Therapeutic Options for Patients with BRAF-mutant Metastatic Colorectal Cancer

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1 Therapeutic Options for Patients with BRAF-mutant Metastatic Colorectal Cancer Axel Grothey, M.D., Professor of Oncology, Clinical and Translational Science Division of Medical Oncology Mayo Clinic, Rochester, MN, USA March 3, 2018

2 Global Incidence of Colorectal Cancer Population Estimates 2 CRC is 3 rd most common cancer in the U.S., with approximately 135,000 new cases and nearly 50,000 deaths from the disease projected in 2017 Annual CRC Mortality* Annual Colorectal Cancer Mortality 160, , , ,000 80,000 60,000 40,000 20,000 0 US EU Japan * Based on SEER and GLOBOCAN epidemiology reports

3 BRAF mutant Colorectal Cancer Poor prognostic marker 3 CRC Mutational Subgroups BRAFm ~10-15% BRAF WT ~85-90% BRAF V600E mutations account for >95% of all BRAF mutations in colon cancer BRAF mutation status a strong predictor of overall survival Median survival with standard cytotoxic chemotherapy approximately one-half to onethird that of patients with BRAF wild-type tumors Management guidelines in US and EU recommend testing of all CRC tumors for BRAF mutation de Roock et al. Lancet Oncol. 2010;11: Van Cutsem E, et al. J Clin Oncol. 2011;29: Di Nicolantonio F, et al. J Clin Oncol. 2008;26: Richman SD, et al. J Clin Oncol. 2009;27: NCCN Guidelines Version Colon Cancer ESMO consensus guidelines for the management of patients with metastatic colorectal cancer 2016

4 BRAF mutant Colorectal Cancer First-line metastatic setting 4 Although promising outcomes with highly aggressive regimen consisting of 5FU, Leucovorin, oxaliplatin, and Irinotecan (FOLFOXIRI) and bevacizumab, median survival still less than half of patients with BRAF wild-type tumors Median Overall Survival (months) in Patients Treated with FOLFOXIRI plus Bevacizumab BRAF mutant subgroup 19.1 BRAF wild-type subgroup 41.7 Cremolini C, et al. Lancet Oncol. 2015;16(13):

5 BRAF mutant Colorectal Cancer First-line metastatic setting 5 Although promising outcomes with highly aggressive regimen consisting of 5FU, Leucovorin, oxaliplatin, and Irinotecan (FOLFOXIRI) and bevacizumab, median survival still less than half of patients with BRAF wild-type tumors Median Overall Survival (months) in Patients Treated with FOLFOXIRI plus Bevacizumab BRAF mutant subgroup 19.1 BRAF wild-type subgroup 41.7 Cremolini C, et al. Lancet Oncol. 2015;16(13):

6 Observed Overall Survival from Phase 2 and Certain Separate Historical Benchmarks in 2nd Line+ BRAFm CRC 6 Median OS in BRAFm mcrc Studies Median OS in Months encorafenib + cetuximab 6 n = 50 Cetuximab+ irinotecan 7 n=50 cetuximab + chemo 1 n = 24 cetuximab + chemo 2 n = 12 FOLFIRI 3 2 nd Line n = 23 FOLFIRI + panitumamab 3 2 nd Line n = 22 cetuximab + chemo 4 n = 22 cetuximab + irinotecan 5 n = De Roock et al., Lancet Oncol, Ulivi et al., J Transl Med Peeters et al., ASCO Saridaki et al., PLoS One Loupakis et al., Br J Cancer Tabernero et al., ASCO Kopetz et al., ASCO 2017

7 Observed ORR and PFS from Phase 2 and Certain Separate Historical Benchmarks in 2nd Line+ BRAFm CRC 7 ORR & PFS in BRAFm mcrc 25% 20% 22% ORR PFS 15% 10% 5% 4% 8% 6% Months % Encorafenib +Cetuximab 1 Cetuximab + irinotecan 5 Cetuximab + Chemo 2 Irinotecan 3 0 Encorafenib +Cetuximab 1 Cetuximab + irinotecan 5 Cetuximab + Chemo 2 FOLFIRI 4 2 nd Line Panitumumab + FOLFIRI 4 2 nd Line 1. Tabernero et al., ASCO De Roock et al., Lancet Oncol, Seymour et al., Lancet Oncol, 2013 (supplementary appendix) 4. Peeters et al., ASCO Kopetz et al., ASCO 2017

