colorectal cancer axel grothey professor of oncology mayo clinic rochester axel grothey professor of...
TRANSCRIPT
Colorectal Cancer
Axel Grothey
Professor of Oncology
Mayo Clinic Rochester
Disclosures
• Consulting activities (honoraria went to the Mayo Foundation)• Amgen• Bayer• Pfizer• Roche/Genentech• BMS• Imclone/Eli-Lilly
I WILL include discussion of investigational or off-label use of a product in my presentation.
CRC as worldwide health problem
• CRC Global Statistics:• 3rd highest incidence rate (~ 1,200,000/yr)• 4th highest mortality rate (~ 608,000/yr)
CA: A Cancer Journal for Clinicians 2011;61:69-90
Worldwide Developed Developing
Sporadic
Lynch Syndrome
Familial
Hereditary
FAP; AFAPMixed Polyposis SyndromeAshkenazi I1307KCHEK2 (HBCC)MYHTGFBR1
PJSFJPCDBRRS
= as yet undiscovered hereditary cancer variants
HamartomatousPolyposis
Syndromes
AC-1 without MMR(Familial CRC of syndrome “X”)
US Preventative Services Task Force Screening Recommendations (October 2008)
The USPSTF recommends CRC screening for men and women aged 50–75* using high-sensitivity fecal occult blood testing (FOBT), sigmoidoscopy, or colonoscopy. The decision to be screened after age 75 should be made on an individual basis.
• High-Sensitivity FOBT – once a year
• Flexible Sigmoidoscopy – every 5 years
• Colonoscopy – every 10 years
Other screening tests in use or being studied (not recommended by the USPSTF )
• Double-Contrast Barium Enema
• Virtual Colonoscopy
• Stool DNA Test
http://www.cdc.gov/cancer/colorectal/basic_info/screening/tests.htm
*no upper age limit in all other guidelines
12.3% of patients presented with recurrent CRC.*2002 data.
24.5% stage II*
18.6% stage IV*12% stage I*
32.6% stage III*
American Cancer Society, 2005; Datamonitor, 2003.
CRC:Demographics and Presentation
• Estimated 2009 U.S. incidence (new cases): 147,000
• Estimated 2008 U.S. mortality: 49,900
National Comprehensive Cancer Network (NCCN), 2008; Greene et al., 2002.AJCC = American Joint Committee on Cancer.
AJCCv6 TNM Staging Definitions
Primary tumor (T) Tis Carcinoma in situ
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades through muscularis propria or subserosa
T4 Tumor directly invades other organs or structures
Regional lymph nodes (N) N0 No regional lymph node metastases
N1 Metastases in 1–3 regional lymph nodes
N2 Metastases in 4 or more regional lymph nodes
Distant metastases (M) M0 No distant metastases
M1 Distant metastases
T4a: perf. visceral peritoneumT4b: invasion of organs
N1a: 1 N+N1b: 2-3 N+
N2a: 4-6 N+N2b: >7 N+
TNM / AJCC v7 Effective Jan 2010
AJCC v7
Gunderson et al, JCO 2009
Stage II Stage III
History of adjuvant therapy of colon cancer
• 5-FU/lev superior to surgery alone
• 5-FU/LV superior to surgery alone
• 5-FU/LV superior to 5-FU/lev
• 6- and 12-month treatment cycles equivalent
• Lev unnecessary
• High-dose and low-dose LV equivalent
• Monthly and weekly treatment equivalent
• LV5FU2 and monthly bolus equivalent
1990 1994 1998 2002
Moertel et al. Ann Intern Med. 1995;122:321.Francini et al. Gastroenterol. 1994;106:899.Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. AbstractO’Connell et al. J Clin Oncol. 1998;16:295.Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982.Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.
