Verastem, Inc. · NASDAQ:VSTM

Verastem — RAS-Targeted Drug Development (September 2020)

25 slides from Verastem's conference presentation, Sep 16, 2020

  1. Slide 1: Synergistic Combinations with the Dual RAF/MEK Inhibitor VS-6766 to Overcome Resistance Mechanisms

    1 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 Synergistic Combinations with the Dual RAF/MEK Inhibitor VS - 6766 to Overcome Resistance Mechanisms Jonathan Pachter, PhD, Chief Scientific Officer – Verastem Oncology RAS - Targeted Drug D

  2. Slide 2: Disclosures

    2 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 2 Disclosures ▪ I am an employee of Verastem Oncology ▪ I will be discussing investigational/off - label uses of VS - 6766 (RAF/MEK inhibitor) and defactinib (focal adhesion kinase inhibitor)

  3. Slide 3: More Complete Shutdown of RAS Pathway-Driven Tumor Growth Requires Addressing Multiple Resistance Mechanisms

    3 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 3 ▪ BRAF & MEK inhibitors can block Growth Factor - stimulated ERK signaling, but Cell Attachment can also stimulate ERK signaling through a FAK - dependent pathway (Slack - Davis, JCB 162 :281, 2003) ▪ GPCR - mediated activation of RhoA and YA

  4. Slide 4: More Complete Shutdown of RAS Pathway Requires Addressing Multiple Resistance Mechanisms

    4 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 RTK RAS RAF MEK ERK RhoA Growth factors β α Y397 Integrin FAK ECM SRC YAP Proliferation/Survival/Migration P • BRAF inhibition induces compensatory activation of pFAK 1 • MEK inhibition induces compensatory activation of pFAK preclinically and

  5. Slide 5: Defactinib reduces compensatory pFAK signal in KRAS mutant patients

    5 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 RTK RAS RAF MEK ERK RhoA Growth factors β α Y397 Integrin FAK ECM SRC YAP Proliferation/Survival/Migration P • In patients with KRAS mt tumors • VS - 6766 induced ↑ pFAK (Y397) as a potential resistance mechanism in the majority of patients • C

  6. Slide 6: VS-6766 is a Unique Small Molecule RAF/MEK Dual Inhibitor

    6 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 6 ▪ VS - 6766 inhibits both MEK & RAF kinase activities ▪ Most MEK inhibitors paradoxically induce MEK phosphorylation (pMEK) by relieving ERK - dependent feedback inhibition of RAF ▪ By inhibiting RAF phosphorylation of MEK, VS - 6766 has adva

  7. Slide 7: Defactinib (VS-6063) – Selective FAK Inhibitor

    7 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 7 Defactinib (VS - 6063) – Selective FAK Inhibitor p F A K ( Y 3 9 7 ; H S c o r e ) D a y 1 D a y 1 0 0 50 100 150 Pre - treatment Post - treatment pFAK (Y397; H - Score) * 03 - 315 OVARIAN CANCER: TUMOR BIOPSIES MESOTHELIOMA: TUMOR BIOPSIES F

  8. Slide 8: Combination of defactinib with VS-6766 or trametinib shows synergy in cell lines

    8 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 8 Combination of defactinib with VS - 6766 or trametinib shows synergy in KRAS mt and BRAF mt cell lines

  9. Slide 9: VS-6766 and FAK inhibitor combination leads to more robust anti-tumor efficacy in vivo

    9 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 9 VS - 6766 and FAK inhibitor combination leads to more robust anti - tumor efficacy in vivo Ovarian cancer model (TOV - 21g KRAS(G13C) mutant) NSCLC cancer model (H2122 KRAS(G12C) mutant) J. Paradis, AACR 2020 0 5 10 15 0 200 400 600 Tumor gro

  10. Slide 10: VS-6766 with Defactinib Shows Robust ORR in KRAS Mutant Low Grade Serous Ovarian Cancer

    10 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 10 • 9 pts with KRAS - G12 mutations • ORR = 56% (5/9); data still maturing • 4/5 PRs in pts who had previous MEKi • 2 pts on treatment for 2.5 yrs Cut - off August 17, 2020 VS - 6766 in Combination with Defactinib Shows Robust ORR with Durabi

  11. Slide 11: VS-6766 ± Defactinib Has a Confirmed 57% ORR in KRAS G12V NSCLC

    11 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 Preclinical evidence suggests combination with Defactinib may improve efficacy in KRAS G12V Activity of VS - 6766 as a single agent and in combo with Defactinib in KRAS G12V 1 additional confirmed PR in KRAS G12V mutant patient as of Mar - 202

  12. Slide 12: KRAS-G12C mutant tumor models differ in sensitivity to G12C inhibitors

    12 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 12 KRAS - G12C mutant tumor models differ in their sensitivity to G12C inhibitors MRTX849 100 mg/kg QD Hallin et al., Cancer Discovery 2020

  13. Slide 13: G12C inhibitors do not maintain sustained inhibition of pMEK & pERK

    13 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 13 G12C inhibitors do not maintain sustained inhibition of pMEK & pERK Densitometry of p - ERK normalized to GAPDH for blots; results represent an average of pERK across 8 cell lines Source: Ryan, M. B. et al. Clin. Cancer Res . (2020) • Susta

