br>108K<br>Multiple Myeloma<br>Incidence5:<br>32K<br>Melanoma<br>Incidence5:<br>108K<br>Ovarian<br>Incidence5:<br>22K<br>Papillary Thyroid<br>Incidence5,6:<br>42K<br>Ovarian<br>Incidence5:<br>22K<br>High Unmet Needs in RAS/RAF/MEK/ERK-Driven<br>Cancers<br>Incidence Sources:<br>1Reference for RAS mt frequencies – Cox et al. Nature Reviews 13: 828, 2014; 2Reference for BRAF mt frequencies – Turski et al. Mol Cancer Ther 15: 533, 2016<br>385% of lung cancer is NSCLC (Lu et. al. Cancer Manag Res. 2019); 490% of all uterine cancers are of the endometrial type (ACS); 5Cancer Statistics 2020, Siegel et. al. CA<br>Cancer J Clin 2020;70:7-30; 68 out of 10 thyroid cancers are of the papillary type (ACS)<br>References:<br>McCormick F Clin Cancer Res 15April2015; Adderley H et al. EBioMedicine 01Mar2019; Papke B et al. Science 17Mar2017; Ryan M et al. Nature Reviews Clinical Oncology<br>01Oct2018; NIH cancer.gov/research/key-initiatives/ras<br>KRAS-mutant<br>Cancers1<br>31% 45% 98%<br>21%<br>NRAS-mutant<br>Cancers1<br>28%<br>BRAF-mutant<br>Cancers2 60% 35 –<br>60%<br>30 –<br>80%<br>20%<br>5%<br>Challenges with conventional approaches<br> Modest progress; limited number of approved therapies<br> Single agent therapies (e.g.,, MEK inhibitors) associated with resistance<br> Tolerable combination regimens with MEK inhibitors have been challenging<br> Current RAS inhibitors in development address only a minority of all RAS<br>mutated cancers<br>Breadth of potential opportunity<br> 30% of all human cancers are driven by<br>mutations of the RAS family of genes<br>Established prognostic significance<br> Patients with mutations of the RAS family<br>have an overall worse prognosis |
| --- |
| 37<br>37<br>KRAS G12V and G12D Represent ~50% of KRAS<br>Mutations across Human 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 Adenocarcinoma1<br>G12D G12V G12R Q61H Q61R G12A G12C<br>0<br>10<br>20<br>30<br>Pancreatic Cancer<br>KRAS Mutation<br>%<br><br>o<br>f<br><br>p<br>a<br>t<br>i<br>e<br>n<br>t<br>s<br>Uterine Endometrioid Carcinoma1<br>G12D G12V G13D G12A G12C G13C Q61H<br>0<br>2<br>4<br>6<br>8<br>10<br>Uterine Endometrioid Carcinoma<br>KRAS Mutation<br>%<br><br>o<br>f<br><br>p<br>a<br>t<br>i<br>e<br>n<br>t<br>s<br>1 TCGA PanCancer Atlas (cBioPortal analysis)<br>2 90% of all uterine cancers are of the endometrial type (ACS)<br>3 Cancer Statistics 2020 (Siegel et al. CA Cancer J Clin 2020; 70:7-30)<br>Annual Incidence3: 58K<br>Annual Incidence2,3:<br>59K<br>% frequency in a total of 780 cancer patients with<br>KRAS mutations1 |
| --- |
| 38<br>38<br>VS-6766 and FAK inhibitor combination leads to<br>more robust anti-tumor efficacy in vivo<br>Ovarian cancer model<br>(TOV-21g KRAS(G13C) mutant)<br>NSCLC cancer model<br>(H2122 KRAS(G12C) mutant)<br>J. Paradis, AACR 2020<br>0 5 10 15<br>0<br>200<br>400<br>600<br>Tumor growth<br>Days on treatment<br>T<br>u<br>m<br>o<br>r<br><br>v<br>o<br>l<br>u<br>m<br>e<br>(<br>m<br>m<br>3<br><br>+<br>/<br>-<br><br>S<br>E<br>M<br>)<br>Vehicle<br>FAKi 50 mg/kg BID<br>VS-6766 0.3 mg/kg QD<br>VS-6766 + FAKi<br>Trametinib 0.3 mg/kg QD<br>0 5 10 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>T<br>u<br>m<br>o<br>r<br><br>v<br>o<br>l<br>u<br>m<br>e<br>(<br>m<br>m<br>3<br><br>+<br>/<br>-<br><br>S<br>E<br>M<br>)<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>FAK i + ME K i combin ation is cytotoxic in vi vo<br>CTL ME K i FAK i<br>Combo<br>***<br>******<br>T rametinib + VS-4718 is more efficient than one alon e.<br>Each inhbitor is cytostatic , the combin ation is cytotoxic<br>In vitro<br>T rametinib + VS-4718 induced mo re apop tosis<br>in vitro than each one alone<br>Vehicle<br>Trametinib 1 mg/kg QD<br>FAKi 50 mg/kg BID<br>Trametinib + FAKi<br>Uveal melanoma model<br>(92.1 GNAQ mutant) |
