1. Alan P. Venook, MD University of California, SF
GREAT DEBATE:
CRC FIRST-LINE TREATMENT
Alan P. Venook, MD University of California, SF

2. Presented by:

3. CRC ESMO GUIDELINES

4. Cytotoxic backbone: Usage patterns
FOLFOX preferred in US
CALGB/SWOG 80405: 74% choose FOLFOX
2nd line trials almost all use irinotecan-based rx
FOLFIRI use likelier in parts of Europe
FOLFOXIRI not yet broadly accepted
Fluoropyrimidine alone in poor KPS patients

5. EGF-R
VEGF

6. CALGB/SWOG 80405: FINAL DESIGN
mCRC
1st-line
KRAS wild type
(codons 12,13)
STRATA:
FOLFOX/FOLFIRI
Prior adjuvant
Prior XRT
FOLFIRI or
FOLFOX
MD choice
Chemo Cetuximab
Chemo + Bevacizumab
N = 1140
1° Endpoint: Overall Survival

7. CALGB/SWOG 80405: Overall Survival
Arm
N (Events)
OS (m)
Median
95% CI
Chemo + Cetux
578 (375)
29.9
Chemo + Bev
559 (371)
29.0
P=0.34
HR ( )

8. RAS mutations: CALGB/SWOG 80405
670/1137 patients (59%) with KRAS codon 12/13 WT tumors evaluable
for tumor RAS status; 621/1137 analyzed (55%)
RAS mutations (%): 95/621 (15.3%) patients
KRAS†
EXON 2
EXON 3
EXON 4
12 13
59 61
117
146
WT +1.3%
1.8%
5.9%
NRAS†*
EXON 2
EXON 3
EXON 4
12 13
59 61
117
146
2.3%
4.2% 0%
†Percentages relate to fraction of RAS evaluable patients with mutations in particular exons;
*One patient had a mutation at both NRAS Exon1 codon12 and NRAS Exon3 codon61

9. Overall Survival By Arm (All RAS Wild Type Patients)
(Events)
Median
(95% CI) HR p
Chemo + Bev
256
(178)
31.2
( )
0.9
( )
0.40
Chemo + Cetux
270
(177)
32.0
( )

10. Quality of Life and Symptoms
Hypotheses: Cetuximab will reduce satisfaction with appearance and diminish overall quality of life
Measures:
EORTC QLQ-C30
Dermatology-Specific Quality of Life (DSQL)
Assessment Timepoints:
Baseline, 6 weeks, 3, 6 and 9 months
Presented by:

11. Slide courtesy of Dueck, Schrag, Naughton
EORTC GLOBAL QOL DSQL SKIN SATISFACTION
BEVACIZUMAB
CETUXIMAB
Slide courtesy of Dueck, Schrag, Naughton
Presented by:

12. Different results from FIRE-3
CRITICISMS OF 80405
Some results still pending / unaudited
Expanded RAS / RR to be updated
Not all data captured
Sidedness / subsequent therapies / CEA
No Central Radiology review
Depth of response / time to response
Different results from FIRE-3

13. FIRE-3 v CALGB/SWOG 80405 RAS status / FOLFIRI comparison
FOLFIRI backbone
RAS status
FIRE 3
BEV v CETUX
CALGB/SWOG
PFS
10.3 v 10.0 mos
11.6 v 10.3 mos OS
25.0 v 28.7 mos
HR: 0.77 (p=0.017)
33.4 v 28.9 mos
HR: 0.92 (p=0.34)
10.2 v 10.4 mos
11.9 v 12.7 mos
25.6 v 33.1 mos
HR: 0.70 (p=0.011)
35.2 v 32.0 mos
HR: 0.90 (p=0.7)
KRAS WT codons 12, 13
ALL RAS WT

14. CRITICISMS OF FIRE-3 1° endpt: Response Rate (Investigator)
RR differential increased w/ central review
Small % pts receive 2nd line biologic
Data presented with shrinking denominator
Bev pts OS nearly 10 months less

15. New EPOC: PFS and OS Primrose, et al, Lancet Oncol, 2014 2014.
PFS: 20.5 mos v mos
OS: NR v 39.1
Primrose, et al, Lancet Oncol,

16. WHAT SEEMS TO BE SETTLED?
EGFR arms similar across studies
All RAS analysis separates patients:
May benefit from EGFR Ab (45%)
Do not benefit and poorer prognosis (55%)
NEW EPOC outliers
Pts in Europe get less benefit from BEV
NO obvious explanation for differences between FIRE-3 and 80405

17. PATIENTS HAVE A CHOICE
marketing, taste, bias