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SHP2 inhibition as the backbone of targeted therapy combinations for the treatment of cancers driven by oncogenic mutations in the RAS pathway

JAM Smith1, M Singh1, RJ Nichols1, ES Koltun2, YC Yang1, , D Wildes1, C Stahlhut1, D Lee3, CJ Schulze1, D Reyes1, A Marquez1, G Lee1, S Li4, C Marcireau5, L Debussche5, MA Goldsmith1, 2, 3, 4, ZP Wang3, AL Gill2, SM Kelsey1, 2, 3, 4

Departments of Biology1, Chemistry2, Non-Clinical Development and Clinical Pharmacology3, and Clinical Development4, Revolution Medicines, Redwood City, California; Sanofi Oncology Research5, Vitry, France

1. RMC-4630 is a Potent, Selective and Orally Bioavailable Allosteric Inhibitor of SHP2

3. Single Agent and Combinatorial Benefits of RMC-4630: EGFRmut NSCLC Xenograft Models

2. Single Agent and Combinatorial Benefits of RMC-4630: KRASG12C NSCLC

4. Single Agent and Combinatorial Benefits of RMC-4630: NF1LOF and KRASAmp Xenograft Models

Conclusions• RMC-4630 is a potent, selective and orally bioavailable SHP2 inhibitor which has

shown preliminary signs of clinical activity in patients with NSCLC harboring KRAS mutations, particularly KRASG12C

• In combination with mutant-selective KRASG12C or EGFR inhibitors RMC-4630 can suppress oncoprotein-mediated signaling and adaptive resistance in preclinical models

• SHP2 inhibition alone, or in combination with targeted inhibition of another pathway node such as MEK, exhibited anti-tumor activity in mouse xenograft models with RAS pathway oncogenic drivers, such as NF1LOF, KRASAmp and KRASG12D or KRASG12V for which there are currently no mutant-selective inhibitors

• Translation of these preclinical findings into clinical benefit could position RMC-4630, an investigational therapeutic agent, as a backbone of targeted therapy combinations for patients bearing cancers with diverse oncogenic mutations in the RAS pathway

SHP2 is a Frontier Target in Oncology• Direct targeting of oncogenic mutations in the RAS pathway is a beneficial therapeutic

strategy for patients with cancers with these mutations. Mutant-selective inhibitors offer a wide therapeutic window but are ultimately limited by emergence of drug resistance

• Escape from mutant-selective inhibitors frequently involves activation of wild-type signaling nodes, including hyperactivation of receptor tyrosine kinases (RTKs), that lead to robust re-activation of the RAS pathway

• SHP2 (PTPN11) is a phosphatase that functions as a convergent node downstream of multiple RTKs to regulate RAS activation. We have recently shown that single agent inhibition of SHP2 has anti-tumor activity in tumors harboring KRASG12C both in the clinic and preclinical models1, 2

• In the context of adaptive resistance to mutant-selective inhibitors, SHP2 inhibition has the potential to suppress oncoprotein-mediated signaling and adaptive signaling driving escape from therapy

• For many RAS pathway oncogenic drivers, including KRASG12D and KRASG12V, NF1LOF, KRASAmp or BRAFClass3, mutant-selective inhibitors are not currently available. Here, a combination strategy simultaneously targeting nodes both up- and down-stream of the oncoprotein (“oncoprotein clamping”) can drive tumor growth inhibition

• Here we show that SHP2 inhibitors have the potential to become the backbone of targeted therapy combinations across the spectrum of RAS-dependent tumors

• We have also shown that SHP2 inhibition, alone or in combination, can promote anti-tumor immunity in preclinical models via effects on the innate and adaptive immune systems4, 5. These effects may influence the overall profile of a SHP2 inhibitor

Therapeutic Combinations for RAS Driven Tumors: Mutant-selective and RAS Pathway Node Inhibitors

