This document summarizes key findings from the PRIME trial evaluating the addition of panitumumab to FOLFOX4 as first-line treatment for metastatic colorectal cancer. Biomarker analysis found that KRAS exon 2 wild-type tumors derived greater benefit from the addition of panitumumab, with a progression-free survival advantage compared to FOLFOX4 alone. Further biomarker testing found mutations in other RAS isoforms or BRAF reduced likelihood of benefit from panitumumab. The results support use of RAS/BRAF mutation testing to select patients for first-line anti-EGFR therapy in combination with chemotherapy.
Colorectal Cancer Research & Treatment News - recap from the May 2014 ASCO conference
1. Welcome to Fight Colorectal Cancer’s &
Colon Cancer Alliance joint Webinar
Research News:
Make Sure You Know the Latest News
About CRC Research and Treatment
Our webinar will begin shortly.
2. ABOUT THE COLON CANCER ALLIANCE
Our mission is to knock colon cancer out of the top three
cancer killers. We are doing this by championing prevention,
funding cutting-edge research and providing the highest
quality patient support services.
In 2013, the Colon Cancer Alliance:
3. Today’s Webinar:
1. Today’s Speaker: Cathy Eng, M.D. @CathyEngMD
2. Archived Webinars: FightColorectalCancer.org/Webinars
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7. Speaker
Cathy Eng, M.D.
Associate Professor in the Department of Gastrointestinal (GI)
Medical Oncology at The University of Texas M. D. Anderson
Cancer Center. Dr. Eng received her medical degree from
Hahnemann University School of Medicine in Philadelphia, PA
Dr. Eng is board certified in internal medicine and medical
oncology.
Twitter: @CathyEngMD
8. Department of GI Medical Oncology
CURRENT DEVELOPMENTS IN
METASTATIC COLORECTAL CANCER
Cathy Eng, M.D., F.A.C.P.
Associate Professor
Associate Medical Director, Colorectal Center
Director of Network Clinical Research, GI Med Oncology
Co-Chairman, SWOG Rectal Subcommittee
July 16, 2014
9. Cancers of the Colon and Rectum
International Statistics
Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014
Incidence
Mortality
1.2 Million
609,000
Worldwide
per annum
USA (2014)
Incidence
Mortality
136,830
50,310
Colorectal cancer is the 3rd most
common cancer in
men and the 2nd in women.
25. Biomarker Development
Review of Definitions:
Prognostic marker
Independent of treatment
May impact surveillance
Predictive marker
Impacts type of treatment provided
27. KRAS
Proto-oncogene
First globally utilized predictive marker for
the treatment of MCRC when considering
anti-EGFR therapy
30%-50% of all patients
MT (exon 2): codons 12, 13, 61, and
rarely 146
KRAS WT does = efficacy of therapy nor
does it indicate duration of response
29. BRAF MT
Serine-threonine kinase belong to the RAF
family
Mutation also leads to constitutive activation
V600E accounts for 90% of mutations
Found in < 10 % of all CRC patients
Associated with hypermethylation of CpG
island.
Mutually exclusive with KRAS MT
Prognostic but NOT predictive
All studies insufficiently powered to provide
sufficient data to determine use of anti-EGFR
therapy based on BRAF status.
30. NRAS
Resembles Kras
Oncogene
< 5% of all mCRC
Mutations in codons 12, 13, 61, 117 and
146
Usually codon 61
Mutually exclusive with KRAS
37. PFS: Wild-Type (WT) KRAS Exon 2 + mutant
(MT) Other RAS
Oliner KS. ASCO 2013. Abstract 3511.
38. OS: Wild-Type (WT) KRAS Exon 2 + mutant
(MT) Other RAS
Oliner KS. ASCO 2013. Abstract 3511.
39. PRIME: Summary and
Clinical Implications
About 17% of patients with mCRC harbor mutations
beyond KRAS exon 2 mutations
Excluding patients with RAS mutations identifies
patients more likely to benefit from anti-EGFR therapy.
