Johanna Bendell1, Susanna V. Ulahannan2, Marianna Koczywas3, Julie Brahmer4, Anna Capasso5, S. Gail Eckhardt5, Michael S. Gordon6, Caroline Mccoach7, Misako Nagasaka8, Kimmie Ng9, Jose Pacheco10, Jonathan W. Riess11, Alexander I Spira12, Conor Steuer13; Richa Dua14, Suman Chittivelu14, Serena Masciari 15, Zhengping Wang14, Xiaolin Wang14, Sai-Hong I. Ou16

1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA; 2Sarah Cannon Research Institute/University Of Oklahoma, Oklahoma City, USA; 3City Of Hope Medical Center, Duarte, USA; 4Johns Hopkins University, Baltimore, USA; 5University Of Texas, Austin, USA; 6HonorHealth Research Institute, Scottsdale, USA; 7University Of California, San Francisco, USA; 8Karmanos Cancer Center, Detroit, USA; 9Dana-Farber Cancer Institute, Boston, USA; 10University Of Colorado, Denver, USA; 11University Of California, Davis, USA; 12US Oncology, Fairfax, USA; 13Emory University, Atlanta, USA; 14Revolution Medicines, Inc., Redwood City, USA; 15Sanofi, Cambridge, USA; 16University Of California, Irvine, USA.

Intermittent dosing of RMC-4630, a potent, selective inhibitor of SHP2, combined with the MEK inhibitor cobimetinib, in a phase 1b/2 clinical trial for advanced solid tumors with activating mutations of RAS signaling

Disclosure Information32nd EORTC-NCI-AACR| October 24-25, 2020 | VIRTUAL

Johanna Bendell, MDI have the following financial relationships to disclose:

Research Funding (All to Institution)

• Gilead, Genentech / Roche, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, EMD Serono, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRex, Forty Seven, AbbVie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, Boston Biomedical, Ipsen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude Oncology, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, Imclone, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Seattle Genetics, TempestTx, Shattuck Labs, Synthorx, Inc., Revolution Medicines, Inc., Bicycle Therapeutics, Zymeworks, Relay Therapeutics, Scholar Rock, NGM Biopharma, Stemcentrx, Beigene, CALGB, Cyteir Therapeutics, Foundation Bio, Innate Pharma, Morphotex, Ongologie, NuMab, AtlasMedx, Treadwell Therapeutics, IGM Biosciences, Mabspace, Hutchinson MediPharma

Consulting /Advisory Role (All to Institution)

• Gilead, Genentech / Roche, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, ARMO, Ipsen, Merrimack, Oncogenex, FORMA, Arch Oncology, Prelude Therapeutics, Phoenix Bio, Cyteir, Molecular Partners, Innate, Torque, Tizona, Janssen, Tolero, TD2 (Translational Drug Development), Amgen, Seattle Genetics, Moderna Therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, Agios, Bicycle Therapeutics, Relay Therapeutics, Evelo, Pfizer, Piper Biotech, Samsung Bioepios

Food/Beverage/ Travel

• Gilead, Genentech / Roche, BMS, Lilly, Merck, MedImmune, Celgene, Taiho, Novartis, OncoMed, BI, ARMO, Ipsen, Oncogenex, FORMA

- and -I will discuss the following off label use and/or investigational use in my presentation: ongoing study of RMC-4630-02.

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RMC-4630: A Potent Allosteric SHP2 Inhibitor

• RMC-4630 is a potent, selective, orally bioavailable, allosteric inhibitor of SHP2, a shared signaling node that regulates the RAS signaling pathway1

• RMC-4630 as a single agent has shown signs of clinical activity in KRASMUT NSCLC and NF1LOF

tumors and improves tumor immune cell profile2,3,4

• Intermittent dosing of RMC-4630 as a single agent optimizes pharmacokinetic profile (peak and trough concentrations) for anti-tumor activity and acceptable tolerability in patients2,3

• Multiple rational combination applications of RMC-4630 supported by preclinical data4,5,6Cell Growth, Survival,

& Cancer

SHP2

RAS

MEKERK

SOS1

Multiple Receptor Tyrosine Kinases (RTKs)

4EBP1mTORC1

31Nichols et al., Nat Cell Biol., 2018; 2S. Kelsey RAS Targeted Drug Development Sept 16th, 2020; 3Ou et al., IASLC-AACR 2020; 4Quintana et al., 2020 Cancer Res.; 5Lee et al., AACR 2019; 6Smith et al., AACR 2020

Combining Upstream and Downstream Pathway Inhibition with SHP2 and MEK Inhibition for ‘Clamping’ KRASMUT Tumor Drivers

Cell Growth, Survival, & Cancer

SHP2

KRASMUT

MEKERKX

X

20 30 40 50 600

500

1000

1500

Days Post Implant

Mea

n Tu

mor

Vol

ume

(mm

3 )

