novel treatment strategies in metastatic colorectal cancer patients with kras wildtype tumors
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Novel treatment strategies in metastatic colorectal cancer patients
with KRAS wildtype tumors
Prof.dr. Cornelis PuntDept. of Medical Oncology
Radboud University Nijmegen Medical Center Nijmegen, The Netherlands
Current standard in 1st line metastatic colorectal cancer
• Chemotherapy + bevacizumab
Questions:
• does the choice of chemotherapy matter?
• how long should bevacizumab be continued?
Bevacizumab in 1st-line advanced CRC: significant benefit in 4 studies with different chemotherapy regimens
* Statistically significant
Regimen Pts (n)
Response
rate
PFS (median)
OS (median)
IFL
IFL + bevacizumab 1
813 35%
45%*
6.2 m
10.6 m*
15.6 m
20.3 m*
5FU/LV
5FU/LV + bevacizumab 2
209 15%
26%*
5.5 m
9.2 m*
12.9 m
16.6 m
XELOX/FOLFOX
XELOX/FOLFOX + bevacizumab 3
1401 38%
38%
8.0 m
9.4 m*
19.9 m
21.3 m
Capecitabine
Capecitabine + bevacizumab 4
156
157
5.7 m
8.5 m*
18.9 m
18.9 m
1Hurwitz et al. NEJM 2004 2Kabbinavar et al. JCO 20053Saltz et al. JCO 2008 4Tebbutt et al. ECCO/ESMO 2009
Progression Free Survival
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18
CapecitabineCapecitabine +Bevacizumab
Capecitabine + Bevacizumab + Mitomycin C
24Months from randomisation
Pro
port
ion
not
pro
gre
ssed
Median PFSC: 5.7 monthsCB: 8.5 monthsCBM: 8.4 months
Hazard ratiosC vs CB: 0.63, p<0.001C vs CBM: 0.59, p<0.001Tebbutt et al. ECCO/ESMO 2009
Number at Risk:C: 156 67 22 4 CB: 157 106 38 15 5CBM: 158 104 40 20 6
KRAS in EGFR signal transductioncetuximab
panitumumab
KRAS wildtype metastatic colorectal cancer: options in 1st line treatment
• Chemotherapy + bevacizumab
• Chemotherapy + anti-EGFR (cetuximab/panitumumab)
Questions:
• is there a preference?
• does the choice of chemotherapy matter?
Published/presented studies in 2009 with anti-EGFR antibodies
1st line irinotecan-based schedule
CRYSTAL FOLFIRI +/- cetuximab
1st line oxaliplatin-based schedule
OPUS FOLFOX +/- cetuximab
COIN* CAPOX/FOLFOX +/- cetuximab
PRIME* FOLFOX +/- panitumumab
1st line combination of targeted agents
CAIRO2 CAPOX, bevacizumab +/- cetuximab
PACCE FOLFOX/FOLFIRI, bevacizumab +/- panitumumab
2nd line irinotecan-based schedule
181* FOLFIRI +/- panitumumab
* prospective evaluation of results in patients with KRAS wildtype
CRYSTAL: FOLFIRI with or without cetuximab in 1st-line treatment of metastatic CRC
Van Cutsem et al. NEJM&ECCO/ESMO 2009
KRAS wildtype FOLFIRI FOLFIRI + cetuximab
P value
n 350 316
response rate 39.7% 57.3% < 0.0001
median PFS (m) 8.4 9.9 0.0012
median OS (m) 20 23.5 0.0094
KRAS mutation FOLFIRI FOLFIRI + cetuximab
P value
n 183 214
response rate 36.1% 31.3% 0.34
median PFS (m) 7.7 7.4 0.26
median OS (m) 16.7 16.2 0.75
CRYSTAL studyAdding cetuximab to FOLFIRI in 1st-line
• results in a significant benefit in median PFS, and in a larger absolute benefit in median OS in patients with KRAS wildtype
• has no detrimental effect in patients with KRAS mutation
Effect of salvage treatments on median OS?
