8-K
Verastem, Inc. (VSTM)
8-K
2023-09-12
For: 2023-09-12
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April 07, 2026
UNITED STATES SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the
Securities Exchange Act of 1934
Date of report (Date of earliest event reported): September 12, 2023
Verastem, Inc.
(Exact Name of Registrant as Specified in Charter)
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|---|---|---|---|---|
| Delaware | | 001-35403 | | 27-3269467 |
| (State or Other Jurisdiction<br>of Incorporation) | | (Commission<br>File Number) | | (IRS Employer<br>Identification No.)<br><br> |
| | | |
|---|---|---|
| 117 Kendrick Street , Suite 500 , Needham , MA | | 02494 |
| (Address of Principal Executive Offices) | | (Zip Code)<br><br> |
Registrant’s telephone number, including area code: (781) 292-4200
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Securities registered pursuant to Section 12(b) of the Act:
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|---|---|---|---|---|
| Title of each class | | Trading Symbol(s) | | Name of each exchange on which registered |
| Common stock, $0.0001 par value per share | | VSTM | | The Nasdaq Capital 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 September 12, 2023, 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
| 91 | ||
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| Exhibit No. | Description | |
| 99.1 | | Corporate Presentation, dated September 12, 2023 |
| 104 | | Cover Page Interactive Data File (embedded within the Inline XBRL document) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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| | VERASTEM, INC. | |
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| Dated: September 12, 2023 | By: | /s/ Daniel W. Paterson |
| | | Daniel W. Paterson |
| | | Chief Executive Officer |
Exhibit 99.1
| Corporate Presentation<br>September 2023 |
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| 2<br>Disclaimers<br>This presentation includes forward-looking statements about, among other things, Verastem Oncology’s programs and product candidates, including anticipated regulatory submissions, approvals,<br>performance and potential benefits of Verastem Oncology’s product candidates, as well as Verastem Oncology’s potential income under its asset purchase agreement with Secura Bio. Inc. and<br>borrowings under its credit facility, that are subject to substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements.<br>Applicable risks and uncertainties include the risks and uncertainties, among other things, regarding: the success in the development and potential commercialization of our product candidates,<br>including defactinib and other compounds in combination with avutometinib (VS-6766); the occurrence of adverse safety events and/or unexpected concerns that may arise from additional data or<br>analysis or result in unmanageable safety profiles as compared to their levels of efficacy; or our ability to obtain, maintain and enforce patent and other intellectual property protection for our<br>product candidates.<br>Other risks and uncertainties include those identified under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, as filed with the<br>Securities and Exchange Commission (SEC) on March 14, 2023, and in any subsequent filings with the SEC, which are 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 we undertake no obligation to update or revise any of these statements.<br>This presentation contains references to our non-GAAP operating expense, a financial measure that is not calculated in accordance with generally accepted accounting principles in the US<br>(“GAAP”). This non-GAAP financial measure excludes certain amounts or expenses from the corresponding financial measures determined in accordance with GAAP. Management believes this<br>non-GAAP information is useful for investors, taken in conjunction with the Company’s GAAP financial statements, because it provides greater transparency and period-over-period comparability<br>with respect to the Company’s operating performance and can enhance investors’ ability to identify operating trends in the Company’s business. Management uses these measures, among other<br>factors, to assess and analyze operational results and trends and to make financial and operational decisions. Non-GAAP information is not prepared under a comprehensive set of accounting<br>rules and should only be used to supplement an understanding of the Company’s operating results as reported under GAAP, not in isolation or as a substitute for, or superior to, financial<br>information prepared and presented in accordance with GAAP. In addition, this non-GAAP financial measure is unlikely to be comparable with non-GAAP information provided by other<br>companies. The determination of the amounts that are excluded from non-GAAP financial measures is a matter of management judgment and depends upon, among other factors, the nature of<br>the underlying expense or income amounts. Reconciliations between these non-GAAP financial measures and the most comparable GAAP financial measures are included in the footnotes to the<br>slides in this presentation on which a non-GAAP number appears.<br>Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third party sources and Verastem Oncology’s own internal<br>estimates and research. While Verastem Oncology believes these third party sources to be reliable as of the date of this presentation, it has not independently verified, and makes no<br>representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third party sources. In addition, all of the market data included in this presentation<br>involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. |
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| 3<br>We are a<br>biopharmaceutical<br>company<br>committed to<br>developing and<br>commercializing<br>new medicines for<br>patients battling cancer<br>Verastem Oncology<br>Well Positioned to Capitalize on Growth Opportunities<br>Avutometinib (VS-6766; RAF/MEK clamp) and defactinib (FAK<br>inhibitor) are clinically active against RAS pathway-driven cancers<br>30% of all human cancers are driven by mutations in RAS;<br>Avutometinib combinations potentially broadly applicable across a<br>variety of tumor types.<br>Clinical collaborations with Amgen & Mirati evaluating the<br>combinations of avutometinib with sotorasib & adagrasib, respectively,<br>in KRAS G12C NSCLC supported by strong pre-clinical rationale<br>Multiple clinical studies in progress evaluating avutometinib<br>combinations across RAS pathway-driven cancers<br>Cash and investments balance of $183.1 million as of June 30, 2023<br>Up to $150 million of non-dilutive funding available from credit facility<br>Company ended Q2 2023 with $20.3 million GAAP operating expenses and<br>$18.9 million non-GAAP operating expenses*<br>Lead clinical program has<br>best-in-class potential<br>Strong balance sheet<br>Rapid development path to<br>market in LGSOC<br>FDA Breakthrough Therapy Designation; Updated data from Part A of<br>RAMP 201 trial show a confirmed objective response rate of 45% in<br>patients with recurrent low-grade serous ovarian cancer treated with<br>avutometinib and defactinib; target enrollment was achieved in January 2023;<br>timing of accelerated approval filing to be based on data maturity and<br>finalization of confirmatory study plans<br>* Q2 2023 GAAP operating expenses - $20.29M less Q2 2023 stock compensation of $1.43M = $18.86M Q2 2023 non-GAAP operating expenses<br>Significant downstream<br>market opportunity and<br>blockbuster potential |
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| 4<br>Key VSTM Achievements & Anticipated Milestones<br>LGSOC<br>NSCLC<br>1H2023 3Q2023<br>Additional<br>Indications<br>RAMP 201 Complete<br>target enrollment of<br>Expansion Phase<br>Initiate combo study of<br>avutometinib +<br>pembrolizumab in BRAF mt<br>melanoma *<br>*Investigator-sponsored research<br>**RAMP 201 update expected to be provided once go-forward treatment regimen determined, timing of which will be driven by data maturity<br>- - - Indicate anticipated milestones<br>Discovery and development<br>collaboration with GenFleet<br>4Q2023<br>✓<br>RAMP 203: Determine<br>recommended phase 2<br>dose<br>1Q2024<br>Launch LGSOC<br>patient education<br>campaign<br>Discuss confirmatory<br>trial study design with<br>FDA for recurrent<br>LGSOC program<br>Initiate confirmatory<br>study of avutometinib +<br>defactinib in recurrent<br>LGSOC Present updated<br>results of Part A<br>RAMP 201 (ASCO)<br>Present updated results<br>of IST avutometinib +<br>everolimus in KRAS mt<br>NSCLC<br>RAMP 203: Report<br>initial read-out of safety<br>and preliminary efficacy<br>RAMP 204: Initial read-out of safety and<br>recommended dose<br>RAMP 205: determine<br>recommended phase 2<br>dose and complete<br>enrollment of initial<br>phase 2 expansion<br>cohort<br>Pediatric Cancer *<br>Early safety data of<br>avutometinib + cetuximab<br>in KRAS mt CRC *<br>Initial results of<br>Gynecological basket<br>trial*<br>Early efficacy results of<br>thyroid cancer *<br>✓<br>✓<br>✓<br>✓<br>2H2022<br>Initiate combo study of<br>avutometinib +<br>cetuximab in KRAS mt<br>CRC *<br>Initiate RAMP 204<br>(avuto + adagrasib)<br>G12C<br>Top-Line Data from<br>RAMP 202 Selection<br>Phase<br>RAMP 203 advanced to<br>final dose level<br>✓<br>RAMP 201 FDA<br>Meeting - Avuto +<br>defactinib selected as<br>Go-Forward<br>✓<br>RAMP 201 Second<br>Interim Update<br>✓<br>✓<br>✓<br>✓<br>Initiate RAMP 205<br>combo avutometinib +<br>gemcitabine/nab-paclitaxel + defactinib in<br>metastatic pancreatic<br>cancer<br>✓<br>✓<br>✓<br>✓Initiate thyroid cancer * |