ControlRMC-4630 20 mg/kg po q2dCobimetinib 2.5 mg/kg po qdCombination

Dosingstart

RMC-4630 (SHP2 inhibitor) + cobimetinib (MEK inhibitor)

NCI-H441 (NSCLC, KRASG12V)

Smith et al, AACR 2020

4

Phase 1b Dose Escalation Design

Key Eligibility Criteria

• Advanced solid tumors with selected RAS pathway mutations

• Received prior standard of care therapies

• ECOG 0-1• No active brain metastases

Schedule 1Intermittent RMC-4630 D1D4 Daily cobimetinib 21/7

Primary Objective

• Determine recommended phase 2 dose and schedule (RP2DS) for RMC-4630 + cobimetinib

Schedule 2Intermittent RMC-4630 D1D2 Daily cobimetinib 21/7

Schedule 3:Intermittent RMC-4630 D1D2 Intermittent cobimetinib D1D2

1a RMC-4630 80 mg cobimetinib 20 mg

1c RMC-4630 140 mg cobimetinib 20 mg

1b RMC-4630 80 mg cobimetinib 40 mg

2RMC-4630 140 mg cobimetinib 20 mg

3a RMC-4630 140 mg cobimetinib 60 mg

3b RMC-4630 140 mg cobimetinib 40 mg

ClinicalTrials.gov Listing: NCT039891155

Patient Baseline Characteristics

Schedule Dose Levels All (N=49)

Intermittent RMC-4630 D1D4Daily cobimetinib 21/7

1a 80 mg RMC-463020 mg cobimetinib 8

261b 80 mg RMC-463040 mg cobimetinib 6

1c 140 mg RMC-463020 mg cobimetinib 12

Intermittent RMC-4630 D1D2 Daily cobimetinib 21/7 2 140 mg RMC-4630

20 mg cobimetinib 7 7

Intermittent RMC-4630 D1D2 Intermittent cobimetinib D1D2

3a 140 mg RMC-463060 mg cobimetinib 7

163b 140 mg RMC-4630

40 mg cobimetinib 9

Baseline Characteristics All (N=49)

Age, median (range), yrs 57 (33 - 83)Male, (%) 25 (51.0%)Cancer Type, (%)

CRC 20 (40.8%)Lung 16 (32.7%)Pancreatic 10 (20.4%)Other 3 (6.1%)*

ECOG, (%)0 24 (49.0%)1 25 (51.0%)

Median prior cancer therapies, (range) 4 (1-9)

6Data as of 9/21/20* N for “Other” cancer type was corrected from 13 originally shown to 3, correcting a clerical error; (%) changed accordingly

Common Adverse Events Related to Either RMC-4630 or Cobimetinib

Data as of 9/21/20

Related AEs reported in ≥15% of patients for either cobimetinib Schedule

Intermittent RMC-4630£ + daily cobimetinib 21/7

(N=33)

Intermittent RMC-4630∑ +intermittent cobimetinib

(N=16)

Any Grade Grade ≥3 Any Grade Grade ≥ 3

Diarrhea 21 ( 63.6%) 3 ( 9.1%) 7 ( 43.8%) 1 ( 6.3%)Thrombocytopenia* 12 ( 36.4%) 3 ( 9.1%) 5 ( 31.3%) 1 ( 6.3%)Edema** 12 ( 36.4%) 0 2 ( 12.5%) 0Rash*** 8 ( 24.2%) 3 ( 9.1%) 4 ( 25.0%) 0Anemia**** 7 ( 21.2%) 1 ( 3.0%) 3 ( 18.8%) 0Blood creatine phosphokinase 7 ( 21.2%) 1 ( 3.0%) 2 ( 12.5%) 1 ( 6.3%)Fatigue 7 ( 21.2%) 0 2 ( 12.5%) 0Vomiting 5 ( 15.2%) 0 4 ( 25.0%) 0Aspartate aminotransferase (AST) 5 ( 15.2%) 0 3 ( 18.8%) 1 ( 6.3%)Nausea 2 ( 6.1%) 0 6 ( 37.5%) 0Dyspnea 5 ( 15.2%) 0 1 ( 6.3%) 0Retinopathy***** 1 ( 3.0%) 0 4 ( 25.0%) 1 ( 6.3%)Alanine aminotransferase (ALT) 0 0 3 ( 18.8%) 0

* Includes platelet count decrease; ** Company-defined MedDRA Query (CMQ) includes eyelid edema, face edema, generalized edema, lip edema, edema, edema peripheral, periorbital edema, and peripheral swelling. *** Includes rash, rash maculo-papular, and rash pustular; **** Includes hemoglobin decrease; ***** Includes symptoms associated with MEKi retinopathy including vision blurred and visual impairment

7£ RMC-4630 doses tested with daily cobimetinib: 80 mg D1D4 (n=14) and 140 mg D1D4 (n=19)∑ RMC-4630 dose tested with intermittent cobimetinib: 140 mg D1D2

