colorectal cancer research & treatment news - recap from the may 2014 asco conference
DESCRIPTION
Dr. Cathy Eng delivers updates on current trials and studies impacting the treatment of colon and rectal cancer.TRANSCRIPT
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.
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:
Today’s Webinar:1. Today’s Speaker: Cathy Eng, M.D. @CathyEngMD
2. Archived Webinars: FightColorectalCancer.org/Webinars
3. AFTER THE WEBINAR: expect an email with links to the material. Also a survey on how we did, receive a Blue Star pin when completed
4. Ask a question in the panel on the RIGHT SIDE of your screen
5. Follow along via Twitter – use the hashtag #CRCWebinar
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Created for those recently diagnosed with Stage III or Stage IV colorectal cancer, this FREE publication is available at fightcolorectalcancer.org/guideinthefight.
This 65-page workbook provides readers with comprehensive information on diagnosis interpretation, detailed treatment options and future planning.
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DisclaimerThe information and services provided by Fight Colorectal Cancer are for general informational purposes only. The information and services are not intended to be substitutes for professional medical advice, diagnoses, or treatment.
If you are ill, or suspect that you are ill, see a doctor immediately. In an emergency, call 911 or go to the nearest emergency room.
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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
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 CenterDirector of Network Clinical Research, GI Med Oncology
Co-Chairman, SWOG Rectal SubcommitteeJuly 16, 2014
Cancers of the Colon and RectumInternational Statistics
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
Incidence
Mortality
1.2 Million
609,000
1.2 Million
609,000
WorldwideWorldwide
per annum
USA (2014) USA (2014)
Incidence
Mortality
Incidence
Mortality
136,830
50,310
136,830
50,310
Colorectal cancer is the 3rd most common cancer inmen and the 2nd in women.
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
IFL
IFL + be
vacizu
mab
FOLFOX/Cap
eOx
FOLFOX/Cap
eOx +
bev
FOLFIRI
FOLFIRI +
bevac
izumab
mIFL
mIFL + be
vaciz
umab
0
5
10
15
20
25
30
15.6
20.3 19.921.3
23.1
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
(m
onth
s)
*
NO169662
AVF2107g1
BICC-C3,4
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 .
UPDATES IN FIRST-LINE TREATMENT: ANTI- VEGF THERAPY
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)
TRIBE: PFS (ITT Population)
Falcone A. ASCO 2013. Abstract 3505.
TRIBE: Secondary Endpoint (OS)
Falcone A. ASCO 2013. Abstract 3505.
TRIBE: Secondary Endpoints
Endpoint FOLFIRI + Bev(n=256)
FOLFOXIRI + Bev(n=252) P Value
Response rate 53% 65% 0.006
Complete response 3% 5%
Partial response 50% 60%
R0 secondary surgery
All patients 12% 15% 0.327
Liver-only subgroup 28% 32% 0.823
Overall survival
25.8 months 31.0 months
Unstratified hazard ratio (HR): 0.83 (0.66-1.05) 0.125
Stratified HR: 0.78 (0.63-1.00) 0.054
Falcone A. ASCO 2013. Abstract 3505.
TRIBE: Grade ≥3 Adverse Events
Patients, %FOLFIRI + Bev
(n=254)FOLFOXIRI + Bev
(n=250) P Value
Serious adverse events (AEs) 19.7 20.4 NR
Fatal AEs 3.5 2.8 NR
Treatment-related deaths 1.6 2.4 NR
Early deaths (<60 days from randomization) 2.3 3.2 NR
Diarrhea 11 19 0.012*
Stomatitis 4 9 0.048*
Neutropenia 20 50 <0.001*
Febrile neutropenia 6 9 0.315
Neurotoxicity 0 5 <0.001*
Falcone A. ASCO 2013. Abstract 3505.