| --- |
| 39<br>39<br>Overcoming Key Resistance Mechanisms to MEK<br>Inhibitors<br>▪ MEK inhibition induces compensatory<br>activation of pFAK preclinically and<br>clinically<br>Pre dose<br>Post VS-6766<br>Post com<br>bination<br>0<br>50<br>100<br>150<br>p-FAK<br>H<br>-<br>S<br>c<br>o<br>r<br>e<br>o Trametinib induced ↑ pFAK (Y397)<br>preclinically in KRAS mt NSCLC cell<br>lines<br>o Also observed in patients<br>• VS-6766 induced ↑ pFAK (Y397) as<br>a potential resistance mechanism<br>in the majority of patients<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,<br>2020, CT143 |
| --- |
| 40<br>40<br>Pharmacokinetic Profiles of VS-6766 + Defactinib in<br>Combination Similar to that seen in Single Agent Studies<br>Cohort Dose<br>(mg) N Subject AUC0-24h<br>(h*ng/mL)<br>Cmax<br>(ng/mL)<br>1 3.2<br>(with 200mg VS) 3 Mean 6179 354<br>CV% 32.1 30.4<br>2a 4<br>(with 200mg VS) 5 Mean 5353 289<br>CV% 15.8 16.0<br>2b 3.2<br>(with 400mg VS) 1 FRA101-007 3302 229<br>VS-6766<br>Cohort Dose (mg) N Subject AUClast<br>(h*ng/mL)<br>Cmax<br>(ng/mL)<br>1<br>200<br>(with 3.2mg RO) 3<br>Mean 2071 273<br>CV% 103 80<br>2a<br>200<br>(with 4mg RO) 5<br>Mean 2252 318<br>CV% 124 117<br>2b<br>400<br>(with 3.2mg RO) 3<br>Mean 2807 360<br>CV% 31 32<br>Defactinib<br>Reference: Banerji, AACR VM 1, April 27, 2020, CT143 |
| --- |
| 41<br>VS-6766 in Combination with Defactinib Shows<br>Robust ORR with Durability in Refractory LGSOC at<br>Phase 2 Dose Level<br>• ORR in KRAS mt = 50% (3/6); data still maturing<br>• Current overall ORR = 45% (5/11); data still maturing<br>• 9/11 (82%) still on study at RP2D1<br>• 2 pts on treatment for 2.5 yrs<br>0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34<br>FRA101038<br>FRA101037<br>FRA101035<br>FRA102010<br>FRA101033<br>FRA101032<br>FRA101028<br>FRA101024<br>FRA101025<br>FRA101001<br>FRA101002<br>Time on Treatment (months)<br>*<br>*<br>*<br>*<br>*<br>#<br>*<br>*<br>* #<br>*<br>G12A<br>G12V<br>WT<br>WT<br>Undocumented<br>D33E, I24N<br>G12D<br>G12D<br>G12D<br>WT<br>WT<br>Time on Treatment<br><br><br><br><br><br>Previous MEK inhibitor treatment<br>Continuing on treatment *<br>Approaching PR #<br>Time to response <br>Partial Response<br>Stable Disease<br>0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30<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 (months)<br>R<br>e<br>s<br>p<br>o<br>n<br>s<br>e<br>(<br>%<br><br>c<br>h<br>a<br>n<br>g<br>e<br><br>f<br>r<br>o<br>m<br><br>b<br>a<br>s<br>e<br>l<br>i<br>n<br>e<br>)<br>FRA101001 - KRAS G12V<br>FRA101002 - KRAS G12A<br>FRA101024 - KRAS WT<br>FRA101025 - KRAS WT<br>FRA102010 - KRAS G12D<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>All patients on RP2D: 3.2 mg VS-6766 (2x/wk) + 200 mg Defactinib (BID) q3/4 wks<br>1 Data cutoff date August 17, 2020 |
| --- |
