1. Axel Grothey Professor of Oncology Mayo Clinic Rochester
First-Line Treatment of Metastatic Colorectal Cancer - The FIRE-3 Approach -
Axel Grothey
Professor of Oncology
Mayo Clinic Rochester

2. Parameters Influencing Choice of First-line Therapy
Clinical presentation
Tumor biology
RAS mutation status
BRAF mutation status
Tumor characteristics
1L treatment
Patient preference
Patient characteristics
Expectations
Goal of therapy
Spiritual factors
Attitude toward toxicities
Age
Performance status
Comorbidities
Socio-economic factors

3. Overview of EGFR and VEGFR Growth Signaling Pathways
Tumor Cell
Endothelial Cell
VEGF
EGFR
KIT
PDGFR-β
VEGFR
Targeted by bevacizumab and aflibercept*
Targeted by cetuximab and panitumumab
RAS
*Aflibercept also targets PIGF
Pl3K
RAF
BRAF
AKT
MEK
mTOR
ERK
ONCOGENESIS
ANGIOGENESIS
TUMOR MICROENVIRONMENT
Krasinskas AM. Patholog Res Int. 2011;2011:932932; Sitohy B, et al. Cancer Res 2012;72: ; Bendardaf R, et al. Anticancer Res. 2008;28: ; Kitadai Y, et al. Am J Pathol. 2006;169: ; Jayson GC, et al. J Clin Oncol. 2005;23:
G.SM.ON

4. NCIC CTG CO.17: Randomized Phase III Trial in mCRC Cetuximab vs BSC (no cross-over)
KRAS mut
KRAS wild-type
All patients
BSC
n=83
Cetux
n=81
n=113
n=117
n=285
n=287 RR 0%
1.2%
12.8%
6.6%
PFS (mos)
1.8
1.9
3.8
OS (mos)
4.6
4.5
4.8
9.5
6.1
<0.0001
<0.0001
<0.0001
0.0046
Karapetis et al. NEJM 2008

5. Mutations beyond KRAS codon 12/13: 17% additional mutations in
PRIME study led the way
KRAS
EXON 1
EXON 2
EXON 3
EXON 4
12 13 61
117
146
40% 4% 6%
NRAS
EXON 1
EXON 2
EXON 3
EXON 4
12 13
59 61 3% 4% NT
BRAF
EXON 11
EXON 15
17% additional mutations in
KRAS and NRAS !
600 NT 8%
NT=not tested
Douillard et al., NEJM 2013 5 5

6. FIRE-3 Phase III study design
FOLFIRI
+ Cetuximab
Cetuximab:
400 mg/m2
i.v. 120min
initial dose
250 mg/m2
i.v. 60min
q 1w
mCRC
1st-line therapy KRAS wild-type
N= 592 C e t u x i m a b : 4 m g / m 2 i . v . 1 2 m i n i n i t i a l d o s e 2 5 m g / m 2 i . v . 6 m in q 1 w
Randomize 1:1
FOLFIRI + Bevacizumab
Bevacizumab: 5 mg/kg i.v min q 2w B e v a c i z u m a b : 5 m g / k g i . v . 3 - 9 m i n q 2 w
FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2
irinotecan: 180 mg/m2 5-FU: 2,400 mg/m2 (i.v. 46h)
Primary objective: Overall response rate (ORR) (inv assessed)
Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%)
284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher‘s exact test at an alpha level of 2.5%
Heinemann et al., Lancet Oncol 2014

7. FIRE-3 Results in KRAS ex2 wt CRC
ORR in KRAS ex2-WT
Investigator-assessed
1.0
PFS in KRAS ex2 WT
Investigator-assessed
p=0.18
OR=1.18 (95% CI 0.85–1.64)
Treatment arm
0.75
FOLFIRI + cetuximab
FOLFIRI + bevacizumab
PFS estimate
0.50
HR=1.06 (95% CI: 0.88–1.26) p=0.547
0.25
10.0
10.3
OS in KRAS ex2 WT
1.0
Overall response rate (%)
Cetuximab 62%
Bevacizumab 58%
HR=0.77 (95% CI: 0.62–0.96)
Log-rank p=0.017
0.75
Cetuximab
Bevacizumab
OS estimate
0.50
0.25
25.0
28.7 12 24 36 48 60 72
Time (months)
Heinemann, et al. Lancet Oncol 2014

8. Potential reasons for OS difference with same PFS
Imbalance in post-progression therapy
First-line therapy affects sensitivity of cancer cells to subsequent treatments
Early clonal selection
Is there an optimal sequence of treatment options?
First-line therapy is highly effective in a subpopulation of CRC with long-lasting treatment benefit