The Role of Bevacizumab Maintenance Therapy: Chronicity of
Treating Unresectable Disease
CAIRO3: Study Design
Primary endpoint: PFS2 (PFS after re-introduction of bevacizumab + XELOX)
Secondary endpoints: PFS1, OS, TT2PD, ORR, safety
Upon PD1, 60% of patients received bevacizumab + XELOX in arm A and 47% in arm B
Koopman, et al. ASCO GI 2014. Abstract LBA388
Previously untreated
mCRC(n=558)
R
bevacizumab
+ XELOX
(x6)
CRPRSD bevacizumab +
capecitabine (n=279)
Observation (n=279)
bevacizumab + XELOX (n=168)
PD2PD1
PFS2PFS1
TT2PDArm A
Arm B
bevacizumab + XELOX (n=132)
PD2PD1
Median follow-up 48 months (cut-off 060114)
CAIRO3: median PFS1
Koopman, et al. ASCO GI 2014. Abstract LBA388
0 6 12 18 24 30 36
PFS
1 e
stim
ate
1.0
0.8
0.6
0.4
0.2
0
279 84 18 10 7 6 5
Time (months)
Observation
Maintenance
Stratified HR (95% CI)p-value
Median
4.1 months
8.5 months
0.43 (0.36‒0.52) <0.0001
No. at risk:278 173 96 53 36 18 10
4.1 8.5
Induction treatment of 6x cycles bevacizumab + XELOX
prior to randomisation not included (4-5 months)
CAIRO3: median PFS2 (primary endpoint)
Koopman, et al. ASCO GI 2014. Abstract LBA388
8.5 11.7
PFS
2 e
stim
ate
1.0
0.8
0.6
0.4
0.2
0
Time (months)
No. at risk:
0 6 12 18 24 30 36
Observation
Maintenance
Stratified HR (95% CI)p-value
Median
8.5 months
11.7 months
0.67 (0.56‒0.81) <0.0001
Induction treatment of 6x cycles bevacizumab + XELOX prior to randomisation not included (4-5 months)
PFS2 = PFS1 for pts in whom bevacizumab + capecitabine is not reintroduced after PFS1 for any reason
279 182 101 37 16 12 7278 206 136 76 46 26 13
CAIRO3: OS
Koopman, et al. ASCO GI 2014. Abstract LBA388
18.1
21.6
0S e
stim
ate
1.0
0.8
0.6
0.4
0.2
0
Time (months)
No. at risk:
0 6 12 18 24 30 36
279 251 198 131 89 61 35
Observation
Maintenance
Stratified HR (95% CI)p-value
Median
18.1 months
21.6 months
0.89 (0.73‒1.07) 0.22
278 258 206 159 112 72 39
Median duration of follow-up 48 months
Induction treatment of 6x cycles bevacizumab + XELOX prior to randomisation not included (4-5 months)
Impact of Currently Approved Molecular Markers
Biomarker Development
Review of Definitions: Prognostic marker
Independent of treatment May impact surveillance
Predictive marker Impacts type of treatment provided
Molecular Markers for Anti-VEGF
None identified and validated: Bevacizumab Aflibercept Regorafenib
Anti-EGFR Therapy Predictive: KRAS/NRAS Prognostic: BRAF
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
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
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.
NRAS Resembles Kras Oncogene < 5% of all mCRC Mutations in codons 12, 13, 61, 117 and
146 Usually codon 61
Mutually exclusive with KRAS
Front-line chemotherapy with anti-EGFR therapy
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
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 Mutations
NRAS Mutations
Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.
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.
Revised PRIME Consort Diagram
Douillard et al: NEJM, 2013
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
PFS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS
Oliner KS. ASCO 2013. Abstract 3511.
OS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS
Oliner KS. ASCO 2013. Abstract 3511.
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.
Treatment choice: Front line chemotherapy with anti-EGFR therapy
or anti-VEGF therapy?
PEAK Phase II Study Design
Schwarzberg et al: JCO, 2014.
Patients• mCRC
• KRAS wild-type
• ECOG PS 0-2
• 1st line therapy; prior adjuvant chemotherapy allowed if completed >6 mo before inclusion
• N=285 Primary Endpoint: PFS
1:1 Randomization
FOLFIRI + Bevacizumab(Bev: 5 mg/kg every 2 weeks)
FOLFIRI + Panitumumab
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
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
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)
FIRE-3: Overall Response Rate
EndpointFOLFIRI + 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.
FIRE-3: Progression Free Survival
Stintzing S. ASCO 2013. Abstract LBA3506
FIRE-3: Overall Survival
Heinemann V. ASCO 2013. Abstract LBA3506.
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
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.
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
Pro
ba
bil
ity
of
su
rviv
al
Δ = 7.5 months
* KRAS and NRAS exon 2, 3 and 4 wild-typeStinzing et al: ESMO, 2013
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.
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.
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
CALGB / SWOG 80405: FINAL DESIGN
N = 1140
1° Endpoint: Overall Survival
Chemo + Cetuximab
Chemo + Bevacizumab
mCRC1st-line
KRAS wild type(codons 12,13)
STRATA:FOLFOX/FOLFIRI
Prior adjuvantPrior XRT
FOLFIRIor
FOLFOX
MD choice
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
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
CALGB/SWOG 80405: Overall Survival
Arm N (Events)OS (m)
Median95% CI
Chemo + Cetux 578 (375) 29.9 27.0-32.9
Chemo + Bev 559 (371) 29.0 25.7-31.2
P=0.34HR 0.925 (0.78-1.09)
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)
CALGB/SWOG 80405: Overall SurvivalFOLFOX 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=0.09HR 0.9 (0.7-1.0)
CALGB/SWOG 80405: Overall SurvivalFOLFIRI 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=0.28HR 1.2 (0.9-1.6)
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)
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
Anti-EGFR versus Bevacizumab Trials
FIRE CALGB/SWOG
80405PEAK
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
2nd line Anti-Angiogenic Options
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
ML18147 (TML): Continuing Bevacizumab Beyond Progression Increases OS (ITT)
OS
(%
)
MosCT (n = 410)BEV + CT (n = 409)
100
80
60
40
20
00 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
PF
S (
%)
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)
4.1
mo
5.7 mo
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
1234567
1234567
VEGF TrapKd = 0.5 pM
Fc
VEGFR-1Kd 10-30 pM
VEGFR-2Kd 100-300 pM
Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:11393-11398.
EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Stratification factors:Prior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)
1:1
mCRC afterfailure of an oxaliplatin
based regimenR
600 pts Aflibercept 4 mg/kg IV+ FOLFIRI q 2 weeks
600 pts Placebo + FOLFIRIq 2 weeks
68
30% of patients had prior BEVPrimary endpoint: OSPI: Allegra et al
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/FOLFIRIMedian: 12.06 mos
Aflibercept/FOLFIRIMedian: 13.50 mos
PF
S (
%)
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/FOLFIRIMedian: 4.67 mos
Aflibercept/FOLFIRIMedian: 6.90 mos
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/FOLFIRIMedian: 11.7 mos
Aflibercept/FOLFIRIMedian: 12.5 mos
Pts at Risk, n PlaceboAFL
187186
170178
138150
115121
8189
5459
3736
2222
1313
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/FOLFIRIMedian: 12.4 mos
Aflibercept/FOLFIRIMedian: 13.9 mos
Pts at Risk, n PlaceboAFL
427426
403388
347348
286295
205222
139157
94112
6582
3862
No Previous Bevacizumab
Treatment of heavily pretreated metastatic colorectal cancer
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.
Biochemicalactivity
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
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
RPlacebo 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
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
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
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
Should all RAS WT patients receive anti-EGFR therapy
front-line?
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
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.
Pro
po
rtio
n p
rog
res
sio
n f
ree 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 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
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.
Upcoming: Liver-Only Trials
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
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
Up and Coming: Novel Agents
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 cycleN = 330
Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15N = 335
SCREEN
RANDOMIZE
Survival and safety follow-up
RAINBOW: Gastric Cancer
Wilke et al: ASCO GI 2014
1:1
RAINBOW: Overall SurvivalHR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
RAM + PTX PBO + PTX
Patients / Events 330 / 256 335 / 260
Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)
6-month OS 72% 57%
12-month OS 40% 30%
RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0
PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Censored
Δ mOS = 2.3 months
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 + PlaceboN = 525
SCREEN
RANDOMIZE
Endpoint: OS
Phase III: FOLFIRI +/- Ramucirumab
1:1
http://clinicaltrials.gov/show/NCT01183780, accessed 2/16/14
MET/HGF Signaling Pathway
Raghav and Eng, Colorectal Cancer, 2012
AMG-102
ARQ-197
MetMab
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
Phase II – MetMab ACCOMPLISH
Bendell et al: J Clin Oncol 30, 2012 (suppl; abstr TPS3640)
Primary Endpoint: PFS
Final results: Pending
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.
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
Rare Population Subsets
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.
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
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)
MOLECULAR CHARACTERISTICS
TRIBE: PFS Subgroup Analyses
Falcone A. ASCO 2013. Abstract 3505.
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)
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.
Poor prognostic indicator
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
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.
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
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
Patient baseline characteristicsCharacteristic 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 priortherapy, median(range)
2 (1-4)
Characteristic N = 12
Site of primary tumor
Colon/rectum 11 (92%)
Appendix 1 (8%)
Prior treatmentexposures
Irinotecan 8 (67%)
Cetuximab 5 (33%)
Vemurafenib 1 (8%)
Microsatellite status 10 tested
MSS 8 (80%)
MSI 2 (20%)
Hong et al: ASCO 2014
Adverse Events by CTCAE version 4.0
Preferred termsGrade 1/2
AEsGrade ≥ 3
AEs
Nausea 9 (75%) 0
Anemia 8 (67%) 1 (8%)
Diarrhea 8 (67%) 3 (25%)
Fatigue 8 (67%) 1 (8%)
Rash 8 (67%) 0
Anorexia 6 (50%) 0
Myalgia 5 (42%) 0
Vomiting 5 (42%) 0
Leukopenia 3 (25%) 0
Mucositis 3 (25%) 0
Preferred terms Grade 1/2 AEs
Grade ≥ 3 AEs
Alopecia 2 (17%) 0
Arthralgia 2 (17%) 1 (8%)
Dyspnea 2 (17%) 0
Cramping 1 (8%) 0
Dysgeusia 1 (8%) 0
Fever 1 (8%) 0
GERD 1 (8%) 0
HTN 1 (8%) 0
Hypoalbuminemia 1 (8%) 0
Weight Loss 1 (8%) 0
Hong et al: ASCO 2014
Responses by RECIST 1.1 in all restaged patients
*
Hong et al: ASCO 2014
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
Months on Study (N=12)
Hong et al: ASCO 2014
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
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
N=39
N=39
Target activation June 15 with Central IRB. Open through CTSU for all cooperative groups.
PI: Kopetz
Is there a role for immunotherapy?
Computed Tomographic (CT) Scans of the Chest Showing Tumor Regression in a Metastatic Melanoma Patient Who Received the Concurrent Regimen of Nivolumab and Ipilimumab.
Wolchok JD et al. N Engl J Med 2013;369:122-133.
BMS CA209142 study: NCT02060188
MSI-H: MDACC PI - Overman
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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