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| 5<br>Avutometinib is a Differentiated Agent with the Potential to Serve as the<br>Backbone for Combinations Across RAS Pathway-Driven Cancers<br>• Unique RAF/MEK clamp mechanism of action<br>• Novel intermittent dosing schedule; convenient oral regimen<br>• Breakthrough Therapy Designation for combination of avutometinib and defactinib for treatment of recurrent low-grade serous ovarian cancer (LGSOC) after one or more prior lines of therapy including platinum-based<br>chemotherapy<br>• Potential best-in-class safety & tolerability profile relative to marketed MEK inhibitors, with potential for<br>combinability with agents from multiple target classes<br>• Promising signals of clinical activity in various RAS pathway-driven cancers, including in patients whose tumors<br>previously progressed on other MEK inhibitors<br>• Preclinical anti-proliferative activity across multiple MAPK pathway alterations (e.g. KRAS, NRAS, BRAF, NF1 mt) and<br>multiple solid tumor indications<br>• Strong preclinical combination data with other agents targeting RAS pathway (e.g. KRAS G12C inhibitors) and parallel<br>pathways (e.g. FAK inhibitors)<br>RAF-Rapidly accelerated fibrosarcoma<br>MEK-Mitogen-activated protein kinase kinase<br>RAS-Rat sarcoma virus<br>MAPK-Mitogen-activated protein kinase<br>KRAS-Kirsten rat sarcoma virus<br>NRAS-Neuroblastoma RAS viral oncogene homolog<br>BRAF-v-raf murine sarcoma viral oncogene homolog B1<br>NF1-Neurofibromatosis type 1 |
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| 6<br>Strong Scientific Rationale for Avutometinib and FAK Inhibitor Combination<br>Anti-Tumor Efficacy in KRAS Mutant and Wild-Type LGSOC models<br>KRAS mutant LGSOC PDX model<br>RTK<br>RAS<br>RAF<br>MEK<br>ERK YAP<br>Growth factors<br>β<br>α<br>Y397<br>Integrin<br>FAK<br>Extracellular Matrix<br>SRC<br>RhoA<br>Tumor Growth<br>P<br>AKT<br>avutometinib<br>defactinib<br>Feedback Reactivation<br>0 10 20 30<br>0<br>100<br>200<br>300 Tumor growth<br>Days after first dose<br>Tumor volume<br>(mm3 +/- SEM)<br>vehicle FAKi avutometinib<br>avutometinib + FAKi<br>KRAS wild-type LGSOC PDX model<br>0 10 20 30<br>0<br>200<br>400<br>600<br>800<br>1000<br>1200 Tumor growth<br>Days after first dose<br>Tumor volume<br>(mm3 +/- SEM)<br>vehicleFAKi avutometinib<br>avutometinib + FAKi<br>Pre dose Post avutometinib Post avutometinib + defactinib<br>0<br>50<br>100<br>150 pFAK<br>H-Score<br>References: Banerji, BTOG Dublin, Jan 23, 2019; Banerji, AACR VM 1, April 27, 2020, CT143; Banerji, unpublished; Santin, unpublished |
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| 7<br>LGSOC Unmet Need & Opportunity<br>• LGSOC is a less common type of ovarian cancer that is often diagnosed in younger women<br>o LGSOC is a unique disease that is distinct from high-grade serous ovarian cancer (HGSOC) in its pathology,<br>protracted clinical course and low response to chemotherapy and thus requires a more tailored therapeutic approach<br>o An estimated 1,000-2,000 patients are diagnosed with LGSOC per year in the U.S., with prevalence of ~6,000<br>• There are currently no approved therapies specifically indicated for recurrent LGSOC<br>o Recent clinical trials in recurrent LGSOC showed that standard-of-care chemo and endocrine therapy are relatively<br>ineffective (6-13% ORR).<br>o LGSOC has a chemo-resistant nature and optimal treatment has not yet been defined. NCCN guidelines include<br>clinical trials and observation highlighting the lack of approved & effective therapies<br>• LGSOC is known to be driven by the MAPK (RAS) pathway in ≥70% of patients<br>• A phase I/II study in the UK (FRAME) evaluated the combination of avutometinib and defactinib<br>o Results in recurrent LGSOC showed a 46% confirmed ORR with durable responses and favorable safety/tolerability<br>• RAMP 201: A registration-directed Phase 2 trial of avutometinib and avutometinib + defactinib in recurrent LGSOC<br>o Updated data from ASCO 2023 showed a 45% confirmed ORR in the combination arm with tumor shrinkage in 86% of<br>evaluable patients<br>References: Monk et al., The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer, 2019; Slomovitz et al., Low-Grade serous<br>ovarian cancer: State of the Science, 2020; Grisham et al., Low-Grade Serous Ovarian Cancer: Current Treatment Paradigms and Future Directions, 2018; AACR<br>Project GENIE Cohort v9.0-public and Verastem unpublished analysis; Banerjee et al., Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the<br>FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer, ESMO 2021; Malpica et al., Interobserver and intraobserver variability of a two-tier<br>system for grading ovarian serous carcinoma, 2007; NCCN guidelines v1.2023; Zwimpfer et al. Cancer treatment Reviews 112 (2023).<br>➢ Breakthrough Therapy Designation was granted for avutometinib and defactinib in recurrent LGSOC after one<br>or more prior lines of therapy |
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| 8<br>Avutometinib Mono<br>N=72 (incl Part A + B)<br>Avutometinib + Defactinib<br>N=72 (incl Part A+B)<br>Avutometinib + Defactinib<br>N=32<br>* Dosing: Avutometinib + Defactinib combo: Avutometinib 3.2 mg PO 2x/wk 21/28 days + Defactinib 200 mg PO BID: 21/28 days;<br>Avutometinib monotherapy: Avutometinib 4.0 mg PO 2x/wk 21/28 days<br>** Lower Dose: Avutometinib + Defactinib combo: Avutometinib 1.6 mg PO 2x/wk 21/28 days + Defactinib 200 mg PO BID: 21/28 days;<br> Completed Enrollment<br>KRAS mt<br>(n=16)<br>KRAS wt<br>(n=16)<br>Primary Endpoint:<br>Objective Response Rate<br>(blinded independent review)<br>Evaluation of ORR in Combination Arm:<br>1) In KRAS mt patients<br>2) All patients (KRAS mt & wt)<br>Avutometinib Mono<br>N=32<br>KRAS mt<br>(n=16)<br>KRAS wt<br>(n=16)<br>KRAS mt<br>(n=36)<br>KRAS wt<br>(n=36)<br>KRAS mt<br>(Total n=36)<br>KRAS wt<br>(Total n=36) Recurrent LGSOC<br> Prior<br>chemotherapy<br> Measurable disease<br>(RECIST 1.1)<br> Prior MEKi allowed<br>Combination Arm:<br>✓ Target Enrollment Reached (N=72)<br>❖ Expanded Enrollment Ongoing (Lower Dose)<br>n +20<br>n +20<br>n +20<br>n +20<br>RAMP 201 (ENGOTov60/GOG3052): Registration-Directed Phase 2 Trial of<br>Avutometinib Defactinib in Patients with Recurrent LGSOC<br>Part A<br>Selection Phase*<br>Part B<br>Expansion Phase*<br>Avutometinib + Defactinib<br>Expanded Enrollment +40 pts<br>KRAS mt<br>KRAS wt<br>Part C<br>Expansion Phase*<br>Combo<br>Part D<br>Expansion Phase**<br>(Combo Lower Dose)<br>Avutometinib + Defactinib<br>Expanded Enrollment Ongoing<br>+ 20-30 pts<br>KRAS mt<br>KRAS wt<br>✓ ✓ ✓<br>✓ |
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| RAMP 201<br>ASCO 2023 Update |
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| 10<br>Updated Data from Part A of RAMP 201<br>“These results demonstrate avutometinib in combination with defactinib can deliver high response rates for patients with recurrent LGSOC with a<br>promising safety profile to date. It is particularly encouraging to see extensive tumor shrinkage in women who have had several treatment lines,<br>including prior MEK inhibitors. These latest findings suggest the combination may offer a new treatment option for women with this hard-to-treat<br>cancer, and we are hopeful it will become the new standard of care.” –Dr. Susana Banerjee, MBBS, MA PhD, FRCP, global and lead investigator of the study,<br>Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London<br>ASCO 2023 data<br>Avutometinib + Defactinib<br>Total (n=29)<br>ORR, % (n)<br>45% (13) 95% CI: (26%, 64%)<br>KRAS mt<br>60% (9/15)<br>KRAS wt<br>29% (4/14)<br>Tumor shrinkage, % (n) 86% (25)<br>Median Time to Response 5.5 months (range 1.6-14.7 months)<br>Relative Dose Intensity 83% ± 20%<br>• 29 patients were evaluable for efficacy with a minimum follow-up of 12 months and 13 (45%) patients remain on study treatment<br>• Patients were heavily pretreated with a median of 4 prior systemic regimens (up to 11)<br>• 3 out of 4 patients who received prior MEK inhibitors responded to the combination<br>• Median duration of response and median progression free survival have not been reached<br>• Safety and tolerability continued to be favorable and consistent with previously reported data<br>• The discontinuation rate due to ≥ 1 adverse event was12% in the combination overall to date (4.9% due to elevated blood CPK)<br>• Finalized the design of a randomized confirmatory trial with the FDA, which is planned to begin in the second half of 2023<br>Reference: Banerjee et al., ASCO June 2023 |
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| 11<br>Recent LGSOC Trials with Standard of Care Highlight High Unmet Need<br>in Recurrent LGSOC<br>Trial<br>Median<br>Number<br>of Prior<br>lines of<br>Therapy<br>Prior<br>MEK<br>Allowed<br>Prior<br>Bevaciz<br>umab<br>Therapy Response Rate<br>ORR<br>Image<br>Assessment<br>Median PFS<br>Months (95% CI)<br>Discontinuation<br>Rate<br>Due to AEs<br>GOG 2811<br>2<br>(1-10) No * Low %<br>Standard of Care 6%<br>95% CI: (3%, 12%) INV 7.2 (5.6-9.9) 13%<br>Trametinib 26%<br>95% CI: (19%, 35%)<br>INV 13.0 (9.9-15.0) 36%<br>MILO2<br>2<br>(1-8) No * Low %<br>Standard of Care 13%<br>95% CI: (7%, 21%) BICR 10.6 (9.2 to 14.5) 17%<br>Binimetinib 16%<br>95% CI: (11%, 22%) BICR 9.1 (7.3-11.3) 31%<br>1 Study GOG 281 trial Gershenson et al., Lancet 2022<br>2 MILO Study Monk et al., J Clin Oncol 2020.<br>* Low historical use of bevacizumab during trial conduct. % not reported<br>MILO: no more than 3 lines of prior chemotherapy<br>INV = Investigator<br>BICR = Blinded independent central review<br>PFS = Progression free survival<br>CI = confidence interval<br>SoC = Standard of Care<br>GOG 281: (chemotherapy / endocrine therapy)<br>PLD (liposomal doxorubicin), paclitaxel, topotecan, letrozole or tamoxifen<br>MILO: (chemotherapy only)<br>PLD (liposomal doxorubicin), paclitaxel or topotecan |