Practical interpretation: until an all-RAS test becomes
available, EGFR monoclonal antibodies have the
potential to be detrimental in patients who may harbor
an unrecognized RAS mutation when administered with
oxaliplatin-based chemotherapy regimens
Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.
50. Events
n/N (%)
Median
(months)
95% CI
― FOLFIRI + Cetuximab 91/171
(53.2%)
33.1 24.5 – 39.4
― FOLFIRI + Bevacizumab 110/171
(64.3%)
25.6 22.7 – 28.6
HR 0.70 (95% CI: 0.53 – 0.92)
p (log-rank)= 0.011
FIRE-3: Overall survival RAS* all wild-type
0.0
12 24 36 48 60 72
months since start of treatment
171
171
No. at
risk
128
127
71
68
39
26
20
9
6
1
0.75
1.0
0.50
0.25
0.0
Probabilityofsurvival
Δ = 7.5 months
* KRAS and NRAS exon 2, 3 and 4 wild-typeStinzing et al: ESMO, 2013
51. FIRE-3 Update: Overall Survival by
All-RAS MutationStatus
Study Population
FOLFIRI +
Cetuximab
FOLFIRI +
Bevacizumab
HR
P
Value
ITT (N=592) 28.7 months 25.0 months 0.77 0.017
RAS WT (n=342) 33.1 months 25.6 months 0.70 0.011
RAS MT (n=65) 16.4 months 20.6 months 1.20 0.57
BRAF MT (n=48) 12.3 months 13.7 months 0.87 0.65
Stintzing S. European Cancer Conference 2013. Abstract LBA17.
52. FIRE-3: Summary and Clinical Implications
Current data limitations
No central assessment of response
OS data continues to mature
Practical impact
EGFR antibodies added to FOLFIRI can be
considered a viable option in first-line, KRAS wild-
type mCRC
Heinemann V. ASCO 2013. Abstract LBA3506.
53. CALGB/SWOG 80405: PHASE III TRIAL OF
FOLFIRI OR FOLFOX WITH BEVACIZUMAB OR
CETUXIMAB FOR PATIENTS W/ KRAS WILD TYPE
UNTREATED METASTATIC ADENOCARCINOMA
OF THE
COLON OR RECTUM
A Venook, D Niedzwiecki, HJ Lenz, F Innocenti, M Mahoney,
B O’Neil, J Shaw, B Polite, H Hochster, R Goldberg, R Mayer,
R Schilsky, M Bertagnolli, C Blanke
ALLIANCE and SWOG
54. CALGB / SWOG 80405:
FINAL DESIGN
N = 1140
1° Endpoint: Overall Survival
Chemo + Cetuximab
Chemo + Bevacizumab
mCRC
1st-line
KRAS wild type
(codons 12,13)
STRATA:
FOLFOX/FOLFIRI
Prior adjuvant
Prior XRT
FOLFIRI
or
FOLFOX
MD choice
55. CALGB/SWOG 80405: Eligibility Criteria
• Untreated Metastatic CRC
• Tumor KRAS wild type codons 12 & 13
• > 12 months since adjuvant therapy
• ECOG 0-1
• Preserved organ function
AT ENROLLMENT
• CHOOSE: FOLFOX or FOLFIRI
• INTENT: Palliative or Part of strategy to resect
all metastases
56. CALGB/SWOG 80405: Statistics
Assumption: OS: 22 mos to 27.5 mos
Δ 5.5 months
90% power to detect HR of 0.80 (2-sided α=0.05)
ACCRUAL GOAL = 1140 (1137)
Estimate 326 eligible pre-amendment (333)
KRAS wild type, single biologic arm
Estimate 814 post-amendment (804)
Actual
57. CALGB/SWOG 80405: Overall Survival
Arm N (Events)
OS (m)
Median
95% CI
Chemo +
Cetux 578 (375) 29.9 27.0-32.9
Chemo + Bev 559 (371) 29.0 25.7-31.2
P=0.34
HR 0.925 (0.78-1.09)
58. CALGB/SWOG 80405: Progression-Free Survival
(Investigator Determined)
Arm N (Events)
PFS (m)
Median
95% CI