9. FIRE-3 Update: Tested Mutations 17% additional RAS mutations!
KRAS wt exon 2 subset
KRAS
EXON 1
EXON 2
EXON 3
EXON 4
12 13 61
146 wt
4.0%
5.9%
NRAS
EXON 1
EXON 2
EXON 3
EXON 4
12 13
59 61
3.6%
2.1%
0.2%
BRAF
EXON 11
EXON 15
17% additional RAS mutations!
600 0%
10% 9 9

10. Overall survival Final RAS* wild-type population
Events n/N (%)
Median
(months)
95% CI
― FOLFIRI + Cetuximab
107/199
(53.8%)
33.1
24.5 – 39.4
― FOLFIRI + Bevacizumab
133/201
(66.2%)
25.0
23.0 – 28.1
HR (95% CI: 0.54 – 0.90)
p (log-rank)=
1.0
0.75
Probability of survival
0.50
0.25
Δ = 8.1 months
0.0 12 24 36 48 60 72
months since start of treatment
No. at risk
199
201
147 79 82 46 34 23 11 7 1
* KRAS and NRAS exon 2, 3 and 4 wild-type
Stintzing S, et al. Presented at: ESMO (LBA 11). 10 10

11. Independent Evaluation
FIRE-3: ORR
Primary Analysis
FOLFIRI + Cetux, %
FOLFIRI + Bev,
Odds Ratio P*
ITT population
n=592
62.0
58.0
1.18
( )
0.183
Assessable for response
n=526
72.2
63.1
1.52
( )
0.017
Independent Evaluation
CT Evaluable Population
FOLFIRI + Cetux, %
FOLFIRI + Bev,
Odds Ratio P†
KRAS exon 2 WT
n=493
66.5
55.6
1.58
( )
0.016
Final RAS WT
n=330
72.0
56.1
2.01
( )
0.003
*P=Fisher’s exact test (one-sided); †P=Fisher’s exact test (two-sided).
Stintzing S, et al. Presented at: ESMO (LBA 11).

12. Waterfall-Plot
Tumor response in final RAS wild-type population (n=330)
+100%
Cetuximab + FOLFIRI
Bevacizumab + FOLFIRI
+20%
-30%
-100%
Median time to tumor nadir:
FOLFIRI + Cet: weeks
FOLFIRI + Bev: weeks
Stintzing S, et al. Presented at: ESMO (LBA 11).

13. FIRE-3: Median tumor diameter by treatment time (final RAS)6
week
75%
50%
100% 12 22 32
95% CI
103 95
FOLFIRI + Cet
FOLFIRI + Bev
109
126 79 99 45 43
Cetuximab + FOLFIRI
Bevacizumab + FOLFIRI
Median tumor diameter of patients not PD
Stintzing S, et al. Presented at: ESMO (LBA 11).

14. FIRE-3: Second Line Therapies
Modest et al., ASCO 2014

15. FIRE-3: Second Line Regimens
Modest et al., ASCO 2014

16. FIRE-3: Duration of 2nd Line Therapy
Modest et al., ASCO 2014

17. FIRE-3: Outcome of 2nd Line Therapy
Modest et al., ASCO 2014

18. FIRE-3 and CALGB/SWOG 80405: Efficacy by RAS Status
CT + Bev vs CT + Cetux
CALGB/SWOG 80405
Primary endpoint
Response rate
Overall survival
CT backbone
All FOLFIRI
FOLFOX 74%/FOLFIRI 26%
ITT (KRAS WT Exon 2) (n=295 vs 297) (n=559 vs 578)
RR, %
58 vs 62
P=0.183
57.2 vs 65.6
P=0.02
PFS, months
10.3 vs 10.0; HR=1.06 (P=0.547)
10.8 vs 10.4; HR=1.04 (P=0.55)
Median OS, months
25.0 vs 28.7
HR=0.77 (P=0.017)
29.0 vs 29.9
HR=0.92 (P=0.34)
RAS WT (n=201 vs 199) (n=256 vs 270)
58.7 vs 65.3; OR=1.33 (P=0.18)
53.8 vs 68.6; (P<0.01)
10.2 vs 10.3; HR=0.97 (P=0.77)
11.3 vs 11.4; HR=1.1 (P=0.31)
OS, months
25.0 vs 33.1
HR=0.70 (P=0.006)
31.2 vs 32.0
HR=0.9 (P=0.40)
Stintzing S, et al. Presented at: ESMO. 2014 (abstr LBA11). Lenz H-J, et al. Presented at: ESMO (abstr 501O).
Venook. Presented at: WCGC