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| 12<br>Current Trials with Combination of Avutometinib and Defactinib<br>Consistent Overall Response Rate of ~45%<br>Trial<br>Median<br>Number<br>of Prior<br>lines of<br>Therapy<br>Prior<br>MEK<br>Allowed<br>Prior<br>Bevaciz<br>umab<br>Therapy Response Rate<br>ORR<br>Image<br>Assessment<br>Median PFS<br>Months (95% CI)<br>Discontinuation<br>Rate<br>Due to AEs<br>FRAME1 3 Yes 12 % Avutometinib +<br>Defactinib<br>46%<br>95% CI: (26%, 67%) INV 23 (11 - NR) 4%<br>RAMP 201<br>Part A<br>(ASCO 2023<br>data)<br>2<br>4 Yes 65% Avutometinib +<br>Defactinib<br>45%<br>95% CI: (26%, 64%)<br>52%*<br>BICR Not Yet Reached 10%**<br>INV = Investigator<br>BICR = Blinded independent central review<br>PFS = Progression free survival<br>1 Banerjee et al., ESMO Sept 2021<br>2 Banerjee et al., ASCO June 2023<br>* Confirmed + Unconfirmed Objectives responses<br>**12% discontinuation in all combination pts (Part A + B (n=81): 4.9% due to elevated blood CPK) |
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| 13<br>RAMP 201 (Part A)<br>Interim Analysis - Blinded ICR<br>N=29<br>Combination of Avutometinib and Defactinib<br>Initial Data from RAMP 201 Trial Reinforce Findings from FRAME Trial<br>Reference: Banerjee et al., ESMO Sept 2021<br>FRAME<br>Investigator Assessment<br>N=24<br>FRA101007 FRA101014 FRA101042 FRA101012 FRA103003 FRA101032 FRA103002 FRA101038 FRA102018 FRA101015 FRA102010 FRA101019 FRA101024 FRA101028 FRA101039 FRA101025 FRA101037 FRA103001 FRA101035 FRA101033 FRA104001 FRA101009 FRA101001 FRA101002<br>-80<br>-60<br>-40<br>-20<br>0<br>20<br>Best Response<br>(% change from baseline)<br>Best response by RECIST<br>*<br>* *<br>*<br>*<br>* *<br>* *<br>*<br>*<br>*<br>*<br>KRAS mutant KRAS wild-type<br>* Still on treatment KRAS undocumented<br>ASCO 2023 data<br>-80<br>-60<br>-40<br>-20<br>0<br>20<br>Best Response<br>(% Change From Baseline) KRAS wild-type KRAS mutant * Still on Treatment<br>*<br>*<br>*<br>*<br>* * * *<br>*<br>* *<br>*<br>*<br>+117.7%<br>-100% |
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| 14<br>Avutometinib + Defactinib (n=81)<br>Any Grade Grade ≥3<br>Nausea, n (%) 50 (61.7) 0<br>Diarrhea, n (%) 40 (49.4) 3 (3.7)<br>Blood CPK increased, n (%) 39 (48.1) 15 (18.5)<br>Oedema peripheral, n (%) 34 (42.0) 1 (1.2)<br>Vomiting, n (%) 30 (37.0) 0<br>Vision blurred, n (%) 29 (35.8) 0<br>Dermatitis acneiform, n (%) 28 (34.6) 2 (2.5)<br>Fatigue, n (%) 27 (33.3) 3 (3.7)<br>Rash, n (%) 25 (30.9) 2 (2.5)<br>Dry skin, n (%) 18 (22.2) 0<br>Anemia, n (%) 14 (17.3) 3 (3.7)<br>RAMP 201: Safety and Tolerability Profile of Avutometinib + Defactinib<br>No New Safety Signals; Few Discontinuations Due to Adverse Events<br>Most Common Treatment-Related Adverse<br>Events (>20%) in All Treated Patients<br>• Majority of adverse events are mild to<br>moderate and manageable/reversible1<br>• Few discontinuations due to adverse events<br>(12.3% in combo due to ≥ 1 TEAE 4.9% due<br>to elevated blood CPK*)<br>* No association to date with clinically<br>significant toxicities, including<br>rhabdomyolysis<br>ASCO 2023 data<br>Reference: Banerjee et al., ASCO June 2023;<br>1 J Clin Oncol 41, 2023 (suppl 16; abstr 5515) |
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| 15<br>Plan to File for Accelerated Approval based on Completed RAMP 201<br>and FRAME Study Results<br>• Target enrollment for primary analysis (n=72) in<br>combination has been achieved<br>• Plan to file for accelerated approval based on the<br>totality of the data from the RAMP 201 and FRAME<br>studies<br>• The Company plans to initiate the confirmatory study<br>in 2H 2023<br>• Combination of avutometinib with defactinib selected<br>as go forward treatment regimen<br>• Combination development continues in all recurrent<br>LGSOC, regardless of KRAS status<br>• Encouraging efficacy results include independently<br>confirmed responses<br>• No new safety signals; few discontinuations due to<br>adverse events<br>• Updated RAMP 201 Part A data presented at ASCO<br>2023<br>• Design of Confirmatory Trial finalized with FDA<br>Update Next Steps |
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| 16<br>Forward Plan: Confirmatory Trial – Randomized Controlled Trial (RCT)<br>❖RAMP-301: Prospective Randomized Controlled Trial<br>Confidential. © Verastem Inc. 2023<br> Recurrent LGSOC<br> KRAS mt+wt<br> Prior platinum<br>chemotherapy<br> Prior MEKi allowed<br> Prior Bev allowed<br> Measurable disease<br>(RECIST 1.1)<br>• A+D Dosing: Avutometinib 3.2 mg PO 2x/wk 21/28 days + Defactinib 200mg PO BID: 21/28 days<br>• ChemoHormonal ICT: Liposomal doxorubicin (PLD), Paclitaxel, Topotecan, Letrozole, Anastrozole<br>Randomized 1:1<br>Strat Factors<br>include:<br>KRAS Mut Status<br>(KRAS mt vs wt)<br>Avutometinib + Defactinib*<br>Investigator’s Choice<br>Treatment (ICT)*<br>Recurrent LGSOC<br>(N=135)<br>Avutometinib +<br>Defactinib*<br>Recurrent LGSOC<br>(N=135)<br>ICT<br>Crossover upon PD<br>Primary Endpoint:<br>Progression-Free Survival (PFS) by BICR**<br>Secondary Endpoints include:<br>• Objective Response Rate (ORR)<br>• Duration of Response (DoR)<br>• Disease Control Rate (DCR)<br>• Safety / Tolerability<br>• Patient Reported Outcomes<br>• Overall Survival<br>Primary Analysis: Hierarchical Evaluation<br>1) KRAS mutant LGSOC only<br>2) All recurrent LGSOC<br>** BICR: Blinded Independent Central Review |
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| 17<br>Comprehensive approach to establish more complete blockade of RAS pathway & resistance<br>pathways<br>Indication Incidence/<br>Prevalence Regimen Setting<br>Gynecologic<br>Cancers<br>LGSOC Avutometinib + defactinib Relapsed Refractory molecularly profiled LGSOC<br>Gynecologic<br>Basket* Avutometinib + defactinib Recurrent RAS Pathway-driven (RAS/RAF/NF1) endometrioid cancer, mucinous<br>ovarian cancer, high-grade serous ovarian cancer or cervical cancer<br>NSCLC<br>Adenocarcinoma<br>KRAS G12C<br>Avutometinib +<br>sotorasib<br>Recurrent KRAS G12C with prior KRAS G12C inhibitor(i) treatment or KRAS<br>G12Ci naïve<br>Avutometinib +<br>adagrasib Recurrent KRAS G12C with prior KRAS G12Ci treatment that progressed<br>BRAF mt Avutometinib + defactinib Recurrent BRAF V600E & non-V600E mutant NSCLC<br>Pancreatic PDAC<br>Avutometinib +<br>defactinib +<br>gemcitabine/nab-paclitaxel<br>Previously untreated (front-line) metastatic pancreatic ductal adenocarcinoma<br>(PDAC)<br>CRC KRAS mt* Avutometinib +<br>cetuximab Recurrent metastatic KRAS mt<br>Breast<br>Cancer ER+* Avutometinib +<br>abemaciclib + fulvestrant<br>Recurrent ER+/HER2- breast cancer following progression on CDK4/6i +<br>aromatase inhibitor<br>Melanoma BRAF V600E* Avutometinib +<br>pembrolizumab<br>Recurrent BRAF V600E/K or NRAS (Phase 1 only) mutant Melanoma following<br>progression on prior anti-PD1 therapy<br>1 References: 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, Malpica, Shih, Huntsman, Fader., Grisham et al, Low-Grade serous ovarian cancer:<br>State of the Science; Gynecol Oncol; 2020. Grisham, Iyer, Low-Grade Serous Ovarian Cancer: Current Treatment Paradigms and Future Directions; Curr Treat Options Oncology; 2018; Globocan 2020; 2Pakkala and Ramalingam JCI Insight 2018); 3Cancer Statistics 2020, Siegel et. al. CA<br>Cancer J Clin 2020;70:7-30; 4Cancer Statistics 2020, Siegel et. al. CA Cancer J Clin 2020;70:7-30 5CbioPortal; 6Uterine cancer is one of the leading gynecologic neoplastic disorders in the US, of which over 80% are endometrioid adenocarcinomas (EA); 7Endometrioid OC (EnOC) accounts<br>for approximately 10% of all OC, with the majority of cases diagnosed as low grade, early stage disease with excellent clinical; 8Mucinous ovarian cancer: 3-11% of ovarian cancer (Hada et al., 2021); 990% of Ovarian Cancer is Epithelial Ovarian Cancer<br>(https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf); 10HGSOC the most common type of ovarian cancer, accounting for approximately 75% of epithelial ovarian cancers.<br>(https://ocrahope.org/news/high-grade-serous-carcinoma/#:~:text=High%2Dgrade%20serous%20carcinoma%20is,unless%20another%20type%20is%20specified.)<br>Incidence4<br>:<br>58K 98%<br>Incidence2,3:<br>114K<br>Incidence2,3:<br>114K 13%<br>Prevalence1<br>:<br>6K<br>Incidence5<br>:<br>148K<br>45%<br>Incidence4<br>:<br>108K 54%<br>Incidence5<br>:<br>279K 22.5%<br>4.5%<br>Incidence6-10:<br>85K<br>*IST |