Chemo + Bev 559 (498) 10.8 9.7-11.4
Chemo + Cetux 578 (499) 10.4 9.6-11.3
P=0.55
HR 1.04 (0.91 -1.17)
59. CALGB/SWOG 80405: Overall Survival
FOLFOX Subgroup
Arm N (Events)
OS (m)
Median
95% CI
FOLFOX + Cetux 426 (277) 30.1 26.6-34.8
FOLFOX + Bev 409 (290) 26.9 24.7–30.0
P=0.09
HR 0.9 (0.7-1.0)
60. CALGB/SWOG 80405: Overall Survival
FOLFIRI Subgroup
Arm N(Events)
OS (m)
Median
95% CI
FOLFIRI + Bev 150 (81) 33.4 27.3-41.3
FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2
P=0.28
HR 1.2 (0.9-1.6)
61. CALGB/SWOG 80405: Grade 3-4 Toxicities
Toxicity Chemo + Bev
N = 534 (%)
Chemo +Cetux
N = 547 (%)
Total Grade 3 278 (52) 295 (54)
Hematologic 142 (26.6) 150 (27.4)
Non-Hem 234 (43.8) 259 (47.3)
Total Grade 4 66 (12.4) 75 (13.7)
Total Grade 5 7 (1.3) 3 (0.5)
Neuropathy Gr ≥ 3 71 (14) 68 (12)
Rash Gr 3 0 40 (7)
Diarrhea Gr ≥ 3 45 (8) 59 (11)
Hypertension Gr ≥ 3 35 (7) 3 (1)
GI Events Gr ≥ 3 10 (2) 2 (0.5)
62. CALGB/SWOG 80405: Data Pending
Response Rate
Duration of therapy / dose intensity
Analysis special subsets:
Patients rendered NED
Patients recur after adjuvant therapy
Details 2nd and later treatments
Concordance KRAS analysis: local v. central
63. Anti-EGFR versus Bevacizumab Trials
FIRE
CALGB/SWOG
80405
PEAK
Number of patients 592 1137 285
Chemotherapy backbone FOLFIRI
FOLFOX or
FOLFIRI
FOLFOX
Primary endpoint
Response
rate
Overall survival PFS
Anti-EGFR Cetuximab Cetuximab Panitumumab
KRAS selection Codon 12/13 Codon 12/13 Codon 12/13
Expanded RAS available to date Yes No Yes
Response rate (anti-EGFR v anti-
VEGF; %)
62 v 58 N/A 58 v 54
Median PFS (anti-EGFR v anti-VEGF;
months)
10.0 v 10.3 10.4 v 10.8 10.9 v 10.1
Median Overall survival (anti-EGFR v
anti-VEGF; months)
28.7 v 25.0 * 29.9 v 29.0 34.2 v 24.3 *
* Statistically significant
65. ML18147 (TML): Continuing Bevacizumab
Beyond Progression
A randomized, open-label phase III intergroup study
Standard second-line CT (oxaliplatin or
irinotecan based) until PD
(n = 411)
BEV 2.5 mg/kg/wk +
standard second-line CT (oxaliplatin or
irinotecan-based) until PD
(n = 409)
Progressive mCRC after
BEV + standard first-line
CT (either oxaliplatin or
irinotecan based)
(n = 820)
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
Stratified by first-line CT (oxaliplatin or irinotecan
based), first-line PFS (≤ 9 or > 9 mos), time
from last BEV dose (≤ 42 or > 42 days),
ECOG PS at baseline (0/1 or 2)
Primary endpoint: OS
66. ML18147 (TML): Continuing Bevacizumab
Beyond Progression Increases OS (ITT)
OS(%)
Mos
CT (n = 410)
BEV + CT (n = 409)
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48
9.8 mos 11.2 mos
Unstratified* HR: 0.81 (95% CI:
0.69-0.94; log-rank P = .0062)
Stratified† HR: 0.83 (95% CI:
0.71-0.97; log-rank P = .0211)
*Primary analysis method. †Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS
(≤ 9 mos, > 9 mos), time from last dose of BEV (≤ 42 days, > 42 days), ECOG PS at baseline (0, ≥ 1).