| 42<br> Synergy of VS-6766 + everolimus observed broadly<br>across cancer cell lines with various KRAS mutation<br>variants<br> A well-tolerated RP2D for VS-6766 + everolimus has<br>been established with intermittent dosing of both agents<br>(twice weekly; 3 wks on/1 wk off)<br> KRAS mutant NSCLC expansion cohort is currently<br>ongoing with VS-6766 + everolimus<br>Status: Combination of VS-6766 with Everolimus<br>(mTOR inhibitor)<br>VS-6766 + Everolimus<br>Presented at RAS-Targeted Drug Discovery<br>(February 23-25, 2021)<br>S<br>W<br>1<br>5<br>7<br>3<br>H<br>1<br>3<br>7<br>3<br>H<br>3<br>5<br>8<br>M<br>I<br>A<br>P<br>A<br>C<br>A<br>2<br>H<br>2<br>1<br>2<br>2<br>A<br>4<br>2<br>7<br>S<br>K<br>L<br>U<br>1<br>H<br>P<br>A<br>F<br>I<br>I<br>A<br>S<br>P<br>C<br>1<br>H<br>P<br>A<br>C<br>H<br>2<br>2<br>9<br>1<br>H<br>2<br>4<br>4<br>4<br>C<br>A<br>P<br>A<br>N<br>2<br>H<br>4<br>4<br>1<br>P<br>A<br>N<br>C<br>0<br>3<br>2<br>7<br>C<br>F<br>P<br>A<br>C<br>1<br>-40<br>-20<br>0<br>20<br>40<br>VS-6766 + M2698<br>C<br>o<br>m<br>b<br>i<br>n<br>e<br>d<br><br>S<br>y<br>n<br>e<br>r<br>g<br>y<br><br>S<br>c<br>o<br>r<br>e<br>NSCLC<br>Panc<br>Synergy<br>Antagonism<br>80% (4/5) 66% (4/6) 80% (4/5)<br>KRAS<br>G12C<br>KRAS<br>G12D<br>KRAS<br>G12V<br>Indication |
| --- |
| 43<br>43<br>VS-6766 upregulates MHC Class I antigens on tumor<br>cells: a mechanism for potentiation of I/O efficacy<br>Cell Line Tumor type RAS/RAF mutation<br>status<br>A549 Lung KRASmut G12S<br>TOV21g Ovarian KRASmut G13C<br>SKMEL5 Melanoma BRAFmut V600E<br>IGR-1 Melanoma BRAFmut V600E<br>WM115 Melanoma BRAFmut V600E<br>A549 TOV21g SKMEL5 IGR1 WM115<br>0<br>2<br>4<br>6<br>B2M<br>R<br>e<br>l<br>a<br>t<br>i<br>v<br>e<br><br>m<br>R<br>N<br>A<br><br>L<br>e<br>v<br>e<br>l<br>s DMSO<br>VS-6766<br>KRAS mt BRAF mt<br>A549 TOV21g SKMEL5 IGR1 WM115<br>0<br>2<br>4<br>6<br>8<br>HLA-A<br>R<br>e<br>l<br>a<br>t<br>i<br>v<br>e<br><br>m<br>R<br>N<br>A<br><br>L<br>e<br>v<br>e<br>l<br>s<br>DMSO<br>VS-6766<br>KRAS mt BRAF mt<br>A549 TOV21g SKMEL5 IGR1 WM115<br>0<br>2<br>4<br>6<br>TAP-1<br>R<br>e<br>l<br>a<br>t<br>i<br>v<br>e<br><br>m<br>R<br>N<br>A<br><br>L<br>e<br>v<br>e<br>l<br>s DMSO<br>VS-6766<br>KRAS mt BRAF mt<br>A549 TOV21g SKMEL5 IGR1 WM115<br>0.0<br>0.5<br>1.0<br>1.5<br>2.0<br>2.5<br>TAP-2<br>R<br>e<br>l<br>a<br>t<br>i<br>v<br>e<br><br>m<br>R<br>N<br>A<br><br>L<br>e<br>v<br>e<br>l<br>s DMSO<br>VS-6766<br>KRAS mt BRAF mt<br>VS-6766 @ 1 µM (except SKMEL5 and IGR-1, 300 nM) |
| --- |
| 44<br>44<br>VS-6766 enhances tumor growth inhibition when combined<br>with anti-PD-1 in the CT26 KRAS (G12D) syngeneic model<br>-100<br>0<br>100<br>200<br>300<br>400<br>Response at Day 13<br>%<br><br>C<br>h<br>a<br>n<br>g<br>e<br><br>i<br>n<br><br>T<br>u<br>m<br>o<br>r<br><br>V<br>o<br>l<br>u<br>m<br>e<br>Vehicle<br>VS-6766<br>anti-PD-1<br>VS-6766 + anti-PD-1<br>20 40 60 80 100<br>0<br>20<br>40<br>60<br>80<br>100<br>Survival<br>Time<br>P<br>e<br>r<br>c<br>e<br>n<br>t<br><br>s<br>u<br>r<br>v<br>i<br>v<br>a<br>l<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-PD-1<br>Day 28,<br>Last dose<br>VS-6766<br>0 10 20 30 40 50 60 70 80 90 100<br>0<br>20<br>40<br>60<br>80<br>100<br>Survival<br>Days after first dose<br>P<br>e<br>r<br>c<br>e<br>n<br>t<br><br>s<br>u<br>r<br>v<br>i<br>v<br>a<br>l<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-challenge in<br>tumor-free mice showed<br>immune memory with<br>increased memory T cells<br>0 2 4 6 8 10 12 14 16 18 20 22 24 26<br>0<br>200<br>400<br>600<br>800<br>1000<br>1200<br>Tumor growth<br>Days after first dose<br>T<br>u<br>m<br>o<br>r<br><br>v<br>o<br>l<br>u<br>m<br>e<br>(<br>m<br>m<br>3<br><br>+<br>/<br>-<br><br>S<br>E<br>M<br>)<br>Vehicle<br>VS-6766 0.5 mg/kg QD<br>anti-PD-1 3 mg/kg 2xW<br>VS-6766 + anti-PD-1 |