5. Combination Benefit for SHP2 and MEK Inhibition in Other KRAS-Mutant Xenograft Models

References1. Nichols et al., Nat Cell Biol. 2018 20(9):1064-10732. Ou et al. AACR-IASCLC 20203. Clinical Trials.Gov: NCT036349824. Quintana et al., 2020 Cancer Research 10.1158/0008-54725. Shifrin et al., 2020 AACR A7744 P28376. Planchard et al., Annals Oncology 26: 2073–2078, 2015

Acknowledgements:Jingjing Jiang for expert input into design and execution of in vivo pharmacology modelsCRO support: WuXi AppTec (Suzhou, China); Champions Oncology (Maryland, USA); Charles River Laboratories/OncotestGmbh (Freiburg, Germany); Genendesign (Shanghai, China); Xentech (Evry, France); TD2 (Arizona, USA)

Best Change in Tumor Burden from Baseline NSCLC with any KRAS Mutation for RMC-4630 Monotherapy2, 3

Disease Control Rate: NSCLC KRASmut 12/18 (67%) NSCLC KRASG12C 6/8 (75%)

Data presented for efficacy evaluable population (N = 18) defined as patients with baseline and at least one post-baseline scan or who died or had clinical progression prior to first post-baseline scan.Four patients are not represented in this figure: 2 patients had clinical progression prior to first scan, 1 patient did not have measurements for one of the target lesions but progressed due to new lesion, and 1 patient had missing tumor measurements in the database at the time of data extract.• Confirmed PR # Unconfirmed PR

✘ ✘

Each animal represented as separate barN = number of regressions >10% at end of study; 10 mice/group

Clinical Preclinical NCI-H358 KRASG12C NSCLC Xenograft

• All treatments were well-tolerated

RMC-4630 (PO) PK/PD in vivo

RMC-4630 anti-tumor activity in vivoNCI-H358 KRASG12C NSCLC xenograft

NCI-H358 KRASG12C NSCLC xenograftCompound RMC-4630 RMC-45501

Tool Compound

SHP2 biochemical potency (IC50, nM) 1.29 1.52

RAS pathway suppression (pERK IC50, nM)NCI-H358 KRASG12C 20 28

Anti-proliferative activity (3D CTG IC50, nM)NCI-H358 KRASG12C

NCI-H1975 EGFRL858R/T790M3225

4363

Selectivity- Phosphatase panel- Kinase panel

> 3,000> 3,000

> 3,000> 3,000

SHP2 inhibitors - in vitro profile

KRASG12V Pancreatic

KRASG12V NSCLCNCI-H441

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KP-4 HPAC

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CO-04-0004, CRC

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Osimertinib 8 30 to 2616

EGFRL858R/T790M/C797S in vitro

EGFRL858R/T790/METAmp NSCLC PDX6

Osimertinib-Sensitive Osimertinib-ResistantNCI-H1975 EGFRL858R/T790M NSCLC CDX

Anti-proliferative activity (2D CTG) in parental NCI-H1975 or cells transfected with human EGFRL858R/T790M/C797S under six different promotersN= 12-15 mice/group

One-way Anova: * p< 0.05; *** p < 0.0001

N = 3 mice/group; graphs show tumor volume data for individual mice, expressed as % of initial tumor volume at time of study start.

N = 12 mice/group; graphs in B show tumor volume data for individual animals shown in A, expressed as % change in tumor volume from time of study start

A

B

Each animal represented as separate barN = number of regressions >10% at end of study; 10 mice/group

Ordinary one-way ANOVA, * p< 0.01, ** p< 0.05, ***p<0.001

LUN #352

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• All treatments were well-tolerated

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• PDX models of tumors bearing NF1 mutations predicted to result in loss of function (LOF): deletions, insertions, premature stops, truncations

• Tumor growth inhibition in 62% of NF1LOF PDX models (n=55)• Tumor regressions in 25% (23/93) of responders (93/166 mice)

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www.revolutionmedicines.com

A5307P1943

Questions?jan@revmed.com

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