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| 18<br>Discovery and Development Collaboration with GenFleet Strengthens<br>Pipeline Targeting RAS Pathway-Driven Cancers<br>• Increases the breadth of Verastem’s oncology pipeline with strategically-aligned RAS pathway focus<br>o Exclusive option for Verastem to license up to 3 programs with development and commercialization rights outside China<br>o Potential development in combination with Verastem’s current pipeline<br>o Lead program in IND enabling studies; programs 2 & 3 in discovery phase<br>o Small molecule programs focused on anti-cancer targets related to the RAS/MAPK pathway or surrounding cancer cell signaling<br>• Strategic collaboration builds on Verastem Oncology and GenFleet’s experience in RAS pathway-driven cancers<br>o Collective worldwide strengths in RAS pathway discovery and development<br>o Established network of collaborators, including leading scientific and clinical experts<br>o Leverages experience from GenFleet’s KRAS G12C inhibitor program and Verastem’s avutometinib/defactinib program<br>• Risk-sharing structure of the collaboration with milestone-based options provides capital efficient approach<br>o At execution, Verastem to pay GenFleet an upfront payment to obtain exclusive option right to 3 programs<br>o Combined with the upfront amount, payments for future annual R&D support, development milestones and option payment for<br>first program through completion of Phase I trial could equal up to $11.5 million<br>o Potential total deal size across all 3 programs up to $625.5 million excluding royalties if Verastem exercises its in-license options<br>o Includes exclusive rights for Verastem to obtain a license to each of the compounds after successful completion of pre-determined milestones in Phase 1 trials |
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| 19<br>Broad Development Opportunities Across Multiple RAS/MAPK Pathway-Driven Cancers<br>R<br>Avutometinib egistration-Directed<br>Clinical Trials<br>Signal Finding<br>Clinical Trials<br>RAS<br>Pathway<br>Dependent<br>Cancers<br>Biomarker<br>Selection<br>Rational<br>Combination<br>s<br>High Priority Registration Indication<br>Registration-Directed Trial Initiated in 4Q20<br> LGSOC1,2 (RAMP 201)-Target enrollment<br>reached<br>Key Signal Finding<br> Avutometinib + G12Ci in KRAS G12C NSCLC2<br>(RAMP 203 - sotorasib) & (RAMP 204 - adagrasib)<br> Avutometinib + defactinib in BRAF mt (V600E & non-V600E) NSCLC1,2 (RAMP 202)<br> Avutometinib + defactinib and gemcitabine/nab-paclitaxel in first line pancreatic cancer (RAMP 205)2<br> Avutometinib + defactinib in RAS/RAF/NF1 mt<br>gynecological cancers1,2<br> Avutometinib + cetuximab in KRAS mt CRC2<br> Avutometinib + abemaciclib and fulvestrant in ER+<br>breast cancer2<br> Avutometinib + pembrolizumab in BRAF V600E<br>melanoma2<br>Rational Combinations<br> KRAS inhibitors2<br>(G12Ci & G12Di)<br> Anti-EGFR2<br> Everolimus1,2<br> CDK4/6 inhibitor2<br> Anti-PD-1<br>1,2<br> Chemotherapy2<br>RAS Pathway Dependent Cancers<br> Gynecological1,2<br> NSCLC1,2<br> Colorectal1,2<br> Melanoma1,2<br> Pancreatic2<br> Thyroid1,2<br>Biomarker Selection<br> KRAS mt1,2<br> BRAF mt (V600 & non-V600)1,2<br> NRAS mt1,2<br> CRAF mt/fusions2 1 Supported by clinical data<br>2 Supported by preclinical data |
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| 20<br>INDICATION REGIMEN<br>STUDY<br>NAME PRECLINICAL PHASE 1 PHASE 2 PHASE 3<br>CLINICAL<br>COLLABORATION<br>WITH<br>LGSOC1 Avutometinib + defactinib RAMP 201<br>R/R LGSOC Avutometinib + defactinib IST-FRAME<br>Gynecological Cancers (RAS<br>Pathway-driven) Avutometinib + defactinib IST<br>Mesonephric2 Avutometinib + defactinib IST<br>R/R NSCLC (BRAF mt) Avutometinib + defactinib RAMP 202<br>R/R NSCLC (KRAS G12C) Avutometinib + sotorasib RAMP 203<br>R/R NSCLC (KRAS G12C) Avutometinib + adagrasib RAMP 204<br>Pancreatic Ductal<br>Adenocarcinoma<br>Avutometinib + gemcitabine/nab-paclitaxel + defactinib RAMP 205<br>R/R NSCLC (KRAS mt) Avutometinib + everolimus<br>(mTORi) IST<br>R/R Colorectal Cancer (KRAS<br>mt)<br>Avutometinib + cetuximab<br>(EGFRi) IST<br>ER+ Breast Cancer Avutometinib + abemaciclib +<br>fulvestrant IST<br>BRAF V600E Melanoma2 Avutometinib + pembrolizumab IST<br>Robust Clinical Program: Avutometinib in multiple combinations across<br>RAS/MAPK pathway-driven tumors<br>1 FDA Breakthrough Therapy Designation<br>2<br> Imminent initiation<br>Registration-directed trial: accelerated approval<br>cohort fully enrolled |
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| 21<br>Key Financial Statistics<br>Cash, cash equivalents & investments $183.1M<br>GAAP Operating Expenses $20.3M<br>Non-GAAP Operating Expenses* $18.9M<br>Shares Outstanding 25.2M**<br>As of and for the quarter ended June 30, 2023<br>• Oxford Finance LLC Credit Facility<br>• Up to $150M available in a series of term loans<br>• $40M term loans outstanding<br>• Remaining $110M available upon achievement of pre-defined milestones or at lender’s discretion<br>• Floating interest rate, subject to a floor and a cap; 5% final payment charge, and loan subject to 1-3% early payment fee<br>• Interest only payments through April 2025<br>• No financial covenants<br>• Secura Bio, Inc. (Secura) Asset Purchase Agreement – COPIKTRA<br>• Regulatory and commercial milestone payments up to $95M<br>• Entitled to receive 50% of royalties, milestones, and sublicensee revenue payments made to Secura related to COPIKTRA<br>• Low double-digit royalties on annual net sales over $100M in US, EU, and UK<br>Sources of Non-Dilutive Capital<br>* Q2 2023 GAAP operating expenses - $20.29M less Q2 2023 stock compensation of $1.43M = $18.86M Q2 2023 non-GAAP operating expenses<br>**Excludes Series A Preferred (0.8M Shares on as-converted basis), Series B Preferred (4.2M Shares on as-converted basis), and outstanding unexercised pre-funded<br>warrants (1.5M Shares). |
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| Avutometinib RAF/MEK Clamp<br>Program Overview |
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| 23<br>Avutometinib is a Unique Small Molecule RAF/MEK Clamp<br>Avutometinib<br>(RAF/MEK Clamp)<br>Mirdametinib<br>(MEKi)<br> Avutometinib inhibits MEK,<br>BRAF & CRAF by trapping<br>these molecules in inactive<br>complexes<br> MEK inhibitors paradoxically<br>induce MEK phosphorylation<br>(pMEK) by relieving<br>ERK-dependent feedback<br>inhibition of RAF<br> By inhibiting RAF<br>phosphorylation of MEK,<br>avutometinib has advantage of<br>not inducing pMEK<br> Avutometinib inhibits ERK<br>signaling more completely;<br>may confer enhanced<br>therapeutic activity<br>References: Ishii et al., Cancer Res, 2013; Lito et al., Cancer Cell, 2014<br>RTK<br>Growth factors<br>Avutometinib<br>RAS<br>RAF<br>MEK<br>ERK<br>Tumor Growth<br>Avutometinib conc. (µmol/L) Avutometinib conc. (µmol/L)<br>% Inhibition<br>% Inhibition |
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| 24<br>Avutometinib is a Unique RAF/MEK Clamp which Induces Inactive<br>Complexes of 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>+ Avutometinib<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 Avuto<br>DMSO Tram Avuto<br>RTK<br>RAS<br>RAF<br>MEK<br>ERK<br>Tumor Growth<br>KSR<br>Growth factors<br>+ Trametinib<br>Feedback<br>reactivation<br>of RAF<br>maintains<br>pMEK;<br>Adaptive<br>resistance<br>Reference: Coma et al., AACR 2022 |
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| 25<br>Avutometinib Inhibits Cell Proliferation Across Multiple RAS/MAPK Pathway<br>Alterations and Multiple Solid Tumor Histologies<br>Reference: Pachter RAS-Targeted Drug Development Summit 2022; 3D proliferation assay SW1463 MIAPACA2 H358 H1373 SW837 H2122 H2030 SW1573 HPAC<br>ASPC1 HPAFII SNU-C2B<br>LS513 LS 180 SKLU1 A427 SNU-C2A<br>H441 SW403 SK-CO-1 SW620 PANC0327 H2291 SNG-M<br>SW480 H2444 CAPAN2 CFPAC1 PSN1 KP2 HUP-T3 H2009 H1573 SW1116 A549 LS123 NCI-H747 HCT 116 DLD-1 T84 HCT-15 Calu-6 HT-29 WM-266-4 SW1417 A-375 C32 SK-MEL-5<br>IGR-1 Colo-205 A2058 HS852.T RKO<br>NCI-H2087 RL95-2 NCI-H2087 GAK<br>SK-MEL-2 HEC-151 H1573 DLD-1 HS940.T H1373 HMCB<br>HCT 116 RKO<br>SW48 AN3 CA<br>RL95-2 LS513<br>5637<br>0.01<br>0.1<br>1<br>10<br>Avutometinib IC50<br>(3D proliferation assay)<br>Avutometinib IC50 (M)<br>KRAS G12V<br>KRAS G12D<br>KRAS G12C BRAF V600E<br>Indication<br>NSCLC<br>Panc CRC<br>MAPK pathway lateration: Indication:<br>NF1 mt Melanoma NRAS mt KRAS G12R<br>BRAF class 2 mt<br>KRAS G12C KRAS G12D KRAS G12V Other KRAS mt BRAF mt NRAS mt<br>ARAF mt RAF1 mt Endometrial Bladder<br>NF1 mt<br>KRAS G12S<br>KRAS G13D<br>KRAS Q61K<br>KRAS G12A<br>ERK2 mt<br>Other mt |
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| 26<br>Optimized Dosing Schedule Defined:<br>Favorable Tolerability Profile with Novel Intermittent Dosing Regimen<br>Avutometinib monotherapy<br>Daily at MTD<br>N=6<br>28-day cycle<br>RP2D<br>Avutometinib monotherapy<br>4mg twice weekly<br>N=26<br>28-day cycle<br>RP2D<br>(Avutometinib 3.2mg twice<br>weekly + defactinib 200mg<br>twice 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 |
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| 27<br>Avutometinib 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 - 2042 if issued<br>Feb 2027 + 5 yrs (PTE) = 2032<br>Sept 2040<br>Methods of Treating<br>PTE<br>2041 - 2042 if issued<br>Combinations |
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| Avutometinib Defactinib in<br>Low-Grade Serous Ovarian Cancer |
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| 29<br>LGSOC is a Unique RAS Pathway-Driven Cancer with a High Unmet Need<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-yr prevalence ~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-Associated mts<br>References: AACR Project GENIE Cohort v9.0-public and Verastem unpublished analysis<br>References: Monk, Randall, Grisham, The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer, Am Soc Clin Oncol Educ Book; 2019;<br>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; Malpica et al., Am J. Surg Pathol 2007<br>KRAS mutant, 30%<br>NRAS, BRAF,<br>ARAF mutant,<br>20%<br>Other RAS-associated<br>gene mutations,<br>20%<br>Non-RAS-associated, 30% |