Recurrence rate over time
83% of recurrencesoccur within the
first 3 years
Sargent et al., ASCO 2009
Beyond 5-FU in the adjuvant setting
Completed studies:• Capecitabine (X-ACT)
• Oxaliplatin (MOSAIC, NSABP C-07, XELOXA)
• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)
• Bevacizumab (NSABP C-08, AVANT)
• Cetuximab in KRAS wt CC (N1047, PETACC-8)
Ongoing studies:• QUASAR2 (Cape +/- BEV)
X-ACT: Cape vs Mayo - 5-year DFS
(median follow-up 6.8 years)5-year n DFS (%)
Capecitabine 1, 004 60.8
5-FU/LV 983 56.7
1.0
0.8
0.6
0.4
0.2
0
0 6 42 48 78 96
Months
HR=0.88 (95% CI: 0.77–1.01)NI margin 1.20
12 18 24 30 36 54 60 66 72 84 90
ITT population
Est
imat
ed p
rob
abil
ity
ITT (intent-to-treat) population; NI = non-inferiorityTwelves C, et al. Eur J Cancer Suppl
2007;5:1 (Abstract 1LB)
102
Test of non-inferiority p<0.0001Test of superiority p=0.0682
MOSAIC: Study Design
Primary end-point: disease-free survival
Secondary end-points: safety, overall survival
n=2246
Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries)
• Completely resected colon cancer
• Stage II, 40%; Stage III, 60%
• Age 18–75 years
• KPS ≥60
• No prior chemotherapy
R
LV5FU2
FOLFOX4(LV5FU2 + oxaliplatin 85 mg/m²)
(n=1123)
(n=1123)
LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1
Andre NEJM 2004
MOSAIC: Disease-free Survival - Final Update
5-year DFS %
HR [95% CI] p-value FOLFOX4 LV5FU2
ITT 73.3 67.4 0.80
[0.68–0.93]
0.003
Stage III 66.4 58.9 0.78
[0.65–0.93]
0.005
Stage II 83.7 79.9 0.84
[0.62–1.14]
0.258
High-risk stage II n=576
82.1 74.9 0.74
[0.52–1.06]
—
Low-risk stage II n=323
86.3 89.1 1.22
[0.66–2.26]
—
Data cut-off: June 2006
Δ7.5
Δ7.2
Andre JCO 2009
MOSAIC: OS: Stage II and Stage III
0.1%
4.4%
Andre JCO 2009
Long-term Safety
Data cut-off: January 2007
Peripheral Sensory Neuropathy
Evaluable patients n=811
Grade 0 84.3%
Grade 1 12.0%
Grade 2 2.8%
Grade 3 0.7%
Andre JCO 2009
Should patients with stage II colon cancer receive adjuvant therapy?
% o
f P
atie
nts
QUASAR: OS in patients with “no clear indication for chemo” (mostly stage II)
5-FU/LV vs surgery alone
P = .025-year OS, Observation = 77.4% vs Chemotherapy = 80.3%Relative risk = 0.83 (95% CI, 0.71-0.97)
Years
QUASAR group, Lancet 2007
0 1 2 3 4 5 6 7 8 9 100
20
40
60
80
100Observation (n=1622)
Chemotherapy (n=1617)
5-yr OS difference: 2.9%
“High-risk” Stage II Colon Cancer
• Clinical-pathological parameters• T4 tumors• Less than 10 (12) LNs examined• Obstruction/perforation• Lymphatic or vascular invasion• Undifferentiated histology
• Molecular parameters• Single marker vs signature - TBD
Defective MMR (dMMR) - Colon cancer
• Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression
• ~15% of Sporadic CC, >90% loss of MLH1
• Clinical Correlations: Right sided, female, early stage, excellent prognosis!
• Tumors: Poorly differentiated, Signet-ring-cell, Lymphocytic infiltration, near diploid
• dMMR cells resistant to 5-FU1,2
1Carethers, 1999; 2Arnold 2003
Decision Algorithm in Adjuvant Therapy
Resected Colon Ca
Stage II Stage III
FOLFOXXELOX
High-Risk
dMMR
No therapy!5-FU/LV or
Capecitabine*
*
*pts not considered candidates for oxaliplatin
T4 and/or<12 LNs
Low-Risk
Intermed. Risk
yes
yes
no
no
?Marker signature?
Grothey, Oncology 2010
What is the Standard Adjuvant Therapy in Colon Cancer ?
