Alphabet Soup - Biomarker testing for colon and rectal cancer patients - KRAS, RAS
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Transcript of Alphabet Soup - Biomarker testing for colon and rectal cancer patients - KRAS, RAS
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Department of GI Medical Oncology
ALPHABET SOUP: MAKING SENSE OF KRAS, BRAF, RAS AND OTHER BIOMARKERS
IN METASTATIC COLORECTAL CANCER
Cathy Eng, M.D., F.A.C.P.Associate Professor
Associate Medical Director, Colorectal CenterDirector of Network Clinical Research, GI Med Oncology
Co-Chairman, SWOG Rectal SubcommitteeApril 23, 2014
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Cancers of the Colon and RectumInternational 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 inmen and the 2nd in women.
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Advances in the Treatment of Metastatic Colorectal Cancer
1980 1985 1990 1995 2000 2005
Therapeutic concepts
Palliative CTNeoadjuvant CT
CapecitabineOxaliplatin
Cetuximab
Bevacizumab
Irinotecan5-FU
Panitumumab Targeted therapies
{
5-FU = 5-fluorouracil; CT = chemotherapy.
{Cytotoxic chemotherapies
Ras
OS: 20M
OS: 32 months
AfliberceptRegorafenib
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IFL
IFL + b
evaciz
umab
FOLFOX/Cap
eOx
FOLFOX/Cape
Ox + be
v
FOLFIRI
FOLFIRI +
beva
cizum
abmIFL
mIFL + be
vaciz
umab
0
5
10
15
20
25
30
15.6
20.3 19.9 21.323.1
28
17.619.2
First-Line Bevacizumab in mCRC: Overall Survival
*P<0.001; †P = 0.0769.1. Hurwitz H et al. N Engl J Med. 2004;350:2335-2342; 2. Saltz LB et al. J Clin Oncol. 2008;26:2013-2019; 3. Fuchs C et al. J Clin Oncol. 2007;25:4779-4786; 4. Fuchs C et al. J Clin Oncol. 2008;26:689-690;
OS
(mon
ths)
*
NO169662
AVF2107g1
BICC-C3,4
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Approved Anti-VEGF Agents Antiangiogenic agent Description Target Approval
BevacizumabRecombinant humanized
monoclonal antibody VEGF-A
1st-line mCRC1,2:•FDA 2004•EMEA 20052nd-line mCRC1:•FDA 2006, 2013
Aflibercept Fully human fusion protein
VEGF-AVEGF-B
PIGF
2nd-line mCRC3,4:•FDA 2012•EMEA 2013,•TGA 2013
Regorafinib Small molecule TKI VEGFR-1,2 & 3 PDGFR-b,
TIE-2, FGFR-1, Ret, Kit, & Raf kinases
Salvage5,6:•FDA 2012•CHMP 2013•TGA 2013
CHMP, Committee for Health and Medicine Products; EMEA, European Medicines Agency; FDA, United States Federal Drug Administration, FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; PlGF, placental growth factor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor .
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Biomarker Development
Review of Definitions: Prognostic marker
Independent of treatment May impact surveillance
Predictive marker Impacts type of treatment provided
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Molecular Markers for Anti-VEGF
None identified and validated: Bevacizumab Aflibercept Regorafenib
Anti-EGFR Therapy Predictive: KRAS/NRAS Prognostic: BRAF
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Current Molecular Markers
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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
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Copyright © American Society of Clinical Oncology
Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007
Cetuximab and K-ras modulate signaling through the epidermal growth factor receptor (EGFR) pathway
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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.
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NRAS Resembles Kras Oncogene < 5% of all mCRC Mutations in codons 12, 13, 61, 117 and
146 Usually codon 61
Mutually exclusive with KRAS
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Front-line chemotherapy with anti-EGFR therapy
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Update on PRIME Study Phase III
Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.