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| 30<br>Low-Grade and High-Grade Serous Ovarian Cancer Are Different Diseases<br>Variable LGSOC HGSOC<br>Nuclear atypia Uniform round to<br>oval with little<br>variation<br>+++<br>Marked variation<br>Mitotic Index <12 mitoses per<br>10 hpf<br>>12 mitoses per<br>10 hpf<br>Chromatin and<br>variation in size of<br>nucleus<br>Little Marked (nuclear<br>size ratio ≥3)<br>Mutation KRAS ++<br>BRAF +<br>ER/PR +++<br>P53 +++<br>BRCA1/2 +<br>Precursor Serous borderline<br>tumor<br>Tubal<br>intraepithelial<br>neoplasia<br>LGSOC<br>HGSOC<br>Reference: Malpica et al., Am J. Surg Pathol 2007 |
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| 31<br>Recurrent LGSOC: High Medical Need<br>No Approved Treatment Options – Limited Benefit from Available Therapies<br>References:<br>1 NCCN guidelines v1.2023<br>No Category 1 recommendations (high-level evidence).<br>Category 2a (lower-level evidence with uniform NCCN consensus)<br>unless otherwise indicated<br>f: There is no standard sequencing of drugs for recurrent<br>disease. Considerations include prior therapies, disease burden, relative<br>efficacy, and relative toxicity profile.<br>t: An aromatase inhibitor (i.e., letrozole, anastrozole, exemestane) is<br>preferred if not used previously. Fulvestrant, tamoxifen, or leuprolide<br>acetate is recommended if an aromatase inhibitor was given previously.<br>Recurrent Low-Grade Ovarian Cancer – Treatment Guidelines 1 |
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| 32<br>Recent LGSOC Trials Highlight High Unmet Need<br>Trial<br>Number of Prior<br>Systemic<br>Therapies<br>Median (range)<br>Prior<br>MEK<br>allowed<br>Prior<br>Bevacizumab Therapy Response Rate<br>ORR<br>Image<br>Assessment<br>Median PFS<br>Months (95% CI)<br>Discontinuation<br>Rate<br>due to AEs<br>GOG<br>2811<br>2<br>(1-10) No * Low %<br>SoC<br>(n=130)<br>6%<br>95% CI: (3%, 12%) INV 7.2 (5.6-9.9) 13%<br>Trametinib<br>(n=130)<br>26%<br>95% CI: (19%, 35%) INV 13.0 (9.9-15.0) 36%<br>MILO2<br>2<br>(1-8) No * Low %<br>SoC<br>(n=101)<br>13%<br>95% CI: (7%, 21%) BICR 10.6 (9.2 - 14.5) 17%<br>Binimetinib2<br>(n=198)<br>16%<br>95% CI: (11%, 22%) BICR 9.1 (7.3-11.3) 31%<br>1 Study GOG 281 trial Gershenson et al., Lancet 2022<br>2 MILO Study Monk et al., J Clin Oncol 2020.<br>SoC = Standard of Care<br>(endocrine / chemotherapy)<br>INV = Investigator<br>BICR = Blinded independent central review<br>PFS = Progression free survival<br>CI = confidence interval<br>NR = Not reached<br>* Low historical use of bevacizumab during trial conduct. % not reported<br>MILO: no more than 3 lines of prior chemotherapy |
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| 33<br>FRAME Study: Solid Foundation for the Development of Avutometinib in<br>Combination with Defactinib in Recurrent LGSOC (n=24)<br>Reference: Banerjee et al., ESMO Sept 2021<br>Data cut off April 2021<br>MEKi: MEK inhibitor<br>Bev: Bevacizumab<br>PFS: Progression free survival<br>NR: Not reached<br>• Overall response rate (ORR) = 46% (11 confirmed PRs/24)<br>o KRAS mutant ORR = 64% (7 confirmed PRs/11)<br>o KRAS wild-type ORR = 44% (4 confirmed PRs/9)<br>o KRAS status undetermined (1 unconfirmed PR/4)<br>• Response too early to determine for 2 pts on study for 5 months<br>• Median 3 lines of Prior Treatment (Prior MEKi 10 pts, Prior Bev 4 pts)<br>• Responses in patients previously treated with MEKi<br>• 54% (13/24) patients still on treatment<br>• 1 patient discontinuing for adverse events as of April 2021<br>• Median PFS 23 months (95% CI 10.6-NR) across all LGSOC<br>0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>20 Response by RECIST<br>Time (cycles)<br>Response<br>(% change from baseline) 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 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 FRA103002 - undocumented FRA101042 - KRAS G12D<br>FRA103003 - KRAS WT<br>FRA102018 - KRAS WT<br>FRA101007 FRA101014 FRA101042 FRA101012 FRA103003 FRA101032 FRA103002 FRA101038 FRA102018 FRA101015 FRA102010 FRA101019 FRA101024 FRA101028 FRA101039 FRA101025 FRA101037 FRA103001 FRA101035 FRA101033 FRA104001 FRA101009 FRA101001 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 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 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>Still on treatment *<br>KRAS G12D<br>Undocumented *<br>* Undocumented<br>Stable disease<br>F<br>R<br>A1010<br>0<br>7<br>F<br>R<br>A101014<br>F<br>R<br>A1010<br>4<br>2<br>F<br>R<br>A101012<br>F<br>R<br>A10<br>3<br>0<br>0<br>3<br>F<br>R<br>A1010<br>3<br>2<br>F<br>R<br>A10<br>3<br>0<br>0<br>2<br>F<br>R<br>A1010<br>3<br>8<br>F<br>R<br>A10<br>2<br>018<br>F<br>R<br>A101015<br>F<br>R<br>A10<br>2<br>010<br>F<br>R<br>A101019<br>F<br>R<br>A1010<br>2<br>4<br>F<br>R<br>A1010<br>2<br>8<br>F<br>R<br>A1010<br>3<br>9<br>F<br>R<br>A1010<br>2<br>5<br>F<br>R<br>A1010<br>3<br>7<br>F<br>R<br>A10<br>3<br>0<br>01 F<br>R<br>A1010<br>3<br>5<br>F<br>R<br>A1010<br>3<br>3<br>F<br>R<br>A10<br>4<br>0<br>01 F<br>R<br>A1010<br>0<br>9<br>F<br>R<br>A1010<br>01 F<br>R<br>A1010<br>0<br>2<br>-80<br>-70<br>-60<br>-50<br>-40<br>-30<br>-20<br>-10<br>0<br>10<br>B<br>e<br>st R<br>e<br>s<br>p<br>o<br>n<br>s<br>e<br>(%<br>c<br>h<br>a<br>n<br>g<br>e fro<br>m<br>b<br>a<br>s<br>elin<br>e)<br>U<br>n<br>d<br>o<br>c<br>u<br>m<br>e<br>nte<br>d<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>G12<br>D<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>D<br>3<br>3<br>E, I2<br>4<br>N<br>U<br>n<br>d<br>o<br>c<br>u<br>m<br>e<br>nte<br>d<br>Prior MEK inhibitor<br>*<br>*<br>K<br>RA<br>S<br>G12<br>A<br>K<br>RA<br>S<br>G12<br>V<br>K<br>RA<br>S<br>G12<br>D<br>K<br>RA<br>S<br>G12<br>V<br>*<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>G12<br>D<br>Confirmed partial response<br>Unconfirmed partial response<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>wt<br>*<br>*<br>Best response by RECIST<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>G12<br>D<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>wt<br>K<br>RA<br>S<br>G12<br>D<br>K<br>RA<br>S<br>D<br>5<br>7-T<br>5<br>8in<br>s<br>* *<br>* *<br>*<br>*<br>Still on treatment *<br>K<br>RA<br>S<br>G12<br>D<br>U<br>n<br>d<br>o<br>c<br>u<br>m<br>e<br>nte<br>d<br>*<br>*<br>U<br>n<br>d<br>o<br>c<br>u<br>m<br>e<br>nte<br>d<br>Stable disease |
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| 34<br>Avutometinib Mono<br>N=72 (incl Part A + B)<br>Avutometinib + Defactinib<br>N=72 (incl Part A+B)<br>Avutometinib + Defactinib<br>N=32<br>* Dosing: Avutometinib + Defactinib combo: Avutometinib 3.2 mg PO 2x/wk 21/28 days + Defactinib 200 mg PO BID: 21/28 days;<br>Avutometinib monotherapy: Avutometinib 4.0 mg PO 2x/wk 21/28 days<br>** Lower Dose: Avutometinib + Defactinib combo: Avutometinib 1.6 mg PO 2x/wk 21/28 days + Defactinib 200 mg PO BID: 21/28 days;<br> Completed Enrollment<br>KRAS mt<br>(n=16)<br>KRAS wt<br>(n=16)<br>Primary Endpoint:<br>Objective Response Rate<br>(blinded independent review)<br>Evaluation of ORR in Combination Arm:<br>1) In KRAS mt patients<br>2) All patients (KRAS mt & wt)<br>Avutometinib Mono<br>N=32<br>KRAS mt<br>(n=16)<br>KRAS wt<br>(n=16)<br>KRAS mt<br>(n=36)<br>KRAS wt<br>(n=36)<br>KRAS mt<br>(Total n=36)<br>KRAS wt<br>(Total n=36) Recurrent LGSOC<br> Prior<br>chemotherapy<br> Measurable disease<br>(RECIST 1.1)<br> Prior MEKi allowed<br>Combination Arm:<br>✓ Target Enrollment Reached (N=72)<br>❖ Expanded Enrollment Ongoing (Lower Dose)<br>n +20<br>n +20<br>n +20<br>n +20<br>RAMP 201 (ENGOTov60/GOG3052): Registration-Directed Phase 2 Trial of<br>Avutometinib Defactinib in Patients with Recurrent LGSOC<br>Part A<br>Selection Phase*<br>Part B<br>Expansion Phase*<br>Avutometinib + Defactinib<br>Expanded Enrollment +40 pts<br>KRAS mt<br>KRAS wt<br>Part C<br>Expansion Phase*<br>Combo<br>Part D<br>Expansion Phase**<br>(Combo Lower Dose)<br>Avutometinib + Defactinib<br>Expanded Enrollment Ongoing<br>+ 20-30 pts<br>KRAS mt<br>KRAS wt<br>✓ ✓ ✓<br>✓ |
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| RAMP 201<br>ASCO 2023 Update |
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| 36<br>Updated Data from Part A of RAMP 201<br>“These results demonstrate avutometinib in combination with defactinib can deliver high response rates for patients with recurrent LGSOC with a<br>promising safety profile to date. It is particularly encouraging to see extensive tumor shrinkage in women who have had several treatment lines,<br>including prior MEK inhibitors. These latest findings suggest the combination may offer a new treatment option for women with this hard-to-treat<br>cancer, and we are hopeful it will become the new standard of care.” –Dr. Susana Banerjee, MBBS, MA PhD, FRCP, global and lead investigator of the study,<br>Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London<br>ASCO 2023 data<br>Avutometinib + Defactinib<br>Total (n=29)<br>ORR, % (n)<br>45% (13) 95% CI: (26%, 64%)<br>KRAS mt<br>60% (9/15)<br>KRAS wt<br>29% (4/14)<br>Tumor shrinkage, % (n) 86% (25)<br>Median Time to Response 5.5 months (range 1.6-14.7 months)<br>Relative Dose Intensity 83% ± 20%<br>• 29 patients were evaluable for efficacy with a minimum follow-up of 12 months and 13 (45%) patients remain on study treatment<br>• Patients were heavily pretreated with a median of 4 prior systemic regimens (up to 11)<br>• 3 out of 4 patients who received prior MEK inhibitors responded to the combination<br>• Median duration of response and median progression free survival have not been reached<br>• Safety and tolerability continued to be favorable and consistent with previously reported data<br>• The discontinuation rate due to ≥ 1 adverse event was12% in the combination overall to date (4.9% due to elevated blood CPK)<br>• Finalizing the design of a randomized confirmatory trial with the FDA, which is planned to begin in the second half of 2023 |