Preliminary Data Suggest Acceptable Tolerability with RMC-4630 140 mg D1D2 + Cobimetinib 40 mg D1D2

Data as of 9/21/20

Intermittent RMC-4630£ + daily cobimetinib£ 21/7

(N=33)

Cohort 3a RMC-4630 140 mg D1D2 +cobimetinib 60 mg D1D2

(N=7)

Cohort 3b RMC-4630 140 mg D1D2 +cobimetinib 40 mg D1D2

(N=9)

With related§ grade ≥3 AEs 14 (42.4%) 3 (42.9%) 2 (22.2%)

With AEs leading to dose interruption¥ 17 (51.5%) 6 (85.7%) 4 (44.4%)

With AEs leading to dose reductions¥ 3 (9.1%) 4 (57.1%) 0

With AEs leading to dose discontinuation¥ 7 (21.2%) 1 (14.3%) 0

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£ RMC-4630 and cobimetinib doses included: RMC-4630 80 mg D1D4 + cobimetinib 20 mg 21/7 (n=8), RMC-4630 80 mg D1D4 + cobimetinib 40 mg 21/7 (n=6), RMC-4630 140 mg D1D4 + cobimetinib 20 mg 21/7 (n=12), and RMC-4630 140mg D1D2 + cobimetinib 20 mg 21/7 (n=7)

§ Related to either RMC-4630 or cobimetinib¥ Dose interruption, reduction, or discontinuation of either RMC-4630 or cobimetinib

pERK EC50 in NCI-H358 KRASG12C/WT NSCLC Xenograft Model

0 24 48 72 96 120 144 168

10

100

1000

Time (h)

Tota

l Pla

sma

Con

c (n

M)

RMC-4630 140 mg D1D2-Steady StateRMC-4630 140 mg D1D2 -Week 1

0 24 48 72 96 120 144 168

10

100

1000

Time (h)

Tota

l Pla

sma

Con

c (n

M)

Cobimetinib 40 mg D1D2-Steady StateCobimetinib 40 mg D1D2-Week 1

EC50

EC50

RMC-4630 Cobimetinib

Intermittent Dosing (D1D2) of RMC-4630 and Cobimetinib Exceeds Target Plasma Exposures

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Best Change in Tumor Burden from Baseline in KRASMUT Colorectal Cancer

RMC-4630 140 mg D1D2

140 mg D1D2

140 mg D1D2

140 mg D1D2

140 mg D1D4

140 mg D1D4

140 mg D1D2

cobimetinib 20 mg daily 60 mg D1D2 60 mg D1D2 20 mg daily 20 mg daily 20 mg daily 60 mg D1D2

Cha

nge

from

bas

elin

e (%

)G12S

G12VG12D

Patients treated with RMC-4630 140mg twice weekly¥100

50

0

-50

¥Data presented for the 7 patients with KRAS mutant colorectal cancer treated with RMC-4630 140 mg twice weekly and varying cobimetinib dose and schedules (table below) out of the efficacy evaluable population (N=8) defined as patients with baseline scan and at least one post-baseline scan, or who died, or had clinical progression prior to first post-baseline scan

*Unconfirmed PR

SD*

10Data as of 9/21/20

Tumor Images for Patient with KRASG12D

Colon Cancer

• 53-year-old white female• KRASG12D colorectal cancer• Two prior therapies

• FOLFOX + Avastin • FOLFIRI + Avastin

• RMC-4630 140mg D1D2 + cobimetinib 60mg D1D2

• 30% reduction in tumor burden at end of cycle 2; 25% reduction at end of cycle 4 – unconfirmed PR

• PD at 6 months

Baseline Scan

Left pelvic peritoneal nodule 2.0 cm x 1.5 cm

Left pelvic peritoneal nodule 1.4 cm x 1.0 cm

End Cycle 2 Scan

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Conclusions

• Preclinical studies show that combined SHP2 and MEK inhibition has activity against RAS-addicted tumors for which no RAS mutant-directed therapy is currently available

• The SHP2 inhibitor RMC-4630 can be administered to patients in combination with the MEK inhibitor cobimetinib using a dual intermittent dosing strategy

• Intermittent RMC-4630 plus intermittent cobimetinib has acceptable tolerability at doses that exceed target plasma exposures based on anti-tumor activity in preclinical models of RAS-pathway driven cancers

• Preliminary evidence of anti-tumor activity in KRASMUT colorectal cancer has been observed

• Phase 2 testing of a recommended phase 2 dose and schedule is expected to start this year

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Acknowledgements

• We would like to thank the patients and their families, physicians, and study teams for participating in this study

• This study is conducted by Revolution Medicines, Inc. under its collaboration with Sanofi (ClinicalTrials.gov identifier: NCT03989115)

• Cobimetinib is provided by Genentech under a clinical collaboration agreement

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