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
100
80
60
40
20
0
PFS(%) 0 6 12 18 24 30 36 42
Mos
Unstratified* HR: 0.68 (95% CI:
0.59-0.78; log-rank P < .0001)
Stratified† HR: 0.67 (95% CI: 0.58-
0.78; log-rank P < .0001)
4.1mo
5.7 mo
67. Aflibercept (VEGF-Trap)
Fully human fusion protein and
soluble recombinant decoy
VEGF receptor consisting of
VEGFR-1 Ig domain 2
VEGFR-2 Ig domain 3
Human IgG1 Fc
Stronger binding than
bevacizumab
Blocks VEGF and PlGF
t1/2: ~ 17 days
The Structure of VEGF Trap
1
2
3
4
5
6
7
1
2
3
4
5
6
7
VEGF Trap
Kd = 0.5 pM
Fc
VEGFR-1
Kd 10-30 pM
VEGFR-2
Kd 100-300 pM
Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:11393-11398.
68. EFC10262: VELOUR
Phase III Trial 2nd Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Stratification factors:
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
1:1
mCRC after
failure of an
oxaliplatin
based regimen
R
600 pts
Aflibercept 4 mg/kg IV
+ FOLFIRI q 2 weeks
600 pts
Placebo + FOLFIRI
q 2 weeks
68
30% of patients had prior BEV
Primary endpoint: OSPI: Allegra et al
69. VELOUR Study: Survival Results
Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.
OS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Stratified HR: 0.817 (95.34% CI:
0.713-0.937; log-rank P = .0032)
Placebo/FOLFIRI
Median: 12.06 mos
Aflibercept/FOLFIRI
Median: 13.50 mos
PFS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30
Stratified HR: 0.758 (95% CI: 0.661-
0.869; log-rank P < .0001)
Placebo/FOLFIRI
Median: 4.67 mos
Aflibercept/FOLFIRI
Median: 6.90 mos
70. Overall Survival: Stratified by Previous
Bevacizumab; ITT Population
Tabernero J, et al. Eur J Cancer. 2013;[Epub ahead of print].
OS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30 33 36 39
HR: 0.862 (95.34% CI: 0.673-1.104)
Placebo/FOLFIRI
Median: 11.7 mos
Aflibercept/FOLFIRI
Median: 12.5 mos
Pts at Risk, n
Placebo
AFL
187
186
170
178
138
150
115
121
81
89
54
59
37
36
22
22
13
13
Previous Bevacizumab
OS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30 33 36 39
HR: 0.788 (95.34% CI: 0.699-0.927)