OPUS: FOLFOX with or without cetuximab in 1st-line treatment of metastatic CRCKRAS wildtype FOLFOX FOLFOX +
cetuximabP value
n 73 61
response rate 34% 57% 0.0027
median PFS (m) 7.2 8.3 0.0064
median OS (m) 18.5 22.8 0.38
KRAS mutation FOLFOX FOLFOX + cetuximab
P value
n 47 52
response rate 53% 34% 0.029
median PFS (m) 8.6 5.5 0.0153
Median OS (m) 17.5 13.4 0.20
Bokemeyer et al. J Clin Oncol 2009 and ECCO/ESMO 2009
OPUS study
Adding cetuximab to FOLFOX in 1st-line
• results in a significant benefit in median PFS in patients with KRAS wildtype
• has a detrimental effect in patients with KRAS mutation
Randomized phase II study with limited number of patients
KRAS wildtype FOLFOX/XELOX FOLFOX/XELOX + cetuximab
P value
n 367 362
response rate 50% 59% 0.015
median PFS (m) 8.6 8.6 0.60
median OS (m) 17.9 17.0 0.68
COIN: FOLFOX/XELOX with or without cetuximab in 1st-line treatment of metastatic CRC
Maughan et al. ECCO/ESMO 2009
KRAS mutation FOLFOX/XELOX FOLFOX/XELOX + cetuximab
P value
n 268 297
response rate 41% 40% 0.87
median PFS (m) 6.9 6.5 0.46
median OS (m) 14.8 13.6 0.80
COIN studyAdding cetuximab to FOLFOX or CAPOX in 1st-line
• does not result in any benefit in patients with KRAS wildtype
• has no detrimental effect in patients with KRAS mutation
Cetuximab significantly increased non-haematological toxicity, grade 3 diarrhea FOLFOX 20% vs 11%, p=0.005; CAPOX 26% vs 15%, p<0.001
Capecitabine dose was reduced during trial (1000 mg/m2 to 850 mg/m2 bid)
In patients with KRAS wildtype treated with cetuximab: non-significant advantage for FOLFOX compared to CAPOX
Patients in cetuximab arm received significantly less 2nd line treatment (overall 56% vs 62% p=0.014; KRAS WT 54% vs 65%, p=0.006)
Cross-over of anti-EGFR therapy in only 6%
PRIME: FOLFOX with or without panitumumab in 1st-line treatment of metastatic CRC
KRAS wildtype FOLFOX FOLFOX + panitumumab
P value
n 331 325
response rate 48% 55% 0.068
median PFS (m) 8.0 9.6 0.02
median OS (m) 18.8 not reached 0.16
KRAS mutation FOLFOX FOLFOX + panitumumab
P value
n 219 221
response rate 40% 40% 0.98
median PFS (m) 8.8 7.3 0.02
median OS (m) 18.7 15.1 0.004
Douillard et al. ECCO/ESMO 2009
PRIME study
Adding panitumumab to FOLFOX in 1st-line
• results in a significant benefit in median PFS in patients with KRAS wildtype
• has a detrimental effect in patients with KRAS mutation
Longer follow-up is requiredCross-over of anti-EGFR agents in 10% of KRAS wildtype
patients
Arm A (without cetuximab) 10.7 months (9.7-12.3) Arm B (with cetuximab) 9.4 months (8.4-10.5)
Hazard ratio for progression 1.21, p 0.018
Tol et al. NEJM 2009
CapecitabineOxaliplatin
Bevacizumab
CapecitabineOxaliplatin
BevacizumabCetuximab
Randomization, n = 755
CAIRO2Progression-free survival
CB
CBC
0 6 12 18 24 30
Months since randomization
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion
prog
ress
ion
free
and
aliv
e
368 287 163 65 22 5
368 277 133 55 23 2
No. at risk
Without cetuximab
With cetuximab
KRAS wildtype CAPOX + bev. CAPOX + bev. + cetuximab
P value
n 156 158
response rate 50% 61% 0.06
median PFS (m) 10.6 10.5 0.30
median OS (m) 22.4 21.8 0.64
KRAS mutation CAPOX + bev. CAPOX + bev. + cetuximab
P value
n 108 98
response rate 59% 46% 0.03
median PFS (m) 12.5 8.1 0.003
median OS (m) 24.9 17.2 0.03
Tol et al. NEJM 2009
CAIRO2 study: CAPOX plus bevacizumab with or without cetuximab
in 1st-line treatment of metastatic CRC
CAIRO2 study
Adding cetuximab to CAPOX plus bevacizumab in 1st-line
• has no benefit in patients with KRAS wildtype
• results in a significant decrease in median PFS and OS in patients with KRAS mutation
Significantly lower incidence of hypertension in cetuximab-arm: negative interaction between cetuximab and bevacizumab?