• FOLFOX (or XELOX) is standard adjuvant therapy in
• stage III and
• can be considered in high-risk stage II colon cancer
• very consistent results for oxaliplatin across trials
• Capecitabine (or 5FU/LV) for
• patients who are not considered candidates for oxaliplatin (elderly?)
• unselected stage II, pMMR
• Irinotecan, bevacizumab, and cetuximab have failed!
Advances in the Treatment of Stage IV CRC
1980 1985 1990 1995 2000 2005
5-FUIrinotecan
CapecitabineOxaliplatin
CetuximabBevacizumab
Best supportive care (BSC)
median overall survival
Panitumumab
Treatment paradigms for mCRC
• Some patients with stage IV disease can be cured by an interdisciplinary approach
• In the palliative setting: FOLFOX = XELOX = FOLFIRI (XELIRI has problems with toxicity)
• Most patients tolerate a chemotherapy doublet, but not all need it
• The addition of biologics to chemotherapy has improved outcomes, but not as much as we hoped
• We are on the verge of individualized therapy based on molecular predictive factors
Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients
OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005
0 10 20 30 40 50 60 70 80
Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV
LV5FU2
FOLFOXIRI
CAIRO
22
21
20
19
18
17
16
15
14
13
12
Med
ian
OS
(m
o)
Patients with 3 drugs (%)
P =.0001
First-Line Therapy
2007
Murine Ab“momab”
ChimericMouse-Human Ab
“ximab”
Humanized Ab“zumab”
Fc
Fab
Human Ab“mumab”
Biologic Agents in Colorectal Cancer = Monoclonal Antibodies
(17-1A) Cetuximab Bevacizumab
PanitumumabEGFR
VEGF
Nomenclature of Monoclonal Antibodies
-mab monoclonal antibody
-mo-mab mouse mab
-xi-mab chimeric mab
-zu-mab humanized mab
-mu-mab human mab
-tu-xx-mab tumor-directed xx mab
-li-xx-mab immune-directed xx mab
-ci-xx-mab cardiovascular-directed xx mab
-vi-xx-mab virus-directed xx mab
Inf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab
Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy
IFL+ Placebo (n=411)
IFL+ Bevacizumab(n=402) P Value
Median survival (mo)
15.6 20.3 0.00004
PFS (mo) 6.2 10.6 <0.00001
ORR (%)
CR
PR
35
2.2
32.5
45
3.7
41.2
0.0036
Duration of resp. (mo)
7.1 10.4 0.0014
Hurwitz et al. N Engl J Med 2004
Phase III Trial of IFL +/-Bevacizumab in MCRC: PFS
HR=0.54, P<0.00001
Median PFS: 6.2 vs 10.6 mo
0.2
0 10 20 300
0.8
1.0
0.4
0.6
Progression-free survival (mo)
Pro
po
rtio
n p
rog
res
sio
n-f
ree
Treatment Group
IFL + placeboIFL + bevacizumab
Hurwitz et al. N Engl J Med 2004
XELOX + placebo N=350
FOLFOX4 + placebo N=351
XELOX + bevacizumab
N=350
FOLFOX4 + bevacizumab
N=350
XELOX N=317
FOLFOX4 N=317
Initial 2-arm open-label study
(N=634)
Protocol amended to 2x2 placebo-controled design after bevacizumab
phase III data1 became available (N=1401)
RecruitmentJune 2003 – May 2004
RecruitmentFeb 2004 – Feb 2005
XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design
1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy & Saltz, JCO 2008
PFS chemotherapy + bevacizumab superiority: primary endpoint
0 5 10 15 20 25
Months
PF
S e
stim
ate
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)p = 0.0023
9.48.0
1.0
0.8
0.6
0.4
0.2
0
FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events
Saltz et al., JCO 2008
CONcePT study: IO arm
2400
x 8
Cumulative oxaliplatin
680 mg/m2
Months
42400
x 8
8680 mg/m2
2400
200855
2005
200855
x 8 1360 mg/m2 12
etc.