Placebo/FOLFIRI
Median: 12.4 mos
Aflibercept/FOLFIRI
Median: 13.9 mos
Pts at Risk, n
Placebo
AFL
427
426
403
388
347
348
286
295
205
222
139
157
94
112
65
82
38
62
No Previous Bevacizumab
72. Regorafenib (BAY 73-4506), an oral multikinase
inhibitor targeting multiple tumor pathways1-3
1. Wilhelm SM et al. Int J Cancer 2011.
2. Mross K et al. Clin Cancer Research 2012.
3. Strumberg D et al. Expert Opin Invest Drugs 2012.
Biochemical
activity
Regorafenib IC50
mean ± SD nmol/l (n)
VEGFR1 13 ± 0.4 (2)
Murine VEGFR2 4.2 ± 1.6 (10)
Murine VEGFR3 46 ± 10 (4)
TIE2 311 ± 46 (4)
PDGFR-β 22 ± 3 (2)
FGFR1 202 ± 18 (6)
KIT 7 ± 2 (4)
RET 1.5 ± 0.7 (2)
RAF-1 2.5 ± 0.6 (4)
B-RAF 28 ± 10 (6)
B-RAFV600E 19 ± 6 (6)
Regorafenib
Sorafenib
73. Randomized Phase III Regorafenib (BAY
73-4506) vs. BSC (CORRECT Trial)
Multitargeted TKI of VEGFR-2, TIE-2
90% powered to detect a 33.3% % (HR=0.75;
regorafenib/placebo) difference in OS
Primary endpoint: OS
Secondary endpoints: PFS and RR
R
Placebo PO QD
Cycle = 28 Days
Patients with
refractory mCRC
N= 760
Regorafenib 160 mg QD x 21 days
Grothey et al: Lancet. 2013 Jan 26;381(9863):303-12
74. CORRECT: OS (primary endpoint)
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)
Grothey et al: Lancet. 2013 Jan 26;381(9863):303-12
75. Phase III TAS-102 (RECOURSE)
Patients
• Pretreated mCRC
• ECOG PS 0-1
• N=800
Primary endpoint: OS
TAS-102
2:1 Randomization
Placebo
Yoshino et al: World GI Congress, 2014
76. RECOURSE RESULTS:
Improved median OS was 7.1 months for
TAS-102 vs. 5.3 months for placebo
(hazard ratio 0.68).
TAS-102 also improved PFS compared to
placebo (hazard ratio 0.48), which was a
secondary endpoint.
Likely submitted for expedited FDA
approval
Yoshino et al: World GI Congress, 2014
77. Should all RAS WT patients
receive anti-EGFR therapy
front-line?
78. New EPOC Study: Chemotherapy
± Cetuximab in Operable KRAS-WT mCRC
Original EPOC study showed 8% PFS benefit to addition of neoadjuvant
FOLFOX to surgery in mCRC patients with operable liver metastases[1]
New EPOC study evaluated addition of cetuximab to standard neoadjuvant
chemotherapy in mCRC[2]
Primary endpoint: PFS
Secondary endpoints: OS, preop response, pathologic resection status,
periop safety, QoL, cost-effectiveness
Patients with
resectable KRAS WT
mCRC with liver mets
(N = 621)
Neoadjuvant Chemotherapy*
(randomized n = 134;
primary analysis n = 116)
Neoadjuvant Chemotherapy*
+ Cetuximab
(randomized n = 137;
N = 117)
1. Nordlinger G, et al. Lancet. 2008. 2. Primrose JN, et al. ASCO 2013. Abstract 3504.
*CAPOX, OxMdG, IrMdG
79. New EPOC: Neoadjuvant Chemotherapy ±
Cetuximab in Operable KRAS-WT mCRC: PFS
Median PFS
significantly
worse with
cetuximab: 14.1
months vs 20.5
months with
chemotherapy
alone
Study stopped at
predefined futility
analysis
Immature data, but
more events
unlikely to change
result
Primrose JN, et al. ASCO 2013. Abstract 3504.
Proportionprogressionfree
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42 48 54 60
Time to progression or death (months)
HR: 1.49 (95% CI: 1.04-2.12); P = .030
Number at risk
Chemo alone
Chemo + Cetuximab
116
117
89
87
65
54
38
24
23
15
12
5
5
3
2
2
1
1
1
0
0
0
Chemo alone
Chemo + cetuximab
80. Why did the new EPOCH study fail?
KRAS is a predictive marker of potential benefit
for the use of EGFR inhibition.
Cetuximab does not have a role in the adjuvant
setting
N0147: FOLFOX +/- cetuximab failed to demonstrate
an improvement in DFS in stage III colon cancer
3-yr DFS: 74.6% vs 71.5% with the addition of
cetuximab (HR, 1.21; 95% CI, 0.98–1.49; P=.08)
Is it the combination of FOLFOX and
cetuximab?
Alberts et al: JAMA. Apr 4, 2012; 307(13): 1383–1393.