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| 37<br>Recent LGSOC Trials with Standard of Care Highlight High Unmet Need<br>in Recurrent LGSOC<br>Trial<br>Median<br>Number<br>of Prior<br>lines of<br>Therapy<br>Prior<br>MEK<br>Allowed<br>Prior<br>Bevaciz<br>umab<br>Therapy Response Rate<br>ORR<br>Image<br>Assessment<br>Median PFS<br>Months (95% CI)<br>Discontinuation<br>Rate<br>Due to AEs<br>GOG 2811<br>2<br>(1-10) No * Low %<br>Standard of Care 6%<br>95% CI: (3%, 12%) INV 7.2 (5.6-9.9) 13%<br>Trametinib 26%<br>95% CI: (19%, 35%)<br>INV 13.0 (9.9-15.0) 36%<br>MILO2<br>2<br>(1-8) No * Low %<br>Standard of Care 13%<br>95% CI: (7%, 21%) BICR 10.6 (9.2 to 14.5) 17%<br>Binimetinib 16%<br>95% CI: (11%, 22%) BICR 9.1 (7.3-11.3) 31%<br>1 Study GOG 281 trial Gershenson et al., Lancet 2022<br>2 MILO Study Monk et al., J Clin Oncol 2020.<br>* Low historical use of bevacizumab during trial conduct. % not reported<br>MILO: no more than 3 lines of prior chemotherapy<br>INV = Investigator<br>BICR = Blinded independent central review<br>PFS = Progression free survival<br>CI = confidence interval<br>SoC = Standard of Care<br>GOG 281: (chemotherapy / endocrine therapy)<br>PLD (liposomal doxorubicin), paclitaxel, topotecan, letrozole or tamoxifen<br>MILO: (chemotherapy only)<br>PLD (liposomal doxorubicin), paclitaxel or topotecan |
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| 38<br>Current Trials with Combination of Avutometinib and Defactinib<br>Consistent Overall Response Rate of ~45%<br>Trial<br>Median<br>Number<br>of Prior<br>lines of<br>Therapy<br>Prior<br>MEK<br>Allowed<br>Prior<br>Bevaciz<br>umab<br>Therapy Response Rate<br>ORR<br>Image<br>Assessment<br>Median PFS<br>Months (95% CI)<br>Discontinuation<br>Rate<br>Due to AEs<br>FRAME1 3 Yes 12 % Avutometinib +<br>Defactinib<br>46%<br>95% CI: (26%, 67%) INV 23 (11 - NR) 4%<br>RAMP 201<br>Part A<br>(ASCO 2023<br>data)<br>2<br>4 Yes 65% Avutometinib +<br>Defactinib<br>45%<br>95% CI: (26%, 64%)<br>52%*<br>BICR Not Yet Reached 10%**<br>INV = Investigator<br>BICR = Blinded independent central review<br>PFS = Progression free survival<br>1 Banerjee et al., ESMO Sept 2021<br>2 Banerjee et al., ASCO June 2023<br>* Confirmed + Unconfirmed Objectives responses<br>**12% discontinuation in all combination pts (Part A + B (n=81): 4.9% due to elevated blood CPK) |
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| 39<br>RAMP 201 Part A: Heavily Pre-Treated Patient Population<br>Prior Platinum-Based Chemotherapy, Endocrine Therapy, Bevacizumab in Most Patients;<br>Prior MEK InhibitorTherapy was Permitted<br>Avutometinib Monotherapy Avutometinib + Defactinib<br>KRAS mt<br>(n=16)<br>KRAS wt<br>(n=17)<br>Total<br>(n=33)<br>KRAS mt<br>(n=16)<br>KRAS wt<br>(n=15)<br>Total<br>(n=31)<br>Age (yrs), median (min, max) 58 (27, 72) 48 (27, 74) 51 (27, 74) 61 (29, 71) 50 (30, 74) 55 (29, 74)<br>ECOG PS, n (%)<br>0 8 (50) 15 (88) 23 (70) 11 (69) 9 (60) 20 (65)<br>1 8 (50) 2 (12) 10 (30) 5 (31) 6 (40) 11 (35)<br>Number of Prior Systemic Regimens, median<br>(min, max) 4 (1, 10) 3 (1, 9) 3 (1, 10) 4 (1, 8) 5 (2, 11) 4 (1, 11)<br>Prior platinum-based chemotherapy, n (%) 15 (94) 17 (100) 32 (97) 16 (100) 15 (100) 31 (100)<br>Prior MEK inhibitor therapy, n (%) 5 (31) 5 (29) 10 (30) 2 (13) 2 (13) 4 (13)<br>Prior Bevacizumab, n (%) 8 (50) 8 (47) 16 (48) 7 (44) 13 (87) 20 (64)<br>Prior Hormonal therapy, n (%) 11 (69) 13 (76) 24 (73) 15 (94) 13 (87) 28 (90)<br>ASCO 2023 data |
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| 40<br>RAMP 201 Part A: Evaluable Patient Population*<br>Positive ORR Confirmed by Blinded Independent Central Review (BICR) Support Avutometinib +<br>Defactinib as Go Forward Regimen in LGSOC - Regardless of KRAS Status<br>Avutometinib Avutometinib + Defactinib<br>KRAS mt<br>(n=15)<br>KRAS wt<br>(n=15)<br>Total<br>(n=30)<br>KRAS mt<br>(n=15)<br>KRAS wt<br>(n=14)<br>Total<br>(n=29)<br>Confirmed ORR, n (%) 2 (13) 1 (6) 3 (10)<br>95% CI (2%, 24%) 9 (60) 4 (29) 13 (45)<br>95% CI (26%, 64%)<br>CR, n (%) 1 (7) 0 1 (3) 0 0 0<br>PR, n (%) 1 (7) 1 (6) 2 (7) 9<br>** (60) 4 (29) 13 (45)<br>SD, n (%) 12 (80) 13 (81) 25 (83) 6 (40) 7 (50) 13 (45)<br>Disease control<br>rate***, n (%) 14 (93) 14 (88) 28 (93) 15 (100) 11 (79) 26 (90)<br>PD, n (%) 1 (7) 2 (13) 3 (10) 0 3 (21) 3 (10)<br>Confirmed +<br>unconfirmed ORR, n (%) 2 (13) 1 (6) 3 (10) 11 (73) 4 (29) 15 (52)<br>* Evaluable for Efficacy: At least one blinded imaging assessment in 31 of 33 and 29 of 31 patients enrolled in respective treatment arms<br>** Includes patient deepened to CR at last assessment; CR not yet confirmed<br>***Disease control rate (SD + PR + CR) at 8 weeks.<br>BICR, blinded independent central review; mt, mutant; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; wt, wild type<br>ASCO 2023 data |
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| 41<br>Combination of Avutometinib and Defactinib<br>High Disease Control Rate + Tumor Reduction in Recurrent LGSOC<br>Part A (Evaluable for Efficacy *)<br>Confirmed ORR: 45%<br>Confirmed/Unconfirmed ORR: 52%<br>Disease Control Rate (SD+PR): 90%<br>Patients still on study treatment: 45%<br>Minimum follow-up: 12 months<br>RAMP 201 (Part A)<br>N=29 Evaluable for Efficacy *<br>* Evaluable for Efficacy: At least one blinded imaging assessment<br>ASCO 2023 data<br>-80<br>-60<br>-40<br>-20<br>0<br>20<br>Best Response<br>(% Change From Baseline)<br>KRAS wild-type KRAS mutant * Still on Treatment<br>*<br>*<br>*<br>*<br>* * * *<br>*<br>* *<br>*<br>*<br>+117.7%<br>-100% |
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| 42<br>RAMP 201 (Part A)<br>Interim Analysis - Blinded ICR<br>N=29<br>Combination of Avutometinib and Defactinib<br>Initial Data from RAMP 201 Trial Reinforce Findings from FRAME Trial<br>Reference: Banerjee et al., ESMO Sept 2021<br>FRAME<br>Investigator Assessment<br>N=24<br>FRA101007 FRA101014 FRA101042 FRA101012 FRA103003 FRA101032 FRA103002 FRA101038 FRA102018 FRA101015 FRA102010 FRA101019 FRA101024 FRA101028 FRA101039 FRA101025 FRA101037 FRA103001 FRA101035 FRA101033 FRA104001 FRA101009 FRA101001 FRA101002<br>-80<br>-60<br>-40<br>-20<br>0<br>20<br>Best Response<br>(% change from baseline)<br>Best response by RECIST<br>*<br>* *<br>*<br>*<br>* *<br>* *<br>*<br>*<br>*<br>*<br>KRAS mutant KRAS wild-type<br>* Still on treatment KRAS undocumented<br>ASCO 2023 data<br>-80<br>-60<br>-40<br>-20<br>0<br>20<br>Best Response<br>(% Change From Baseline) KRAS wild-type KRAS mutant * Still on Treatment<br>*<br>*<br>*<br>*<br>* * * *<br>*<br>* *<br>*<br>*<br>+117.7%<br>-100% |
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| 43<br>Avutometinib + Defactinib (n=81)<br>Any Grade Grade ≥3<br>Nausea, n (%) 50 (61.7) 0<br>Diarrhea, n (%) 40 (49.4) 3 (3.7)<br>Blood CPK increased, n (%) 39 (48.1) 15 (18.5)<br>Oedema peripheral, n (%) 34 (42.0) 1 (1.2)<br>Vomiting, n (%) 30 (37.0) 0<br>Vision blurred, n (%) 29 (35.8) 0<br>Dermatitis acneiform, n (%) 28 (34.6) 2 (2.5)<br>Fatigue, n (%) 27 (33.3) 3 (3.7)<br>Rash, n (%) 25 (30.9) 2 (2.5)<br>Dry skin, n (%) 18 (22.2) 0<br>Anemia, n (%) 14 (17.3) 3 (3.7)<br>RAMP 201: Safety and Tolerability Profile of Avutometinib + Defactinib<br>No New Safety Signals; Few Discontinuations Due to Adverse Events<br>Most Common Treatment-Related Adverse<br>Events (>20%) in All Treated Patients<br>• Majority of adverse events are mild to<br>moderate and manageable/reversible1<br>• Few discontinuations due to adverse events<br>(12.3% in combo due to ≥ 1 TEAE 4.9% due<br>to elevated blood CPK*)<br>* No association to date with clinically<br>significant toxicities, including<br>rhabdomyolysis<br>ASCO 2023 data<br>Reference: Banerjee et al., ASCO June 2023;<br>1 J Clin Oncol 41, 2023 (suppl 16; abstr 5515) |
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| 44<br>Plan to File for Accelerated Approval based on Completed RAMP 201<br>and FRAME Study Results<br>• Target enrollment for primary analysis (n=72) in<br>combination has been achieved<br>• Plan to file for accelerated approval based on the<br>totality of the data from the RAMP 201 and FRAME<br>studies<br>• The Company plans to initiate the confirmatory study<br>in 2H 2023<br>• Combination of avutometinib with defactinib selected<br>as go forward treatment regimen<br>• Combination development continues in all recurrent<br>LGSOC, regardless of KRAS status<br>• Encouraging efficacy results include independently<br>confirmed responses<br>• No new safety signals; few discontinuations due to<br>adverse events<br>• Updated RAMP 201 Part A data presented at ASCO<br>2023<br>• Design of Confirmatory Trial finalized with FDA<br>Update Next Steps |