LVOXBEV
5-FU
Grothey et al, ASCO 2008
AIO 0504 / Roche ML18147Multinational European Trial
Any-OX+ BEV
Any-IRI+ BEV
Any-IRI+ BEV
Any-IRI Any-OXAny-OX+ BEV
R R
N = 820Primary EP: OS
Accrual completed May 31, 2010
AIO 0504 / Roche ML18147Multinational European Trial
Any-OX+ BEV
Any-IRI+ BEV
Any-IRI+ BEV
Any-IRI Any-OXAny-OX+ BEV
R R
N = 820Primary EP: OS
Accrual completed May 31, 2010
January 26, 2012: Press release.Trial met primary endpoint of improvedoverall survival! ASCO 2012!
Pertinent Side-Effects of Anti-VEGF Therapy
• Hypertension
• Arterial thrombotic/ thromboembolic events (ATEs)
• Gastrointestinal perforation (GIP)
• Bleeding
• Delayed wound healing
• (Proteinuria)
Safety and Effectiveness Outcomes, by Age Subgroup in BRiTE (US Patient Registry)
All(N = 1953)
<65 y(n = 1057)
65–74 y(n = 533)
≥75 y(n = 363)
≥80 y(n = 161)
Safety, %
GI perforation 2.0 2.6 1.5 1.1 0.6
Post-op bleeding or WHCs 5.1 5.5 4.5 4.5 3.8
ATE 1.9 1.6 1.3 3.9 3.7
Grade 3/4 bleeding 2.6 2.2 3.4 2.5 1.2
New/worsening HTN 20.7 20.5 20.6 21.2 21.1
Survival
Median PFS, months 9.9 10.2 9.7 9.8 9.2
1-yr survival rate, % 74.4 77.1 72.5 69.4 65.8
Median OS, months 23.5 27.3 21.3 19.5 16.2
Kozloff et al. Oncology 2010
mAbs Target Tumor Cell-Bound EGFR
Extracellular
Intracellular
Ligand
EGF-R
PI3K
Akt
Raf
MEK
MAPK
Cell Motility
MetastasisAngiogenesisProliferation
Cell survivalDNA
PTEN
Ras
mAbs Target Tumor Cell-Bound EGFR
Extracellular
Intracellular
Ligand
EGF-R
PI3K
Akt
Raf
MEK
MAPK
Cell Motility
MetastasisAngiogenesisProliferation
Cell survivalDNA
Ras
PTEN
NCIC CTG CO.17: Randomized Phase III Trial in mCRCCetuximab vs BSC (no cross-over)
KRAS mut KRAS wild-type All patients
BSC
n=83
Cetux
n=81
BSC
n=113
Cetux
n=117
BSC
n=285
Cetux
n=287
RR 0% 1.2% 0% 12.8% 0% 6.6%
PFS (mos) 1.8 1.8 1.9 3.8 1.8 1.9
OS (mos) 4.6 4.5 4.8 9.5 4.6 6.1
Karapetis et al. NEJM 2008
<0.0001
<0.0001 <0.0001
0.0046
CRYSTAL Study (1st Line)
FOLFIRI + Cetuximab
FOLFIRI
EGFR-expressingmetastatic CRC PFS
Stratified by:• Regions • ECOG PS
• Primary Endpoint: PFS (independent review)
• Secondary Endpoints: RR, DCR, OS, Safety, QoL
• Sample Size: 1217 patients randomized, ITT: 1198 pts
N = 599
N = 599
Van Cutsem et al. NEJM 2009
R
5-FU/LV/IRI (FOLFIRI) ± Cetuximab: PFSNon-KRAS adjusted
PFS (mos)
PF
S e
stim
ate
1.0
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 2 4 6 8 10 12 14 16 18 20
FOLFIRI
FOLFIRI + Cetuximab
HR = 0.851P = 0.0479
8.0 vs 8.9 mos
Subgroupeffect
No benefit
Van Cutsem et al, 2009
Relating KRAS status to efficacyPrimary endpoint: PFS – KRAS wild-type
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18
Months
Pro
gre
ss
ion
-fre
e s
urv
iva
l e
sti
ma
te
Cetuximab + FOLFIRI FOLFIRI
KRAS wild-type (n=348) HR=0.68; p=0.017
mPFS Cetuximab + FOLFIRI: 9.9 months mPFS FOLFIRI: 8.7 months
1-yr PFS rate25% vs 43%
Van Cutsem et al. NEJM 2009
CRYSTAL: Efficacy UpdateAfter Additional KRAS Testing
Van Cutsem et al. JCO 2011
KRAS wild-type FOLFIRI FOLFIRI + cetuximab
P value
n 350 316
RR (%) 39.7 57.3 < 0.0001
mPFS (mos) 8.4 9.9 0.0012
mOS (mos) 20 23.5 0.0093
KRAS mutated FOLFIRI FOLFIRI + cetuximab
