BRAF mutant mCRC patients – What would you recommend? FOLFIRINOX/Bev Joleen Hubbard, MD Mayo Clinic, Rochester

Tumor cell proliferation BRAF Mutations in CRC BRAF is primary effector of KRAS signaling BRAF mutations: Occur most frequently in exon 15 (V600E) Found in 4%-14% of patients with CRC Mutually exclusive with KRAS mutations EGF Tumor Cell P P Ras P P Raf MEK Tumor cell proliferation and survival Erk Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol. 2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.

PETACC-3: Survival after relapse according to BRAF mutation status BRAF wildtype Median OS: BRAF mut: 7.49 m BRAF wt: 25.2 m (p = 1.9e-11) Tejpar et al, ASCO 2010 Roth, A. D. et al. JCO 2010

PRIME: PFS in patients with RAS/BRAF-WT mCRC with an ECOG PS of 0/1 1.0 Panitumumab + FOLFOX4 (n=210) / events n=177 FOLFOX4 (n=201) / events n=181 0.75 HR (95% CI) p-value 0.69 (0.56, 0.86) 0.0007 PFS estimate 0.50 0.25 9.3 12.3 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (months) 210 181 137 99 69 55 44 34 24 18 13 7 5 1 201 154 103 60 43 31 24 19 13 10 5 3 3 1 Median PFS in patients with ECOG PS 2: 6.4 vs 7.6 months with panitumumab + FOLFOX4 vs FOLFOX4 (p=0.891; HR=0.94 [95% CI: 0.38-2.31]) Peeters, et al. ASCO 2014. Abstract 3557

PRIME: PFS by BRAF status in patients with WT RAS WT RAS / WT BRAF WT RAS / MT BRAF Events n/N (%) Median months (95% Cl) Panitumumab + FOLFIRI 101/186 (54) 6.9 (5.8, 8.0) FOLFIRI 120/190 (63) 5.5 (3.9, 5.9) Events n/N (%) Median months (95% Cl) Panitumumab + FOLFIRI 19/22 (86) 2.5 (1.7, 3.5) FOLFIRI 19/23 (83) 1.8 (1.8, 3.1) 1.0 1.0 1.0 0.75 0.68 (0.51, 0.90) 0.006 0.75 HR (95% CI) Log rank p-value HR (95% CI) Log rank p-value 0.69 (0.32, 1.49) 0.34 PFS estimate 0.50 PFS estimate 0.50 0.25 0.25 5.5 6.9 1.8 2.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 1 2 3 4 5 6 7 8 9 10 Time (months) Time (months) No. at risk: 186 190 173 182 141 133 133 119 100 78 92 72 67 47 55 41 41 30 36 29 23 20 18 13 9 6 4 2 2 1 2 1 2 1 No. at risk: 22 23 20 22 11 8 8 7 5 2 3 2 2 1 2 1 2 1 1 Peeters, et al. ASCO 2014. Abstract 3557

BRAF mutant mCRC Aggressive biology Less benefit from the typical systemic therapy approaches Can we improve outcomes for these patients?

Aggressive approach for an aggressive disease Similar to strategy as for pancreatic cancer Clinical trial data to support we may be able to significantly improve outcomes for BRAF mutant tumors with the kitchen sink approach

TRIBE Study Design R FOLFIRI+bev FOLFOXIRI+bev INDUCTION 5-FU/LV +Bev PD 508 mCRC pts 1st line unresectable stratified by center PS 0/1-2 adjuvant CT FOLFIRI+bev (up to 12 cycles) 5-FU/LV +Bev R FOLFOXIRI+bev (up to 12 cycles) 5-FU/LV +Bev INDUCTION MAINTENANCE Loupakis et al., NEJM 2014

End-points / Statistics Primary end-point Progression free survival to detect a HR for PFS of 0.75 in favour of FOLFOXIRI + bev with a 2-sided type 1 error= 0.05; power= 80% 379 events required (approx. 450-500 patients to be rand.) Secondary end-points Response Rate Secondary R0-resection rate Overall survival Safety profile Biomarkers evaluation Loupakis et al., NEJM 2014