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| 45<br>RAMP 201 Part A Interim Data Support Meaningful Market Potential for All<br>Recurrent LGSOC Regardless of KRAS Status with Long Duration of Therapy<br>NSCLC KRAS G12C3<br>Pancreatic Cancer3<br>LGSOC3<br>Endometrioid Cancer3<br>Metastatic uveal<br>melanoma3<br>~6K<br>patients US1<br>~80K<br>patients WW1<br>Patient-months of Therapy Per Year2<br>(across all 2L+ patients)<br>1 References: Monk, Randall, Grisham, The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer, Am Soc Clin Oncol Educ Book;<br>2019; Slomovitz, Gourley, Carey, Malpica, Shih, Huntsman, Fader., Grisham et al, Low-Grade serous ovarian cancer: State of the Science; Gynecol Oncol; 2020. Grisham,<br>Iyer, Low-Grade 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;<br>patient population estimates from Globocan 2020, American Cancer Society 2021, AACR Genie Cohort V9.0 public, and scientific publications. Duration of therapy<br>estimates from clinical studies and clinician experience. Patient-months on therapy is for 2nd<br>-line+ patients<br>3 NSCLC KRAS G12C 2nd line patients (incidence); Pancreatic RAS/RAF mutant 2nd<br>-line patients (incidence); LGSOC KRAS mutant and wild-type patients (prevalence);<br>Endometrioid RAS/RAF mutant 2nd<br>-line patients (incidence); Uveal melanoma RAS/RAF mutant 2nd-line patients (incidence)<br>Prevalence<br> - 50,000 100,000 150,000<br>~4K ~2K<br>KRAS<br>wild type<br>KRAS<br>mutation |
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| RAS Pathway-Driven Cancers and<br>Rational Avutometinib Combinations |
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| 47<br>High Unmet Needs in Additional RAS/MAPK Pathway-Driven Cancers<br>NSCLC<br>Incidence3,5:<br>114K<br>Colorectal<br>Incidence5<br>:<br>148K<br>Pancreatic<br>Incidence5<br>:<br>58K<br>Uterine<br>Endometrioid<br>Incidence4,5: 59K<br>Melanoma<br>Incidence5<br>:<br>108K<br>Multiple Myeloma<br>Incidence5<br>:<br>32K<br>Melanoma<br>Incidence5<br>:<br>108K<br>Colorectal<br>Incidence7<br>:<br>148K<br>Papillary Thyroid<br>Incidence5,6:<br>42K<br>Incidence References:<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>350% of NSCLC is adenocarcinoma (Pakkala and Ramalingam JCI Insight 2018 ); 490% of all uterine cancers are of the endometrial type (ACS); 5Cancer Statistics 2020,<br>Siegel et. al. CA Cancer J Clin 2020;70:7-30; 68 out of 10 thyroid cancers are of the papillary type (ACS)7CbioPortal<br>References:<br>McCormick F Clin Cancer Res 15April2015; 6Adderley H et al. EBioMedicine 01Mar2019; Papke B et al. Science 17Mar2017; Ryan M et al. Nature Reviews Clinical<br>Oncology 01Oct2018; NIH cancer.gov/research/key-initiatives/ras<br>KRAS-mutant<br>Cancers1<br>31% 45%<br>98%<br>21%<br>NRAS-mutant<br>Cancers1<br>28%<br>BRAF-mutant<br>Cancers2 60% 10%<br>30 –<br>80%<br>20%<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> Approved RAS inhibitors address only a minority of all RAS mutated cancers (KRAS G12C)<br>Breadth of potential opportunity<br> 30% of all human cancers are driven by<br>mutations of the RAS family of genes6<br>Established prognostic significance<br> Patients with mutations of the RAS family have<br>an overall worse prognosis<br>NSCLC<br>Incidence3,7:<br>194K<br>4.5% |
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| 48<br>Vertical Blockade: Establishing Avutometinib as the Backbone of Therapy for<br>RAS/MAPK Pathway-Driven Tumors<br>▪ Current Challenges<br>• Blocking any single target in the pathway is insufficient for maximum depth and<br>duration of anti-tumor efficacy<br>• e.g. SHP2i, KRAS-G12Ci, KRAS-G12Di, RAFi, MEKi, ERKi<br>• Vertical blockade concept is now well established<br>• Necessary to block more than 1 target in the pathway<br>• Many of these agents (e.g. SHP2i, MEKi) have poor tolerability as monotherapy<br>and in combination<br>▪ Solutions offered by Avutometinib<br>• Vertical blockade (RAF and MEK blockade) in a single drug<br>• Potential best-in-class tolerability with recommended twice weekly dosing<br>regimen<br>• Should enable tolerable combinations<br>• Compelling synergy data (preclinical) for avutometinib combinations (e.g. with<br>KRAS G12C inhibitors) supporting clinical combinations<br>• Ongoing clinical combination studies with G12Ci (sotorasib, adagrasib), anti-EGFR (cetuximab)<br>RTK<br>Growth factors<br>EGFRi<br>G12Ci<br>G12Di<br>RAFi<br>MEKi<br>ERKi<br>Avutometinib<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 |
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| 49<br>Parallel Pathway Inhibition: Establishing Avutometinib as the Backbone of<br>Therapy for RAS/MAPK Pathway-Driven Tumors<br>▪ Current Challenges<br>• Blocking RAS pathway can be circumvented through<br>parallel pathways<br>• e.g. PI3K/AKT/mTOR, FAK, RhoA, YAP<br>• Combinations of MEKi + AKTi have shown poor<br>tolerability<br>▪ Solutions offered with Avutometinib<br>• Promising tolerability and early clinical data with<br>twice weekly avutometinib opens up intermittent<br>dosing options for combinations<br>• Compelling preclinical synergy data with<br>avutometinib in combination with several key anti-cancer agents (e.g. FAKi, mTORi)<br>• RP2D established for avutometinib + FAKi<br>(defactinib) and for avutometinib + mTORi<br>(everolimus) with twice weekly 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>G12Di<br>RAFi<br>MEKi<br>ERKi<br>Avuto<br>RAS<br>RAF<br>MEK<br>ERK<br>SHP2i<br>SOS1i<br>Tumor Growth<br>EGFRi<br>RhoA, YAP, etc. mTOR<br>References: 1 Chen, Mol Cancer Res 2018; 2 Banerji, BTOG Dublin, Jan 23, 2019 |
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| 50<br>Preclinical Synergy of Avutometinib in Combination with Promising Agents<br>for Clinical Investigation<br>H2122 SW837 H1373 SW1573 H358 H2030 MIAPACA2<br>0<br>10<br>20<br>30<br>40<br>50 VS-6766 + AMG 510<br>Combined Synergy Score<br>NSCLC<br>Panc<br>Synergy Antagonism<br>Indication<br>CRC<br>Avutometinib + G12Ci (sotorasib)<br>H2122 SW837 SW1573 H358 MIAPACA2 H1373<br>0<br>10<br>20<br>30<br>40<br>50 VS-6766 + MRTX849<br>Combined Synergy Score<br>NSCLC<br>PDAC<br>Synergy Antagonism<br>Indication<br>CRC<br>Avutometinib + G12Ci (adagrasib)<br>H2122 MIAPACA2 H1373 H358 SW1573 A427 HPAC<br>ASPC1 HPAFII SKLU1 CFPAC1 CAPAN2 H2291 PANC0327 H441 H2444<br>-20<br>-10<br>0<br>10<br>20<br>30<br>40 VS-6766 + Palbociclib<br>Combined Synergy Score KRAS G12C<br>KRAS G12D<br>KRAS G12V<br>100% (5/5) 100% (5/5) 50% (3/6)<br>Indication<br>NSCLC<br>PDAC<br>Synergy Antagonism<br>Avutometinib + mTORi (everolimus)<br>Vertical RAS/MAPK Pathway Inhibition Parallel Pathway Inhibition<br>KP4 Panc 04.03 Panc 08.13 AsPC-1 HPAF-II HPAC<br>LS 180 LS513 SNU-C2B<br>SNU-C2A Gp2D<br>A427 SK-LU-1<br>0<br>20<br>40<br>60 VS-6766 + MRTX1133<br>Combined Synergy Score<br>Indication<br>NSCLC<br>CRC<br>Synergy Antagonism<br>Indication Panc<br>Avutometinib + pan-HERi (afatinib) Avutometinib + SHP2i (RMC-4550) Avutometinib + SOS1i (BI-3406) Avutometinib + CDK4/6i (palbociclib)<br>Avutometinib + G12Di (MRTX1133) |
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| Avutometinib Combinations in<br>Non-Small Cell Lung Cancer |
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| 52<br>High Unmet Need in Refractory KRAS & BRAF mt NSCLC Adenocarcinoma<br>Advanced or Metastatic NSCL Cancer<br>Recommend Histologic and Molecular Subtyping5<br>Appropriate targeted<br>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/BRAF/<br>KRAS G12C (targeted)<br>Non-targeted<br>PD-(L)1 1%<br>Non-Targeted<br>PD-(L)1 1%<br>▪ SOC in recurrent disease is<br>chemotherapy<br>▪ Pre-PD-(L)1 era, chemotherapy<br>response rate ~10% in recurrent<br>disease; 12w PFS of 30–45%<br>Recurrence<br>Recurrence<br>Verastem Clinical Trials:<br>• RAMP 203: Avutometinib + sotorasib in KRAS G12C NSCLC<br>• RAMP 204: Avutometinib + adagrasib in KRAS G12C NSCLC<br>• RAMP 202: Avutometinib + defactinib in BRAF V600E and non-V600E NSCLC<br>NSCLC Adenocarcinoma3<br>0<br>5<br>10<br>15<br>% of Patients<br>KRAS Mutation BRAF Mutation<br>US Annual Incidence7,8: 114K<br>WW Annual Incidence1,2: 882K<br>References:<br>1 Globocan, 2020<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>6 Clinical Cancer Research DOI 10.1158/1078-0432.CCR-18-2062<br>7 50% of NSCLC is adenocarcinoma (Pakkala and Ramalingam JCI Insight 2018)<br>8 Cancer Statistics 2020, Siegel et. al. CA Cancer J Clin 2020;70:7-30<br>KRAS Mutations Represent 25% of Lung Cancer Adenocarcinoma<br>& BRAF Mutations Represent 4% (EGFR 17%, ALK 7%)4,6<br>BRAF V600E<br>BRAF non-V600E |
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| 53<br>0 10 20 30<br>0<br>500<br>1000<br>1500<br>2000 Tumor growth<br>Days after first dose<br>Tumor volume<br>(mm<br>3 +/- SEM)<br>vehicle<br>sotorasib<br>sotorasib + avutometinib<br>sotorasib + avutometinib + FAKi<br>avutometinib<br>trametinib<br>****<br>****<br>****<br>Preclinical Synergy of Avutometinib + G12C Inhibitors in KRAS G12C Models<br>Synergy of avutometinib + G12C inhibitors across<br>G12C mutant NSCLC, CRC & Pancreatic cancer cell lines<br>Doses Tested<br>Sotorasib: 30 mg/kg PO QD<br>Avutometinib: 0.3 mg/kg PO QD<br>FAKi: 50 mg/kg PO BID<br>Trametinib: 0.3 mg/kg PO QD<br>Avutometinib & FAKi potentiate sotorasib efficacy in KRAS G12C<br>NSCLC in vivo; Tumor regression in all mice with triple combination<br>Avutometinib + sotorasib yields deeper and more sustained inhibition<br>of ERK signaling pathway<br>H2122 KRAS G12C NSCLC<br>Sotorasib<br>Avutometinib<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 NSCLC<br>Concentrations Tested<br>Sotorasib: 100 nM<br>Avutometinib: 100 nM<br>Reference: Coma et al., AACR 2021<br>Combined Synergy Score<br>Cell line Indication Sensitivity to<br>G12C inhibitors<br>Avutometinib<br>+ sotorasib<br>Avutometinib<br>+ adagrasib<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>-100<br>0<br>100<br>200<br>300<br>400 Response at Day 10<br>Response @ Day 10<br>(% change from baseline)<br>Vehicle 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 AMG 510 + VS-4718 VS-6766 + AMG 510 + VS-4718<br>Trametinib 0.3mg/kg QD<br>Trametinib + AMG 510<br>vehicle<br>trametinib<br>10 PR<br>avutometinib<br>FAKi sotorasib<br>sotorasib + trametinib<br>sotorasib + avutometinib<br>sotorasib + FAKi VS-676 + FAKi sotorasib + avutometinib + FAKi<br>-30<br>20<br>1 SD<br>2 SD<br>1 SD<br>1 SD<br>1 SD<br>1 PR<br>8 SD<br>2 PR 4 SD<br>3 PR<br>2 SD<br>4 PR |