P value
n 183 214
RR (%) 36.1 31.3 0.34
mPFS (mos) 7.7 7.4 0.26
mOS (mos) 16.7 16.2 0.75
HR 0.7HR 0.8
CRYSTAL
PRIME OPUS COIN NORDIC CAIRO2 181 PIC-COLO
-20
-15
-10
-5
0
5
10
15
20
25
30
17
7
24
7
-1
11
25
22
-5
0
-16
-3
9
-13
-1
-5
KRAS wtKRAS mut
Ch
ang
es i
n r
esp
on
se r
ates
(%
)
2nd Line 1st Line
IRI OX OX OX OX OX IRI IRI
Grothey & Lenz, JCO 2012
CAIRO2: Study design
Primary endpoint
• Progression-free survival
Secondary endpoints
• RR
• OS time
• Toxicity
• Translational research
CapOx + BEV
(COB, n=368)
CapOx + BEV + Cetuximab
(COB-C, n=368)
EGFR-detectablemCRC R
Tol et al. NEJM 2009
Oxaliplatin d/c’d after 6 cyclesi.e. after 18 weeks = 4.5 mos
KRAS wild-typen = 314 (61%)
KRAS mutatedn = 196 (39%)
p value
Median PFS (months)
COB 10.6 12.5 0.80
COB-C 10.5 8.1 0.04
p value 0.30 0.003
Median OS (months)
COB 22.4 24.9 0.82
COB-C 21.8 17.2 0.06
p value 0.64 0.03
CAIRO2 - KRAS genotyping (n=501)
Tol et al. NEJM 2009
Bevacizumab vs EGFR Antibodies in Advanced CRC - Simplified
Agent Strength Weakness
Bevacizumab • Delay in tumor progression
• Gain in time• Toxicity profile
• Limited single agent activity
• Weak effect on RR(per RECIST)
EGFR antibodies
• Single agent activity• Consistent increase
in RR• Activity independent
of line of therapy• Negative predictive
marker available
• Gain in time to progression moderate
• Toxicity profile
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGFVEGF-B
VEGF-C, VEGF-D
Fu
nct
ion
s
Large molecule VEGF inhibitors
Y
Bevacizumab
YRamucirumab
Aflibercept (VEGF Trap)
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 ptsAflibercept 4 mg/kg
IV+ FOLFIRI q 2 weeks
600 pts Placebo + FOLFIRIq 2 weeks
51
30% of patients had prior BEVPIs: Allegra, Van Cutsem
Safety – Most frequent AEs, with ≥ 5% difference in incidence between treatment arms, excluding anti-VEGF class events
Safety Population, % of patients
Placebo, N = 605 Aflibercept N = 611
All Grades Grade 3-4 All
Grades Grade 3-4
Diarrhea 56.5 7.8 69.2 19.3
Neutropenia** Complicated neutropenia
56.3 29.52.8
67.8 36.75.7
Asthenic conditions (HLT) 50.2 10.6 60.4 16.9
Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7
Thrombocytopenia** 33.8 1.7 47.4 3.3
Infections (SOC) 32.7 6.9 46.2 12.3
Decrease appetite 23.8 1.8 31.9 3.4
Weight decreased 14.4 0.8 31.9 2.6
Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 2.8
Skin hyperpigmentation 2.8 0 8.2 0
Dehydration 3.0 1.3 9.0 4.3
Van Cutsem, et al. WCGC 2011
AEs leading to treatment discontinuation:AFL: 26.6%PL: 12.1%
Overall Survival - ITT Population
Cut-off date = February 7, 2011; Median follow-up = 22.28 monthsVan Cutsem, et al. WCGC 2011
Regorafenib – A Multi-Kinase Inhibitor
Cellular Phosphorylation Assays IC50 nMVEGFR-2 Phosphorylation, 293 Cells 8
TIE2-Receptor Phosphorylation, CHO Cells 31
PDGFR-β Phosphorylation, Aortic SM Cells 90
mVEGFR3 Phosphorylation, 293 Cells 150
Mutant RET Phosphorylation, Thyroid TT Cells 10
Mutant c-KIT Phosphorylation, GIST 882 Cells 20
FGF-10 FGFR MCF-7 Cells 150-300
MAPK ERK-P HCC, HepG2 Cells 500
Cell Proliferation Assays IC50 nMVEGF/HuVEC (2% FCS) BrdU 4