8 Rationale for Combining a MEKI, BRAFi and EGFRi in BRAF mutant CRC Efficacy of Binimetinib, Encorafenib and Cetuximab in a Human BRAF-mutant CRC Model 8 Tumor Volume (mm3) Mean ± SEM Vehicle encorafenib (20 mg/kg, po, qd 21) + cetuximab (20 mg/kg, ip, 2qw x 10) encorafenib (20 mg/kg, po, qd 21) + binimetinib (3.5 mg/kg po, bid 21) + cetuximab (20 mg/kg, ip, 2qw x 10) Treatment Day Encorafenib + Cetuximab Encorafenib + Binimetinib + Cetuximab Change in Tumor Volume vs. Baseline (%) Change in Tumor Volume vs. Baseline (%) Individual Animal Number -50 Individual Animal Number

9 Cross-Study Comparison: Combination Therapies Do Not Inhibit perk in CRC to Level Seen in Melanoma 9 Colorectal Melanoma BRAF D D -- D D MEK -- T T T -- EGFR P -- P P -- D=Dabrafenib; P=panitumumab; T=trametinib Atreya et al ASCO 16, Updated Corcoran et al ESMO 16 Clinical efficacy (objective response rates) 10% 1 12% 2 0% 1 21% 1 52% 3 1 Corcoran et al. ESMO 2016; 2 Corcoran et al. J Clin Oncol 2015; 3 Taflinar US label

10 Clinical Activity and Safety Profile of Combination Regimens in BRAF Mutant Metastatic Colorectal Cancer 10 Number of Prior Regimens for Advanced Disease Cetuximab + Encorafenib 1 (n=50) Doublet Therapy Panitumumab + Dabrafenib 2 (n=20) Cetuximab + Vemurafenib + Irinotecan 3 (n=49) Triplet Therapy Panitumumab + Dabrafenib + Trametinib 2 (n=91) 0, n (%) 0 4 (20) 3 (6)* 21 (23) 1, n (%) 21 (42) 8 (40) 27 (55) 27 (30) 2, n (%) 20 (40) 7 (35) 19 (39) 33 (36) 3, n (%) 9 (18) 1 (5) 0 10 (11) ORR (CR + PR) 22% 10% 16%** 21% mpfs, months *Failed adjuvant within 6 months;**confirmed and unconfirmed responses; NR-not reported. CR=complete response; mos=median overall survival; mpfs=median progression-free survival; NR=not reported; ORR=objective response rate; PR=partial response. 1. Tabernero et al. J Clin Oncol. 2016;34:abstr Corcoran et al. Ann Oncol. 2016;27:abstr 455O. 3. Kopetz et al. J Clin Oncol. 2017;35:abst 3505.

11 BRAF V600E Mutations and defective DNA Mismatch Repair 11 In advanced CRC, the overlap of BRAF mutations with a defective DNA mismatch repair system, exhibited as microsatellite instable (MSI), is relatively rare Prospectively collected data in BRAF-mutant mcrc patients showed the prevalence of MSI-High (MSI-H) to be14% of 106 patients in a recent Phase 1b/2 trial (NCT ) (Array, data on file) and 18% of 72 patients in a recent Southwestern Oncology Group (SWOG) randomized phase 2 study Lochead et al. J Natl Cancer Inst. 2013;105: Kopetz et al., J Clin Oncol. 2017;35 (suppl; abstr 3505)

12 Conclusion 12 BRAF V600E is found in 10-15% of mcrc, is associated with poor prognosis and represents an area of unmet medical need No effective standard-of-care therapies available, especially after 1 st -line therapy Pre-clinical and clinical data suggests near complete inhibition of MAPK signaling is most effective in treating BRAF-mutant tumors Based on early clinical data with BRAF inhibitor combinations and with encorafenib and binimetinib, in particular, the BEACON CRC trial has the potential to establish the standard-of-care in BRAF V600E mcrc

13 Phase 3 BRAF-mutant Colorectal Cancer Study Design Potential to Establish MEK + BRAF + EGFR Combination as New Standard of Care 13 Currently Enrolling SAFETY LEAD-IN COMPLETE Safety and tolerability will be assessed in patients receiving binimetinib, encorafenib and cetuximab for the treatment of BRAF V600E-mutant metastatic colorectal cancer n=30 Note: Japan Safety Lead-in will be conducted in 6 patients RANDOMIZED PORTION Patient population BRAF V600E mutant 1-2 prior regimens in metastatic setting n=615 Randomization Triplet Therapy Binimetinib + Encorafenib + Cetuximab n=205 Doublet Therapy Encorafenib + Cetuximab n=205 Control Arm FOLFIRI + Cetuximab or irinotecan + Cetuximab n=205 DISEASE PROGRESSION DISEASE PROGRESSION DISEASE PROGRESSION Continued follow-up for evaluation of OS Primary Endpoint: Overall survival (OS) of the triplet therapy compared to the control arm. Secondary Endpoints: Address efficacy of the doublet therapy compared to the control arm, and the triplet therapy compared to the doublet therapy. Other Secondary Endpoints: Progression-free survival (PFS), objective response rate (ORR), duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial will be conducted at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.