82. BOS-2 (EORTC 40091): Phase II
KRAS WT Resectable Liver Mets
R
A
N
D
O
M
I
Z
E
FOLFOX
• First-line
mCRC
• N=360
FOLFOX + bevacizumab
FOLFOX + panitumumab
Study amended: Wild-type KRAS tumors only
Primary Endpoint: PFS
http://www.clinicaltrials.gov/ct2/show/NCT01508000?term=BOS-2&rank=1
83. BOS -3 (EORTC-1207) Phase II/III Study
Design (Pending)
http://www.clinicaltrials.gov/ct2/show/NCT01646554?term=BOS-2&rank=2
Patients
• mCRC
• KRAS MT
• ECOG PS 0-1
• 1st line therapy; prior
adjuvant chemotherapy
allowed if completed
>12 mo before inclusion
Primary endpoint: PFS
FOLFOX + Aflibercept
(Aflibercept: 4 mg/m2)
1:1 Randomization
FOLFOX
85. Treat until
disease
progression
or intolerable
toxicity
• Important inclusion criteria:
- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma
- Progression after 1st line platinum/fluoropyrimidine based chemotherapy
• Stratification factors:
- Geographic region,
- Measurable vs non-measurable disease,
- Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Survival and
safety follow-
up
RAINBOW: Gastric Cancer
Wilke et al: ASCO GI 2014
1:1
87. Treat until
disease
progression
or intolerable
toxicity
• Important inclusion criteria:
- Progression after 1st line FOLFOX based chemotherapy
• Closed to enrollment, results pending
FOLFIRI +
Ramucirumab 8 mg/kg
N = 525
FOLFIRI + Placebo
N = 525
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Endpoint: OS
Phase III: FOLFIRI +/- Ramucirumab
1:1
http://clinicaltrials.gov/show/NCT01183780, accessed 2/16/14
89. Prior CMET/HGF Agents:
AMG-102:
Randomized phase II study
Fulfilled primary endpoint of RR
ARQ-197
Randomized phase II study
No difference in PFS
Problems
Cmet expression is not uniformly accepted.
Prior studies largely had tumors from the colon or rectum
not metastatic site.
Higher cmet expression is noted in sites of metastatic
disease
Cmet amplification may be a better marker but rare (<
20% of all pts)
Van Cutsem, Eng et al: Clin Can Res, June 2014; Eng et al: ASCO, Abs #3508, June 2013
90. Phase II – MetMab ACCOMPLISH
Bendell et al: J Clin Oncol 30, 2012 (suppl; abstr TPS3640)
Primary Endpoint: PFS
Final
results:
Pending
91. AMG-337: Schema
PI’s: Raghav and Eng (MDACC)
ETA: Fall 2014
Primary Objectives Evaluate efficacy of AMG-337 in MET amplified mCRC,
refractory to anti-EGFR therapy.
Secondary Objectives: Evaluate duration of efficacy of AMG-337 in MET
amplified mCRC, refractory to prior anti-EGFR therapy,
on treatment with AMG-337.
Evaluate survival outcomes in patients with MET
amplified mCRC, refractory to prior anti-EGFR therapy,
after treatment with AMG-337.
Evaluate safety and toxicity of AMG-337 in patients with
mCRC.
92. Other Upcoming/Ongoing Trials
Aflibercept
Different than bevacizumab?
Biomarker study underway (Canada)
Phase I/II: X-TRAP capecitabine + aflibercept, (N=60)
Phase II: Maintenance (N=69)
Phase II Rectal cancer: MDACC (PI’s: Dasari and Eng)
Phase II: Appendiceal CA (PI: Eng)
Phase II: ALIVE-C of FOLFOXIRI +/- Aflibercept (I Chau) in surgically
unresectable liver mets
Regorafenib
Biomarkr studies: Korea
Phase II: FOLFOX + Regorafenib (N=54)
Primary endpoint: RR (closed to enrollment)
Phase III COAST trial: Maintenance Regorafenib vs. placebo following
adjuvant chemotherapy (N=750)
Primary endpoint: DFS
94. BRAF MT
Serine-threonine kinase belong to the RAF
family
Mutation also leads to constitutive activation
V600E accounts for 90% of mutations
Found in < 10 % of all CRC patients
Associated with hypermethylation of CpG
island.