Patients• Previously untreated mCRC
• Fluorouracil-based adjuvant chemotherapy allowed if PD occurred ≥6 mo after completion; no oxaliplatin
• Tumor tissue from primary tumor or metastasis available for biomarker analysis
• ECOG PS 0-2
• N=1183Primary endpoint: PFS
Panitumumab 6.0 mg/kg q 2 wkFOLFOX4 q 2 wk
1:1 Randomization
FOLFOX4 q 2 wk
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Distribution of mutations in mCRC
RAS wt~50%
KRAS mt (exon 2)
~40%
KRAS mt(non exon 2 KRAS mt) &
NRAS mt~10%
Rare KRAS MutationsNRAS Mutations
Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.
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PRIME Biomarker Analysis: Analysis of KRAS/NRAS and BRAF Mutations
RAS and BRAF Status FOLFOX4 Alone Panitumumab + FOLFOX4
KRAS exon 2 (codon 12/13) WTMT
331219
325221
WT KRAS exon 2 tumors tested for RAS and BRAF (n = 321) (n = 320)WT KRAS exon 2/MT other RAS, n (%) 57 (18) 51 (16)
KRAS exon 3 (codon 61), n (%)WTMT
Failure
306 (95)14 (4)1 (0)
308 (96)10 (3)2 (1)
KRAS exon 4 (codons 117/146), n (%)WTMT
Failure
296 (92)15 (5)10 (3)
288 (90)21 (7)11 (3)
NRAS exon 2 (codons 12/13), n (%)WTMT
Failure
307 (96)14 (4)0 (0)
308 (96)8 (3)4 (1)
NRAS exon 3 (codon 61), n (%)WTMT
Failure
305 (95)14 (4)2 (1)
305 (95)12 (4)3 (1)
NRAS exon 4 (codons 117/146), n (%)WTMT
Failure
313 (98)0 (0)8 (2)
316 (99)0 (0)4 (1)
BRAF exon 15 (codon 600), n (%)WTMT
Failure
280 (87)29 (9)12 (4)
286 (89)24 (8)10 (3)
Oliner J, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3511. Oliner J, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 2275.
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Revised PRIME Consort Diagram
Douillard et al: NEJM, 2013
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PRIME: Progression-free survival in patients with (A) Original wild-type (WT) KRAS, (B) Updated All WT RAS, Overall survival in patients with (C)
Original WT KRAS and (D) All WT KRAS
Douillard J et al. JCO 2010;28:4697-4705; NEJM, 2013©2010 by American Society of Clinical Oncology
D
B
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PFS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS
Oliner KS. ASCO 2013. Abstract 3511.
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OS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS
Oliner KS. ASCO 2013. Abstract 3511.
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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.
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Treatment choice: Front line chemotherapy with anti-EGFR therapy
or anti-VEGF therapy?
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PEAK: Randomized Phase II (KRAS WT)
FOLFOX/Pmab (N=142)
FOLFOX/Bev (N=143)
Median PFS (95% CI) 10.9 (9.4-13.0) 10.1 (9.0-12.6)
Median OS (95% CI) 34.2 (26.6-NR) 24.3 (21.0-29.2)
ORR (95% CI) 58 (49-66) 54 (45-62)]
Subsequent therapy:Anti EGFR
21% 38%
Anti-VEGF 40% 24%
Schwarzberg et al: JCO 2014
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PEAK: Randomized Phase II (KRAS WT and rare RAS WT)
FOLFOX/Pmab (N=88)
FOLFOX/Bev (N=82)
Median PFS (95% CI) 13.0 (10.9-15.1) 9.5 (9.0-12.7)
Median OS (95% CI) 41.3 (28.8-41.3) 28.9 (23.9-31.3)
ORR (95% CI) 64 (52.7-73.6) 61 (49-71.2)
Subsequent therapy:Anti EGFR
22% 37%
Anti-VEGF 40% 33%
Schwarzberg et al: JCO 2014
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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)
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FIRE-3: Overall Response Rate
Endpoint FOLFIRI + Cetuximab
FOLFIRI + Bevacizumab OR P Value
ORR, intent-to-treat (ITT) population (N=592)
62.0% 58.0% 1.18 (0.85-1.64) 0.183
Complete response 4.4% 1.4%
Partial response 57.6% 56.6%
Stable disease 17.5% 28.8%
Progressive disease 7.1% 5.4%
Not evaluable 13.1% 7.8%
ORR, Evaluable (N=526) 72.2% 63.1% 1.52(1.05-2.19) 0.017
Heinemann V. ASCO 2013. Abstract LBA3506.