| --- |
| 45<br>NSCLC KRAS<br>G12C3<br>Pancreatic3<br>LGSOC1<br>Endometrioid3<br>Metastatic uveal<br>melanoma3<br>LGSOC Market Opportunity – Reference Calculations<br>Patient-months of Therapy<br>Per Year (across all 2L+ patients)2<br>Average months on<br>Therapy (per patient)2<br>Number of Patients (2L+)2<br> - 10,000 20,000 30,000 40,000<br>1 Prevalence used for LGSOC patient population estimate. Sources: Monk, Randall, Grisham, The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer, Am Soc Clin<br>Oncol Educ Book; 2019; Slomovitz, Gourley, Carey, Malpica, Shih, Huntsman, Fader., Grisham et al, Low-Grade serous ovarian cancer: State of the Science; Gynecol Oncol; 2020. Grisham, Iyer, Low-Grade<br>Serous Ovarian Cancer: Current Treatment Paradigms and Future Directions; Curr Treat Options Oncology; 2018; Globocan 2020<br>2 Patient-months of Therapy metric calculated by multiplying relevant incidence/prevalence rate times estimated duration of therapy; represents US market opportunity only; patient population estimates from<br>Globocan 2020, American Cancer Society 2021, AACR Genie Cohort 9.0 public, and scientific publications. Duration of therapy estimates from clinical studies and clinician experience. Number of patients and<br>months on therapy are for 2nd-line+<br>3 NSCLC KRAS G12C 2nd line patients (incidence); Pancreatic RAS/RAF mutant 2nd-line patients (incidence); Endometrioid RAS/RAF mutant 2nd-line patients (incidence); Uveal melanoma RAS/RAF mutant 2nd-<br>line patients (incidence)<br> - 5.00 10.00 15.00 - 50,000 100,000 150,000 |
| --- |
| 46<br>46 A drug with a Breakthrough designation will have…<br>▪ Increased communication with FDA during drug development and review<br>▪ FDA guidance to ensure that the design of clinical trials are as efficient as practicable<br>▪ A cross-disciplinary project lead assigned to the FDA review team and increased involvement of<br>senior managers and experienced review staff<br>▪ 29/30 drugs previously granted Breakthrough Therapy designation have been approved by the<br>FDA |
| --- |
| 47<br>47 Strong Patent Protection<br>▪ COM for VS-6766 to 2027 & defactinib to 2028, Hatch Waxman should extend to 2032<br>▪ VS-6766 intermittent dosing regimen until 2038 if granted<br>▪ FAK/MEK combination to 2035<br>▪ VS-6766/defactinib combination until 2040 if granted<br>▪ Method of manufacture for VS-6766 to 2032<br>▪ Other activity related to patent protection is ongoing and will continue into the future |
| --- |
| 48<br>Brian Stuglik<br>Chief Executive Officer<br>Cathy Carew<br>Chief People & Organizational<br>Strategy Officer<br>Hagop Youssoufian,<br>MSc, M.D.<br>Head of Medical Strategy<br> Principal – HR Collaborative<br> Ironwood, ActiveBiotics,<br>Dynogen, Tufts Health Plan<br> CMO, BIND Therapeutics, EVP,<br>Progenics,<br> CMO & EVP, Ziopharm<br>Oncology, SVP, Imclone<br> Global VP & Chief Marketing<br>Officer – Lilly Oncology<br> Founding Member – Proventus<br>Health Solutions<br>Daniel Paterson<br>President and Chief<br>Operating Officer<br>Jonathan Pachter,<br>Ph.D.<br>Chief Scientific Officer<br> CEO – The DNA Repair Co.<br>(now On-Q-ity)<br> PharMetrics (now IMS), Axion<br> Head of Cancer Biology – OSI<br>(now Astellas)<br>Rob Gagnon<br>Chief Business and<br>Financial Officer<br> CFO – Harvard Bioscience,<br>Clean Harbors<br> VP of Finance – Biogen Idec<br>Experienced Senior Management Team |
| --- |