  14. Slide 14: G12C inhibition is synergistic with VS-6766 in KRAS G12C mutant NSCLC & CRC cell lines

    14 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 14 G12C inhibition is synergistic with VS - 6766 in KRAS G12C mutant NSCLC & CRC cell lines H2122: AMG 510 + VS - 6766 (RAF/ MEKi ) H2122: MRTX849 + VS - 6766 (RAF/ MEKi ) Synergy Score (Loewe model) Cell line Indication Sensitivity to G12C in

  15. Slide 15: G12C inhibition is synergistic with VS-6766 & defactinib in cell lines

    15 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 15 G12C inhibition is synergistic with VS - 6766 & defactinib in KRAS G12C mutant NSCLC & CRC cell lines AMG 510 + VS - 6766 AMG 510 + Defactinib SW837 (KRAS G12C CRC) AMG 510 + VS - 6766 AMG 510 + Defactinib Loewe Synergy Score H2122 (KRAS G1

  16. Slide 16: Addition of VS-6766 to AMG 510 increases depth & duration of p-ERK inhibition

    16 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 16 Addition of VS - 6766 to AMG 510 increases depth & duration of inhibition of p - ERK relative to AMG 510 across a panel of KRAS - G12C mt NSCLC cell lines p - ERK Actin AMG 510 - + - + - + - + VS - 6766 - - + + - - + + H2122 Moderately sens

  17. Slide 17: Addition of VS-6766 to AMG 510 increases inhibition of MEK/ERK signaling

    17 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 17 Addition of VS - 6766 to AMG 510 increases depth & duration of inhibition of MEK/ERK signaling relative to AMG 510 across a panel of KRAS - G12C mt NSCLC cell lines Concentrations Tested VS - 6766: 100 nM AMG 510: 100 nM H2122 Moderately se

  18. Slide 18: VS-6766 & FAKi potentiate AMG 510 efficacy in KRAS G12C NSCLC in vivo (H2122)

    18 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 18 ▪ VS - 6766 is more effective than trametinib at equal dose ▪ VS - 6766 or FAKi each potentiate the efficacy of AMG 510 ▪ Triple combination of AMG 510 + VS - 6766 + FAKi yields tumor regression in all mice Doses Tested Trametinib: 0.3 mg/k

  19. Slide 19: VS-6766 & FAKi potentiate AMG 510 efficacy in KRAS G12C NSCLC in vivo (H358)

    19 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 19 -100 0 100 200 300 400 Waterfall at Day 21 R e s p o n s e ( % c h a n g e f r o m b a s e l i n e ) Vehicle VS-6766 0.3mg/kg QD AMG 510 10mg/kg QD VS-6766 + AMG 510 VS-4718 50mg/kg BID VS-6766 + VS-4718 AMG 510 + VS-4718 VS-6766 + AMG 510

  20. Slide 20: Role of VS-6766 in Immuno-Oncology: upregulates antigen presentation machinery

    20 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 20 Role of VS - 6766 in Immuno - Oncology: VS - 6766 upregulates antigen presentation machinery (MHC - I) including b 2 microglobulin Cell Line Tumor type RAS/RAF mutation status A549 Lung KRAS mt G12S TOV21g Ovarian KRAS mt G13C SKMEL5 Melano

  21. Slide 21: VS-6766 enhances tumor growth inhibition when combined with anti-PD-1

    21 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 21 VS - 6766 enhances tumor growth inhibition when combined with anti - PD - 1 in the CT26 KRAS (G12D) syngeneic model -100 0 100 200 300 400 Response at Day 13 % C h a n g e i n T u m o r V o l u m e Vehicle VS-6766 anti-PD-1 VS-6766 + anti-P

  22. Slide 22: VS-6766 + anti-PD-1 induces long-lasting immune memory in CT26 model

    22 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 22 Combination of VS - 6766 + anti - PD - 1 induces long - lasting immune memory in the CT26 colorectal cancer model Tumor re - challenge: Tumor - free mice show durable immune memory Tumor - free mice show increase in effector memory T cells

  23. Slide 23: Combinations to Overcome Resistance Mechanisms: Conclusions

    23 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 23 VS - 6766 Combinations to Overcome Resistance Mechanisms: Conclusions ▪ Combination of dual RAF/MEK inhibitor VS - 6766 + FAKi may yield more complete RAS pathway shutdown o Synergy in cellular models with tumor regression in vivo o Clinica

  24. Slide 24: Combinations: Next Steps

    24 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 24 VS - 6766 Combinations: Next Steps ▪ Registration - directed phase II study of VS - 6766 + defactinib vs. VS - 6766 monotherapy in Low Grade Serous Ovarian Cancer ▪ Registration - directed phase II study of VS - 6766 + defactinib vs. VS - 6

  25. Slide 25: Acknowledgments

    25 CONFIDENTIAL. Do Not Distribute. © Verastem Inc. 2018 Acknowledgments Verastem Oncology ▪ Silvia Coma ▪ David Weaver Emory University ▪ C. Ronald Funk ▪ Edmund Waller Thanks for your attention! Acknowledgments Verastem Oncology ▪ Silvia Coma ▪ Sanjib Chowdhury ▪ Winnie Tam Royal Marsden Hospital

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