bFGF/ HuVEC (2% FCS) BrdU 120
PDGFBB/Aortic SM (0.1% BSA) BrdU 121
Thyroid TT RET C643W (10% FCS) 33
GIST 882 KIT K642E (10% FCS) 45
Breast, MDA MB 231 (10% FCS) 570
Melanoma, A375 (10% FCS) 900
HCC HepG2 (10% FCS) 560
CORRECT study design
• Multicenter, randomized, double-blind, placebo-controlled, phase III• 2:1 randomization• Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC,
geographical region
• Global trial: 16 countries, 114 active centers• 1,052 patients screened, 760 patients randomized within 10 months
• Secondary endpoints: PFS, ORR, DCR
• Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers
mCRC after standard therapy
mCRC after standard therapy
RANDOM I ZAT I ON
RANDOM I ZAT I ON
Regorafenib + BSC 160 mg orally once daily
3 weeks on, 1 week off
Regorafenib + BSC 160 mg orally once daily
3 weeks on, 1 week off
Placebo + BSC 3 weeks on, 1 week off
Placebo + BSC 3 weeks on, 1 week off
2 : 1
Primary Endpoint:
OS90% power to detect 33.3%
increase (HR=0.75), with 1-sided overall
a=0.025
Primary Endpoint:
OS90% power to detect 33.3%
increase (HR=0.75), with 1-sided overall
a=0.025
Overall survival (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)
1.00
0.50
0.25
0
0.75
200100500 150 300250 400350 450
Days from randomization
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
Placebo N=255Regorafenib N=505
Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value: 0.0052
Regorafenib Placebo
Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade
Adverse event, %Regorafenib
N=500PlaceboN=253
All grades
Grade 3
Grade 4
Grade 5
All grades
Grade 3
Grade 4
Grade 5
Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0
Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0
Hypertension 27.8 7.2 0 0 5.9 0.8 0 0
Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0
Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0
Anorexia 30.4 3.2 0 0 15.4 2.8 0 0
Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0
Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0
Fever 10.4 0.8 0 0 2.8 0 0 0
Nausea 14.4 0.4 0 0 11.1 0 0 0
Bleeding 11.4 0.4 0 0.4 2.8 0 0 0
Voice changes 29.4 0.2 0 0 5.5 0 0 0
Weight loss 13.8 0 0 0 2.4 0 0 0
Adverse events leading to permanent Tx discontinuation
8.2% 1.2%
Take-Home Messages: Optimized Medical Therapy of Advanced CRC
1. Identify the goal of therapy• For most patients gain of time and
maintaining QOL is more important• Strength of BEV – duration of therapy
matters• RR only matters for
• conversion therapy of liver metastases or• if patient is symptomatic from his tumor
burden
Take-Home Messages: Optimized Medical Therapy of Advanced CRC
2. Treat to progression – and beyond Be mindful about toxicities, stop oxaliplatin before neurotoxicity develops• Some select patients can have CFI
3. Expose patients to all potentially active agents• These agents are the oncologist’s tools to
keep patients alive• Use fluoropyrimidine-based combinations as
default backbone, reserve sequential single agent therapy for select patients
4. We finally have new active agents in CRC: Aflibercept and regorafenib