PACCE: chemotherapy plus bevacizumab with or without panitumumab in 1st-line treatment of metastatic CRC
KRAS wildtype Ox-CT + bevacizumab
Ox-CT + bev. + panitumumab
HR
n 203 201
response rate 56% 50%
median PFS (m) 11.5 9.8 1.36
median OS (m) 24.5 20.7 1.89
Hecht et al. J Clin Oncol 2009
Ox-CT = oxaliplatin-based chemotherapyIr-CT = irinotecan-based chemotherapy, NE = not estimable
KRAS wildtype Ir-CT + bevacizumab
Ir-CT + bev. + panitumumab
HR
n 58 57
response rate 48% 54%
median PFS (m) 12.5 10.0 1.50
median OS (m) 19.8 NE 1.28
KRAS mutation Ox-CT + bevacizumab
Ox-CT + bev. + panitumumab
HR
n 125 135
response rate 44% 47%
median PFS (m) 11.0 10.4 1.25
median OS (m) 19.3 19.3 1.02
Hecht et al. J Clin Oncol 2009
Ox-CT = oxaliplatin-based chemotherapyIr-CT = irinotecan-based chemotherapy
KRAS mutation Ir-CT + bevacizumab
Ir-CT + bev. + panitumumab
HR
n 39 47
response rate 38% 30%
median PFS (m) 11.9 8.3 1.19
median OS (m) 20.5 17.8 2.14
PACCE: chemotherapy plus bevacizumab with or without panitumumab in 1st-line treatment of metastatic CRC
PACCE studyAdding panitumumab to oxaliplatin- or irinotecan-based
chemotherapy plus bevacizumab in 1st-line
• results in a decreased median PFS in patients with KRAS wildtype
• results in a decreased median OS in oxaliplatin-treated patients with KRAS wildtype
Addition of panitumumab increased toxicityCohort of irinotecan-treated patients was relatively small, with
safety as primary endpoint
181: FOLFIRI with or without panitumumab in 2nd-line treatment of metastatic CRC
KRAS wildtype patients
FOLFIRI FOLFIRI + panitumumab
P value
n 294 303
response rate 10% 35%
median PFS (m) 3.9 5.9 0.004
median OS (m) 12.5 14.5 0.12
KRAS mutatedpatients
FOLFIRI FOLFIRI + panitumumab
P value
n 248 238
response rate 14% 13%
median PFS (m) 4.9 5.0 NS
median OS (m) 11.1 11.8 NS
Peeters et al. ECCO/ESMO 2009
181 studyAdding panitumumab to FOLFIRI in 2nd-line
• results in a significant benefit in median PFS in patients with KRAS wildtype
• has no detrimental effect in patients with KRAS mutation
Cross-over of anti-EGFR agents in control arm in 31% of patients
Absolute benefits/hazard ratios of anti-EGFR plus chemotherapy in KRAS wildtype metastatic CRC
Study n Control arm Median PFS(months/HR)
Median OS(months/HR)
Irinotecan-based schedules
CRYSTAL 666 FOLFIRI + 1.5 * 0.69 + 3.5 * 0.79
181(2nd line) 597 FOLFIRI + 2.0 * 0.73 + 2.0 0.85
PACCE 115 IRI-based+ bev. - 2.5 * 1.50 ~* 1.28
Oxaliplatin-based schedules
PRIME 656 FOLFOX + 1.6 * 0.80 ~