Mutually exclusive with KRAS MT
Prognostic but NOT predictive
All studies insufficiently powered to provide
sufficient data to determine use of anti-EGFR
therapy based on BRAF status.
95. Single agent BRAF inhibitor in
mCRC
Single agent vemurafenib
Refractory mCRC
N=21
1 partial response
Median PFS was 3.7M
Kopetz et al: ASCO 2010, Abs #3534
96. TRIBE Phase III Study Design
Falcone A. ASCO 2013. Abstract 3505.
Patients
• Unresectable mCRC
• No prior mCRC treatment
• Adjuvant oxali-containing
chemotherapy allowed if
>12 mo between tx and
relapse
Treat to progression
FOLFIRI + Bev (up to 12 cycles)
5-FU/LV + Bev (Maintenance)
1:1 Randomization
FOLFOXIRI + Bev (up to 12 cycles)
5-FU/LV + Bev (Maintenance)
98. FIRE-3 Phase III Study Design
Heinemann V. ASCO 2013. Abstract LBA3506.
Patients
• mCRC
• KRAS wild-type
• ECOG PS 0-2
• 1st line therapy; prior
adjuvant chemotherapy
allowed if completed
>6 mo before inclusion
• N=592 Primary Endpoint: Response Rate
FOLFIRI + Cetuximab
(Cetuximab: 400 mg/m2 loading dose;
250 mg/m2 weekly)
1:1 Randomization
FOLFIRI + Bevacizumab
(Bev: 5 mg/kg every 2 weeks)
99. FIRE-3 Update: Overall Survival by
All-RAS MutationStatus
Study Population
FOLFIRI +
Cetuximab
FOLFIRI +
Bevacizumab
HR
P
Value
ITT (N=592) 28.7 months 25.0 months 0.77 0.017
RAS WT (n=342) 33.1 months 25.6 months 0.70 0.011
RAS MT (n=65) 16.4 months 20.6 months 1.20 0.57
BRAF MT (n=48) 12.3 months 13.7 months 0.87 0.65
Stintzing S. European Cancer Conference 2013. Abstract LBA17.
Poor prognostic indicator
100. PHASE 1B STUDY OF VEMURAFENIB
IN COMBINATION WITH IRINOTECAN
AND CETUXIMAB IN PATIENTS WITH
BRAF-MUTATED METASTATIC
COLORECTAL CANCER
David S. Hong1, Van Morris2, Badi El-Osta1, Siqing Fu1,
Michael Overman3, Sarina Piha-Paul1, Bryan Kee3, Ralph
Zinner1, David Fogelman3, Imad Shureiqi3, Funda Meric-
Bernstam1, Scott Kopetz3
1Investigational Cancer Therapeutics, 2Cancer Medicine-Fellowship,
3Gastrointestinal Medical Oncology
The University of Texas MD Anderson Cancer Center
101. Introduction
Vemurafenib (V), an oral kinase inhibitor specific to the
mutated V600 isoform of BRAF
FDA approved in melanoma
In vitro data in CRC cell lines has shown that blockade
of mutated BRAF by vemurafenib triggers compensatory
activation of EGFR [Prahallad, 2012].
Inhibition of EGFR combined with vemurafenib results in
synergistic cytotoxicity in preclinical models, which is
further augmented by irinotecan [Yang 2012].
The safety and efficacy of the combination in patients
with BRAF-mutated advanced malignancies have not
been studied.
