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

2. 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.

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

4. 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: ])
Peeters, et al. ASCO Abstract 3557

5. 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 Abstract 3557

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

7. 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

8. TRIBE Study Design R FOLFIRI+bev FOLFOXIRI+bev INDUCTION 5-FU/LV +BevPD
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

9. 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 patients to be rand.)
Secondary end-points
Response Rate
Secondary R0-resection rate
Overall survival
Safety profile
Biomarkers evaluation
Loupakis et al., NEJM 2014

10. 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

11. 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

12. 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 [ ]
p=0.006
Stratified HR: 0.75 [ ]
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

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

14. 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

15. 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 Abstract 3519; Saturday 31 May. Poster Highlights Session 1:15 PM - 4:15 PM E354b Poster Board: #7

16. 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%)

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

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

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

20. 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

21. 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

22. Thank you for your attention!