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| 54<br>Acquired Resistance Mechanisms to KRAS G12Ci Treatment in Patients<br>Further Support Combination of KRAS G12Ci with Avutometinib<br>Summary of Putative Mechanisms of Acquired<br>Resistance to Adagrasib Treatment<br>• Mechanisms of acquired resistance to KRAS G12Ci<br>adagrasib treatment in patients recently reported1,2<br>• The main resistance alterations occurred in<br>• RTK mts or amplifications<br>• KRAS mts or amplification<br>• NRAS mt<br>• BRAF V600E, BRAF or CRAF fusions<br>• MAP2K1 (MEK1) mt/deletion<br>• Avutometinib has shown activity against these KRAS,<br>NRAS, BRAF and CRAF modifications<br>Reference: Andrew Aguirre, unpublished<br>References: 1Awad MM et al., N Engl J Med 2021; 384: 2382-93; 2Tanaka et al., Cancer Discov 2021;11:1–10<br>IC50 (nM)<br>Cell Line Sotorasib Adagrasib Avutometinib<br>G12C 29 3 14<br>G12D 435 382 7<br>G12C/R68S 157 85 13<br>G12C/H95D 11 235 10<br>G12C/Y96C 438 216 4<br>1 - 30 nM 30 - 150 nM 150 - 500 nM |
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| 55<br> Patients must have a<br>KRAS G12C mutation<br>determined using<br>validated test<br> Treatment with at least 1<br>but no more than 3 prior<br>systemic regimens, for<br>Stage 3B-C or 4 NSCLC*<br> Patient may have<br>previously received<br>adjuvant chemotherapy<br>for earlier-stage disease<br> Measurable disease<br>according to RECIST 1.1<br> ECOG performance<br>status ≤ 1<br>RAMP 203: Phase 1/2 Trial of Avutometinib + LUMAKRASTM (Sotorasib) in<br>KRAS G12C Advanced NSCLC<br>RP2D<br>Selected*<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: ~20 patients<br>Stage 2: expand Avutometinib +<br>Sotorasib<br>Dose Finding Cohorts<br>(n=3-6)<br>Cohort 2<br>Patients who Progressed<br>on KRAS G12C Inhibitor<br>Treatment<br>Stage 1: ~20 patients<br>Stage 2: expand<br>Collaboration with Amgen<br>*may include patients with or without prior<br>G12C therapy<br>* Recommended Phase 2 Dose (RP2D):<br>4mg avutometinib/960mg sotorasib<br>NCT05074810<br>Abbreviations: DLT = dose-limiting toxicity; n = number of patients;<br>ORR = overall response rate; RP2D = recommended phase 2 dose<br>Now enrolling expansion phase<br>Completed enrollment |
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| 56<br>RAMP 204: Phase 1/2 Trial of Avutometinib + KRAZATITM (Adagrasib) in<br>KRAS G12C Advanced NSCLC<br> Patients must have a<br>KRAS G12C<br>mutation determined<br>using validated test<br> Treatment with at<br>least 1 but no more<br>than 3 prior systemic<br>regimens, for Stage<br>3B-C or 4 NSCLC<br> Patient must have<br>received prior<br>therapy with a KRAS<br>G12C inhibitor and<br>experience<br>progressive disease<br> Measurable disease<br>according to RECIST<br>1.1<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: 19 patients<br>(including Part A<br>patients) treated with<br>RP2D<br>Stage 2: expand to 55<br>patients<br>RP2D<br>Selection<br>Avutometinib +<br>Adagrasib<br>Dose Finding Cohorts<br>(n=3-6)<br>Collaboration with Mirati Therapeutics<br>NCT05375994<br>Abbreviations: DLT = dose-limiting toxicity; n = number of patients;<br>ORR = overall response rate; RP2D = recommended phase 2 dose |
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| 57<br>RAMP 202: Phase 2 Trial of Avutometinib + Defactinib in BRAF mt NSCLC<br>References:1 Avutometinib 3.2 mg PO 2x/wk (21/28 days) + Defactinib 200 mg PO BID (21/28 days)<br> Patients with Advanced<br>NSCLC<br> 1-2 prior regimens<br> 1 prior platinum-containing<br>chemo<br> Prior CPI unless<br>contraindicated<br> Measurable disease (RECIST<br>1.1)<br> Appropriate approved therapy<br>for other relevant mutations<br> No prior KRAS-specific<br>targeted therapy<br> No prior MEKi, (except for<br>BRAF V600E)<br> No untreated CNS metastases<br> ECOG OS 0-1<br>Avutometinib +<br>Defactinib1<br>BRAF V600E<br>n=15<br>Avutometinib +<br>Defactinib1<br>BRAF non-V600E<br>n=15<br>BRAF Mutant<br> Mutation-specific<br>cohort analyses for<br>ORR<br>Expansion TBD<br>based on results<br>of analysis<br>Initial Phase Analysis<br>NCT04620330 |
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| Additional Avutometinib Combinations<br>for Pancreatic, Colorectal and<br>Melanoma |
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| 59<br>Preclinical Synergy of Avutometinib/FAK Inhibition + Chemotherapy in a<br>KRAS/p53 pancreatic cancer mouse model<br>✓ The combination of avutometinib + FAKi induces tumor growth inhibition and increases survival but<br>does not induce tumor regression<br>✓ Addition of chemo (gemcitabine + paclitaxel) to avutometinib/FAKi induces tumor regression<br>-100<br>0<br>100<br>200<br>300<br>400<br>500<br>% change in tumor volume<br>1-14 days<br>Collaboration with David DeNardo, Washington University; unpublished<br>vehicle<br>avutometinib/FAKi<br>gemcitabine/paclitaxel<br>avutometinib/FAKi<br>+ gemcitabine/paclitaxel |
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| 60<br>RAMP 205: Phase 1/2 Trial of Avutometinib/Defactinib + GEMZARTM<br>(Gemcitabine)/ABRAXANETM (Nab-paclitaxel) in Front Line Metastatic<br>Pancreatic Cancer<br> Patients with confirmed<br>metastatic pancreatic ductal<br>adenocarcinoma<br> Eligible for treatment in the<br>first-line setting with standard<br>gemcitabine and nab-paclitaxel<br> Prior adjuvant or neoadjuvant<br>chemotherapy, radiotherapy or<br>surgery is permitted if the last<br>intervention/ dose was ≥ 12<br>months prior to the diagnosis<br>of metastatic disease<br> Measurable disease according<br>to RECIST 1.1<br> ECOG performance status ≤ 1<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>Patients with PDAC<br>KRAS G12D<br>KRAS G12V<br>KRAS G12R<br>Others<br>Treated with RP2D<br>Stage 1: 17 patients<br>If ≥4 responders, then<br>Stage 2: expand to 29 patients<br>Avutometinib +<br>Defactinib +<br>Gemcitabine +<br>Nab-paclitaxel<br>Dose Finding Cohorts<br>(n=3-6)<br>Collaboration with PanCAN<br>NCT05669482<br>Abbreviations: DLT = dose-limiting toxicity; n = number of patients;<br>ORR = overall response rate; RP2D = recommended phase 2 dose |
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| 61<br>Combination of Avutometinib with anti-EGFR mAb Induces Tumor<br>Regression in a KRAS mt Colorectal PDX Model<br>• Avutometinib + anti-EGFR (panitumumab)<br>induces tumor regression in a KRAS mutant<br>CRC patient-derived xenograft model<br>• G12Ci + anti-EGFR (sotorasib +<br>panitumumab and adagrasib + cetuximab)<br>have shown partial responses in KRAS G12C<br>CRC (Fakih et al. ESMO 2021; Weiss et al.<br>ESMO 2021)<br>• These data support the ongoing<br>clinical evaluation of avutometinib +<br>cetuximab (anti-EGFR) for treatment<br>of KRAS mt CRC (NCT05200442)<br>vehicle<br>avutometinib<br>panitumumab (anti-EGFR)<br>panitumumab + avutometinib<br>Collaboration with Marwan Fakih, City of Hope<br>Pachter, RAS Development Summit, 2021 |
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| 62<br>Combination of Avutometinib + FAK Inhibition with Checkpoint Inhibitor<br>Induces Tumor Regression in an IO-resistant BRAF V600E melanoma model<br>• Avutometinib + IO (anti-PD-1 + anti-CTLA-4)<br>induces tumor regression in an IO-resistant<br>syngeneic BRAF V600E melanoma model<br>(YUMM 1.7)<br>• FAK inhibition deepens and sustains<br>avutometinib-induced tumor regression<br>• These data support the imminent clinical<br>evaluation of avutometinib +<br>pembrolizumab (anti-PD-1) for treatment<br>of BRAF V600E melanoma<br>Collaboration with Silvio Gutkind, UCSD; unpublished<br>vehicle<br>IO (anti-PD-1 + anti-CTLA-4)<br>IO + avutometinib<br>IO + avutometinib + FAKi |
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| 63<br>Avutometinib Development in Multiple Combinations Across RAS Pathway-Driven Tumors with Potential Early Read-Outs in 2H 2023<br>Indication Study<br>KRAS G12C NSCLC RAMP 203: Avutometinib/Sotorasib combo<br>KRAS G12C NSCLC RAMP 204: Avutometinib/Adagrasib combo<br>Pancreatic RAMP 205: Avutometinib/Gem/Abraxane/Defactinib combo<br>KRAS mt NSCLC Avutometinib/Everolimus combo*<br>KRAS mt CRC Avutometinib/Cetuximab combo*<br>ER+ Breast Avutometinib/Abemaciclib/fulvestrant combo*<br>RAS/RAF/NF1 Gynecological Avutometinib/Defactinib combo*<br>BRAF V600E Melanoma Avutometinib/Pembrolizumab combo*<br>Confidential. © Verastem Inc. 2022<br>*Investigator Sponsored Trials |
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| 64<br>Experienced Senior Management Team<br>Cathy Carew<br>Chief Organizational<br>Effectiveness Officer<br>Louis Denis, M.D.<br>Chief Medical Officer<br> Principal – HR Collaborative<br> Ironwood, ActiveBiotics, Dynogen,<br>Tufts Health Plan<br> CMO, Asana BioSciences<br> Boehringer-Ingelheim, Pfizer<br>Daniel Paterson<br>President and Chief Executive<br>Officer<br>Jonathan Pachter,<br>Ph.D.<br>Chief Scientific Officer<br> CEO – The DNA Repair Co. (now<br>On-Q-ity)<br> PharMetrics (now IMS), Axion<br> Head of Cancer Biology – OSI<br>(now Astellas)<br> Schering-Plough<br>Hagop Youssoufian,<br>MSc, M.D.<br>Head of Medical Strategy<br> CMO, BIND Therapeutics, EVP,<br>Progenics,<br> CMO & EVP, Ziopharm Oncology,<br>SVP, Imclone |
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| THANK YOU |
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