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FIRE-3: Progression Free Survival
Stintzing S. ASCO 2013. Abstract LBA3506
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FIRE-3: Overall Survival
Heinemann V. ASCO 2013. Abstract LBA3506.
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Consort FIRE-3 Diagram
N=592KRAS exon 2 wild-type
ITT population
N=407 (69%)RAS evaluable population
N=65 (16%)‘New’ RAS mutant
N=342RAS wild-type
N= 171 FOLFIRI +Cetuximab
N= 34FOLFIRI
Cetuximab
N= 171 FOLFIRI +
Bevacizumab
N= 31FOLFIRI +
Bevacizumab
N=752mCRC 1st-line
unselected patients
N=58FOLFIRI +Cetuximab
N=55FOLFIRI +
Bevacizumab
N=113KRAS exon 2 mutant
population*
KRAS unknown= 30No treatment= 13
No treatment KRAS mt = 4
Stinzing et al: ESMO, 2013
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KRAS Wildtype Exon 2 Additional Subsets
?
? ?
EXON 1 EXON 2 EXON 3 EXON 4
EXON 2 EXON 3 EXON 4
KRAS
NRAS
12 13
12 13
61 146
59 61 117 146
wt
? ?
EXON 1
EXON 15EXON 11BRAF
600? ?
Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.
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Eventsn/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
0.012 24 36 48 60 72
months since start of treatment
171171
No. at risk
128127
7168
3926
209
61
0.75
1.0
0.50
0.25
0.0
Prob
abili
ty o
f sur
viva
l
Δ = 7.5 months
* KRAS and NRAS exon 2, 3 and 4 wild-typeStinzing et al: ESMO, 2013
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FIRE-3 Update: Overall Survival by All-RAS Mutation Status
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.
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FIRE-3: Summary and Clinical Implications
Current data limitations No central assessment of response OS data continues to mature Duration of second and subsequent lines of therapy
not reported Practical impact
EGFR antibodies added to FOLFIRI can be considered a viable option in first-line, KRAS wild-type mCRC
Next steps CALGB 80405 data (in 2014) may clarify results
Heinemann V. ASCO 2013. Abstract LBA3506.
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Should all RAS WT patients receive anti-EGFR therapy
front-line?
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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
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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.
Prop
ortio
n pr
ogre
ssio
n fr
ee
1.00
0.75
0.50
0.25
0.00
0 6 12 18 24 30 36 42 48 54 60Time to progression or death (months)
HR: 1.49 (95% CI: 1.04-2.12); P = .030
Number at riskChemo 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 aloneChemo + cetuximab
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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.
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Upcoming: Liver-Only Trials
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BOS-2 (EORTC 40091): Phase II KRAS WT Resectable Liver Mets
RANDOMIZE
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
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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
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CALGB/SWOG 80405: Results: ASCO 2014
RANDOMIZE
FOLFOX or FOLFIRI* + cetuximab
• First-line mCRC
• Amended accrual; N=2300 wild-type patients
FOLFOX or FOLFIRI* + cetuximab + bevacizumab
FOLFOX or FOLFIRI* + bevacizumab
Study amended: Wild-type KRAS tumors only
Primary endpoint: OS
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SWOG 1406: BRAF MT mCRC
PI: S Kopetz
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Conclusions: All RAS WT tumor types may provide more
benefit in OS if an anti-EGFR therapy is provided in the front-line setting.
Provision of anti-EGFR therapy in the setting of a RAS MT can be detrimental Many institutions utilize outside sites for tissue
processing Not all codons are identified Need a readily available panel with all RAS
mutations