102. Objectives
Primary Objectives
To define the maximum tolerated dose (MTD) of vemurafenib
when used in combination with cetuximab and irinotecan
To define the safety profile of this combination
Expansion phase with BRAF (+) KRAS (-) cancers
To determine the antitumor activity of this combination in patients
with metastatic colorectal cancer (CRC)
To determine the antitumor activity of this combination in patients
with non-CRC advanced solid malignancies
Secondary Objectives
To evaluate clinical response signals of the combination
To assess pharmacodynamics (PD) profile of the combination
Hong et al: ASCO 2014
103. Phase 1, single institution study of vemurafenib
with irinotecan and cetuximab
• Histologically confirmed
metastatic or advanced
solid tumors
• BRAF V600E mutation
• Measurable disease by
RECIST 1.1
• ≥ 18 years old
• ECOG ≤ 2
• Adequate organ
function
• Informed consent
Key Eligibility Criteria Key Exclusion Criteria
• KRAS 12 or 13 mutation
• Treatment for tumor
control within 3 weeks
with investigational drug,
2 weeks with cytotoxic
agent given weekly, or 5
half- lives of biological
targeted agent
• Uncontrolled medical
illness
• Pregnant, lactating, or
breastfeeding
Hong et al: ASCO 2014
104. Patient baseline characteristics
Characteristic N = 12
Age, median
(range)
64.8 (42.5-
73.2)
Gender
Male 7 (58%)
Female 5 (42%)
Caucasian 12 (100%)
ECOG PS
0 1 (8%)
1 10 (83%)
2 1 (8%)
Lines of prior
therapy, median
(range)
2 (1-4)
Characteristic N = 12
Site of primary tumor
Colon/rectum 11 (92%)
Appendix 1 (8%)
Prior treatment
exposures
Irinotecan 8 (67%)
Cetuximab 5 (33%)
Vemurafenib 1 (8%)
Microsatellite status 10 tested
MSS 8 (80%)
MSI 2 (20%)
Hong et al: ASCO 2014
107. Prior to starting trial End of Cycle 4(1st restaging)
69 y/o male with metastatic BRAFV600E refractory to FOLFOX after first restaging on
Vemurafenib+Irinotecan and Cetuximab had a 41% decrease By RECIST1.1
Hong et al: ASCO 2014
109. Response to Therapy
12 patients were enrolled onto the study before the
4/15/2014 cutoff for data analysis. 9 are evaluable.
Partial response or stable disease was noted in all 8
patients with colorectal cancer who underwent
restaging scans after treatment initiation.
Historic response rates for either vemurafenib or
irinotecan+cetuximab in BRAFmut CRC patients are <10%
For the 8 colorectal cancer patients who have
undergone restaging, the response rate was 50%.
(95% CI of 16 to 85%)
Hong et al: ASCO 2014
110. SWOG S1406: a randomized phase II study of irinotecan
and cetuximab with or without vemurafenib in BRAF-
mutant metastatic colorectal cancer
BRAFV600E-mutated
metastatic colorectal
cancer
1-2 lines of prior
systemic treatment
No prior EGFR
monoclonal antibody
KRAS/NRAS wild-type
Arm 1: Irinotecan +
Cetuximab
Arm 2: Irinotecan +
Cetuximab +
Vemurafenib
R
Optional crossover to
arm 2 at progression
Endpoints
Primary:
Progression-free survival
Secondary:
Overall survival
ORR by RECIST 1.1
Grade 3/4 Toxicity
Target activation June 15 with Central IRB. Open through CTSU for all cooperative groups.
PI: Kopetz
112. Computed Tomographic (CT) Scans of the Chest Showing Tumor Regression in a Metastatic
Melanoma Patient Who Received the Concurrent Regimen of Nivolumab and Ipilimumab.
WolchokJDetal.NEnglJMed2013;369:122-133.
114. Conclusions:
Many treatment options are available to patients
but limitations remain for KRAS MT patients.
Controversy remains whether all RAS WT tumor
types may have more benefit for OS if an anti-
EGFR therapy is provided in the front-line setting.
However, provision of anti-EGFR therapy in the
setting of a RAS MT can be detrimental
Many institutions utilize outside sites for tissue processing
Need a readily available panel with all RAS mutations
With categorization based on molecular marker
analysis, it is likely more “rare” subgroups will be
identified.
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118. ABOUT THE COLON CANCER ALLIANCE
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cancer killers. We are doing this by championing prevention,
funding cutting-edge research and providing the highest
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In 2013, the Colon Cancer Alliance:
120. SAVE THE DATE
December 2014 Breakthrough Summit Series for newly diagnosed,
long term survivors and young-onset patients.
Visit ccalliance.org to learn more.
122. Contact Us
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