Patients’ characteristics – ITT population Characteristic, % patients FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 Sex (M / F) 61 / 39 60 / 40 Median Age (range) 60 (29 – 75) 61 (29 – 75) ECOG PS (0 / 1-2) 89 / 11 90 / 10 Synchronous Metastases (Y / N) 81 / 19 79 / 21 Prior Adjuvant CT (Y / N) 13 / 87 Primary Tumor Site (right / left / NR) 24 / 70 / 6 35 / 60 / 5 Number Metastatic Sites (1 / >1) 24 / 76 31 / 69 Liver Only Disease (Y / N) 18 / 82 23 / 77 Resected Primary (Y / N) 65 / 35 69 / 31 Kohne score (low / interm / high / NE) 41 / 44 / 11 / 4 43 / 44 / 7 / 6 Loupakis et al., NEJM 2014

Toxicity Profile – Safety population G3/4 adverse events, % patients FOLFIRI + bev N=254 FOLFOXIRI + bev N=250 p Nausea 3 1.000 Vomiting 4 0.492 Diarrhea 11 19 0.012 Stomatitis 9 0.048 Neutropenia 20 50 <0.001 Febrile neutropenia 6 0.315 Neurotoxicity 5 Hypertension 2 0.157 Venous Thrombosis 7 0.593 Arterial Thrombosis 1 Bleeding Loupakis et al., NEJM 2014

Primary endpoint: PFS (updated) – ITT population FOLFIRI + bev FOLFOXIRI + bev Median follow up: 32.3 mos FOLFIRI + BEV, mPFS : 9.7 mos FOLFOXIRI + BEV, mPFS : 12.1 mos Unstratified HR: 0.77 [0.64-0.93] p=0.006 Stratified HR: 0.75 [0.62-0.90] p=0.003 Progression-free survival probability RR 53% vs 65% P=0.006 F-up time (months) FOLFIRI/bev 256 203 94 46 26 14 7 3 FOLFOXIRI/bev 252 208 125 74 35 21 11 5 2 1 Loupakis et al., NEJM 2014

Secondary endpoint: OS (update) – ITT population Cremolini et al., ASCO GI 2015

Subgroup analyses of PFS – molecular characteristics Factor N HR p 0.4 0.6 0.8 1 Experimental better Control Better Loupakis et al., NEJM 2014

TRIBE: RAS MT, BRAF MT and all WT subgroup analyses Bevacizumab + FOLFIRI Bevacizumab + FOLFOXIRI HR (95% CI) Median PFS, months Median OS, months PFS OS All WT (n=129) 11.3 34.4 13.3 41.7 0.77 (0.52–1.12) 0.84 (0.51–1.38) RAS MT (n=218) 9.5 23.1 12.0 28.6 0.82 (0.62–1.09) 0.86 (0.61–1.23) BRAF MT (n=28) 5.5 10.8 7.5 19.1 0.56 (0.20–1.14) 0.55 (0.24–1.23) Loupakis, et al. ASCO 2014. Abstract 3519; Saturday 31 May. Poster Highlights Session 1:15 PM - 4:15 PM E354b Poster Board: #7

Aggressive approach for aggressive disease Results of BRAF mut patients in the TRIBE study similar to other study utilizing aggressive chemo approach in BRAF mutant cancers Both prospective phase II trials evaluating FOLFOXIRI + bev Masi et al. Lancet Oncol 2010 10 BRAF mut pts (57 total) Loupakis et al. EJC 2014 15 pts BRAF mut (214 screened – 7%)

Bevacizumab with FOLFOXIRI as first-line treatment for metastatic colorectal cancer: a phase 2 trial Masi et al. Lancet Oncol 2010

Bevacizumab with FOLFOXIRI as first-line treatment for metastatic colorectal cancer: a phase 2 trial Masi et al. Lancet Oncol 2010

FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer Loupakis et al. EJC 2014

Improvement in outcomes among BRAF mCRC with aggressive approach Study BRAF WT OS BRAF mut PFS Relapse after PETACC-3 25.5 mos 7.5 mos PRIME (FOLFOX + panitumumab) 6.9 mos 2.5 mos FOLFOXIRI + bev trials TRIBE 13.3 mos 41.7 mos 19.2 mos Masi et al. 13.9 mos 30.9 mos 12.8 mos 23.8 mos Loupakis et al 11.8 mos 24.1 mos 9.2 mos

Conclusions Treat the aggressive biology of BRAF mutant mCRC with an aggressive approach FOLFOXIRI + bev offers a dramatic improvement over traditional doublet + bev regimens Patients are often sick at presentation – FOLFOXIRI + bev offers chance at improved response rates to alleviate symptoms quicker

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