19. Comparison FIRE-3 and 80405 The data we have…
Analysis
FIRE-3
80405
RR investigator assessed +
RR independently assessed -
Early response parameters
PFS OS
RAS analysis in % of study pts
80%
59%
Duration of 1st line Tx
2nd line therapy
Duration of 2nd line Tx
OS after initiation of 2nd line Tx
Effect of Vitamin D levels

20. mFOLFOX6 (Q2W) + panitumumab 6 mg/kg (Q2W)
Phase 2 PEAK study mFOLFOX6 + panitumumab or bevacizumab in 1st-line treatment of WT KRAS exon 2 mCRC P o
mFOLFOX6 (Q2W) + panitumumab 6 mg/kg (Q2W) s E S t n a d f t E e r n o t e d
mCRC
WT KRAS exon 2
(n = 285) f y a o R t t f f r m o e
30 days (+ 3 days) e s l
1:1 a n t
mFOLFOX6 (Q2W) +
bevacizumab 5 mg/kg
(Q2W) l t t u o m d w f e y o n u l t p l o
Tumour assessment Q8W (±7 days); Treatment administered until disease progression, death, or withdrawal from study w u p
Every 3 months (±28 days) until end of study
Study endpoints: PFS (1°); OS, ORR, safety, exploratory biomarker analysis
No formal hypothesis testing was planned
Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7.

21. WT RAS (exons 2, 3, 4 of KRAS/NRAS)
Phase 2 PEAK study PFS outcome ITT set vs biomarker analysis set (Cut-off 03 Jan 2013)
WT KRAS exon 2 (ITT set)
WT RAS (exons 2, 3, 4 of KRAS/NRAS)
100
100 90 90 80 80 70
HR = 0.84 (95% CI, 0.64–1.11)
P = 0.224 70
HR = 0.66 (95% CI, 0.46–0.95)
P = 0.025 60 60
Proportion event-free (%) 50
Proportion event-free (%) 50 40 40 30 30 20 20 10 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Months
Months
Events n (%)
Median (95% CI)
months
Panitumumab + mFOLFOX6 (n = 142)
100 (70)
10.9 (9.7–12.8)
Bevacizumab + mFOLFOX6 (n = 143)
108 (76)
10.1 (9.0–12.0)
Events n (%)
Median (95% CI)
months
Panitumumab + mFOLFOX6 (n = 88)
57 (65)
13.0 (10.9–15.1)
Bevacizumab + mFOLFOX6 (n = 82)
66 (80)
10.1 (9.0–12.7)
Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7.

22. WT RAS (exons 2, 3, 4 of KRAS/NRAS)
Phase 2 PEAK study OS outcome ITT set vs biomarker analysis set (Cut-off 03 Jan 2013)
WT KRAS exon 2 (ITT set)
WT RAS (exons 2, 3, 4 of KRAS/NRAS)
100
100 90 90 80 80 70 70 60 60
Proportion alive (%) 50
Proportion alive (%) 50 40 40 30 30 20
HR = 0.62 (95% CI, 0.44–0.89)
P = 0.009 20
HR = 0.63 (95% CI, 0.39–1.02)
P = 0.058 10 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Months
Months
Events n (%)
Median (95% CI)
Months
Panitumumab + mFOLFOX6 (n = 142)
52 (37)
34.2 (26.6–NR)
Bevacizumab + mFOLFOX6 (n = 143)
78 (55)
24.3 (21.0–29.2)
Events n (%)
Median (95% CI)
months
Panitumumab + mFOLFOX6 (n = 88)
30 (34)
41.3 (28.8–41.3)
Bevacizumab + mFOLFOX6 (n = 82)
40 (49)
28.9 (23.9–31.3)
mOS ∆ 12.4 mos!
Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7.

23. Targeted agents in 1st-line WT RAS mCRC
Looking at present data 1st line use of EGFR antibodies prolongs survival over bevacizumb in WTRAS mCRC
HR 0.83 [ ], p=0.003
FIRE3
PEAK
CALGB
favors anti-EGFR favors anti-VEGF
Gunnar Folprecht, ASCO 2014

24. Conclusions FIRE-3 vs 80405
FIRE-3 and are more similar than different
Consistently higher RR in both trials for cetuximab
Same PFS
3 of 4 OS arms are virtually identical
We have a lot more data on outcome parameters and treatment sequence from FIRE-3 than 80405
The FIRE-3 approach makes biomarker-based treatment selection for mCRC a reality!
We cannot ignore an OS difference of 8.1 months in a well-conducted phase III trial, even if OS was not the primary EP
Data supported by PEAK

25. And most importantly…