-100 0 100 200 300 % Change in Tumor Volume 0 9 10 -50 -100 0 100 200 300 % Change in Tumor Volume 20 30 40 50 60 0 500 1000 1500 Days Post Implant Mean Tumor Volume (mm 3 ) Control RMC-4630 20 mg/kg po q2d Cobimetinib 2.5 mg/kg po qd Combination Dosing start 10 20 30 0 500 1000 1500 Days Post-implant Mean Tumor Volume (mm 3 ) Dosing start Control RMC-4630 10 mg/kg po qd AMG 510 10 mg/kg po qd Combination 15 25 35 45 0 250 500 750 1000 Days Post Implant Mean Tumor Volume (mm 3 ) Dosing start 0 20 40 60 0 200 400 600 Days on Study % Change in Tumor volume 5 10 15 20 25 30 35 0 500 1000 1500 2000 Days Post Implant Mean Tumor Volume (mm 3 ) Dosing start ✱✱ Control RMC-4550 20 mg/kg po q2d Cobimetinib 2.5 mg/kg po qd Combination 10 15 20 25 30 35 0 1000 2000 3000 Days Post Implant Mean Tumor Volume (mm 3 ) Dosing start * SHP2 inhibition as the backbone of targeted therapy combinations for the treatment of cancers driven by oncogenic mutations in the RAS pathway JAM Smith 1 , M Singh 1 , RJ Nichols 1 , ES Koltun 2 , YC Yang 1 , , D Wildes 1 , C Stahlhut 1 , D Lee 3 , CJ Schulze 1 , D Reyes 1 , A Marquez 1 , G Lee 1 , S Li 4 , C Marcireau 5 , L Debussche 5 , MA Goldsmith 1, 2, 3, 4 , ZP Wang 3 , AL Gill 2 , SM Kelsey 1, 2, 3, 4 Departments of Biology 1 , Chemistry 2 , Non-Clinical Development and Clinical Pharmacology 3 , and Clinical Development 4 , Revolution Medicines, Redwood City, California; Sanofi Oncology Research 5 , 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: EGFR mut NSCLC Xenograft Models 2. Single Agent and Combinatorial Benefits of RMC-4630: KRAS G12C NSCLC 4. Single Agent and Combinatorial Benefits of RMC-4630: NF1 LOF and KRAS Amp 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 KRAS G12C • In combination with mutant-selective KRAS G12C 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 NF1 LOF , KRAS Amp and KRAS G12D or KRAS G12V 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 KRAS G12C both in the clinic and preclinical models 1, 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 KRAS G12D and KRAS G12V , NF1 LOF , KRAS Amp or BRAF Class3 , 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 systems 4, 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 References 1. Nichols et al., Nat Cell Biol. 2018 20(9):1064-1073 2. Ou et al. AACR-IASCLC 2020 3. Clinical Trials.Gov: NCT03634982 4. Quintana et al., 2020 Cancer Research 10.1158/0008-5472 5. Shifrin et al., 2020 AACR A7744 P2837 6. Planchard et al., Annals Oncology 26: 2073–2078, 2015 Acknowledgements: Jingjing Jiang for expert input into design and execution of in vivo pharmacology models CRO support: WuXi AppTec (Suzhou, China); Champions Oncology (Maryland, USA); Charles River Laboratories/Oncotest Gmbh (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 Monotherapy 2, 3 Disease Control Rate: NSCLC KRAS mut 12/18 (67%) NSCLC KRAS G12C 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 bar N = number of regressions >10% at end of study; 10 mice/group Clinical Preclinical NCI-H358 KRAS G12C NSCLC Xenograft • All treatments were well-tolerated RMC-4630 (PO) PK/PD in vivo RMC-4630 anti-tumor activity in vivo NCI-H358 KRAS G12C NSCLC xenograft NCI-H358 KRAS G12C NSCLC xenograft Compound RMC-4630 RMC-4550 1 Tool Compound SHP2 biochemical potency (IC 50 , nM) 1.29 1.52 RAS pathway suppression (pERK IC 50 , nM) NCI-H358 KRAS G12C 20 28 Anti-proliferative activity (3D CTG IC 50 , nM) NCI-H358 KRAS G12C NCI-H1975 EGFR L858R/T790M 32 25 43 63 Selectivity - Phosphatase panel - Kinase panel > 3,000 > 3,000 > 3,000 > 3,000 SHP2 inhibitors - in vitro profile KRAS G12V Pancreatic KRAS G12V NSCLC NCI-H441 Capan-2 KRAS G12D Pancreatic KP-4 HPAC LUN #150, NSCLC CO-04-0004, CRC STO#332 WT KRAS Amp (copy number = 4) 10 5 KRAS Amp NF1 LOF Compound Parental EGFR L858R/T790M (IC 50 , nM) Transfected EGFR L858R/T790M/C797S (IC 50 , nM) RMC-4630 265 218 to 557 Osimertinib 8 30 to 2616 EGFR L858R/T790M/C797S in vitro EGFR L858R/T790 /MET Amp NSCLC PDX 6 Osimertinib-Sensitive Osimertinib-Resistant NCI-H1975 EGFR L858R/T790M NSCLC CDX Anti-proliferative activity (2D CTG) in parental NCI-H1975 or cells transfected with human EGFR L858R/T790M/C797S under six different promoters N= 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 bar N = 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 • All treatments were well-tolerated • All treatments were well-tolerated 0 10 20 30 0 200 400 600 800 Days on Study Mean Tumor Volume (mm 3 ) Control RMC-4630 10 mg/kg po qd Cobimetinib 2.5 mg/kg po qd Combination • 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 NF1 LOF PDX models (n=55) • Tumor regressions in 25% (23/93) of responders (93/166 mice) N= 10 mice/group 40 80 120 160 0 500 1000 1500 2000 2500 Days Post Implant Mean Tumor Volume (mm 3 ) Control Osimertinib 5 mg/kg po qd RMC-4630 30 mg/kg po qd Combination Initial tumor volume 256 mm 3 Dosing stopped 40 80 120 160 0 400 800 Days Post Implant -100 Dosing stopped 40 80 120 160 0 400 800 -100 Days Post-implant Dosing stopped 40 80 0 100 Days Post Implant -100 -50 40 80 0 100 -50 -100 Days Post-implant % Change in Tumor Volume Osimertinib Combination 1 2 4 8 10 16 24 1 10 100 1000 10000 0 20 40 60 80 100 Time post-dose (hours) Unbound Plasma Concn (nM) % Inhibition pErk/tErk Relative to Control 10 mg/kg 30 mg/kg -9 -8 -7 -6 -5 0 25 50 75 100 Log Molar [RMC-4630] plasma, unbound % Inhibition of pERK/tERK relative to control EC 50 = 27 nM Time post dose 2h 8h 16h 24h Time post second dose (bid) 2h 8h 0 10 20 30 -100 0 100 200 300 Days on Study % Change in Tumor Volume Control RMC-4630 30 mg/kg po qd Dose/ schedule www.revolutionmedicines.com A5307 P1943 Questions? [email protected] 0 10 20 30 0 500 1000 1500 2000 2500 Days on Study Mean Tumor Volume (mm 3 ) * *** * # *** *** *** * *** 0 5 10 15 20 25 30 0 400 800 1200 1600 Days Post Implant Mean Tumor Volume (mm 3 ) Control RMC-4630 10 mg/kg po qd RMC-4630 30 mg/kg po qd Dosing start *** * 0 5 10 15 20 25 0 1000 2000 3000 Days Post Implant Mean Tumor Volume (mm 3 ) Control Osimertinib 25 mg/kg po 5d on/2d off RMC-4630 30 mg/kg po qd