OPUS 179 FOLFOX + 1.1 * 0.56 + 4.3 0.85
COIN 729 FOLFOX/CAPOX 0 0.95 - 0.9 1.04
CAIRO2 314 CAPOX+ bev. - 0.1 1.06 - 0.6 1.03
PACCE 404 OX-based+ bev. - 1.7 * 1.36 - 3.8* 1.89
* statistically significant
Absolute benefits/hazard ratios of anti-EGFR plus chemotherapy in KRAS mutated metastatic CRC
Study n Control arm Median PFS(months/HR)
Median OS(months/HR)
Irinotecan-based schedules
CRYSTAL 397 FOLFIRI - 0.3 1.17 - 0.5 1.03
181 (2nd line) 486 FOLFIRI + 0.1 0.85 + 0.7 0.94
PACCE 86 IRI-based+ bev. - 3.6 1.19 - 2.7 * 2.14
Oxaliplatin-based schedules
PRIME 440 FOLFOX - 1.5 * 1.29 - 3.6 * 1.53
OPUS 99 FOLFOX - 3.1 * 1.72 - 4.1 1.29
COIN 565 FOLFOX/CAPOX - 0.4 1.06 - 1.2 0.98
CAIRO2 206 CAPOX+ bev. - 4.4 * 1.46 - 7.7 * 1.52
PACCE 260 OX-based+ bev. - 0.6 1.25 0 1.02
* statistically significant
Chemotherapy + anti-EGFR antibodiesconclusions
• Benefit of anti-EGFR antibodies is limited to patients with KRAS wild-type tumors
• Detrimental effect of anti-EGFR antibodies in KRAS mutant tumors is only observed with oxaliplatin-based schedules
• Combination of bevacizumab with cetuximab/panitumumab should not be used
Punt & Tol, Nature Rev Clin Oncol 2009
Chemotherapy + anti-EGFR antibodiesquestions
1) Is this better than bevacizumab in 1st line in patients with KRAS wildtype tumors?
Cross study comparisons do not suggest an outright superiority for anti-EGFR over bevacizumab
Absolute benefits of bevacizumab plus chemotherapy in metastatic CRC
Study n Control arm Median PFS(months/HR)
Median OS(months/HR)
Irinotecan-based schedules
Hurwitz et al. 813 IFL + 4.4 * 0.54 + 4.7 * 0.66
Oxaliplatin-based schedules
Saltz et al. 1401 FOLFOX/CAPOX + 1.4 * 0.83 + 1.4 0.89
Giantonio et al. (2nd line) 577 FOLFOX + 2.6 * 0.61 + 2.1 * 0.75
Fluoropyrimidine monotherapy
Kabbinavar et al. 209 5FU/LV + 3.7 * 0.50 + 3.7 0.79
Tebbutt et al. 313 CAP + 2.8 * 0.63 0 0.86
* statistically significant
Bevacizumab or cetuximab? CALGB study 80405
First-line metastatic colorectal cancer
+ bevacizumab
FOLFOX or FOLFIRI + cetuximab
+ bevacizumab+cetuximab
Currently ongoing only in patients with KRAS wildtype tumors
R
Chemotherapy + anti-EGFR antibodiesquestions
2) Is there a preference between irinotecan and oxaliplatin in patients with KRAS wildtype tumors?
Cross-study comparisons do not suggest an outright preference, only few prospective data available
Choice of chemotherapy in combination with cetuximab: randomized phase II study FOLFOX vs FOLFIRI
FOLFOX + cetuximab
FOLFIRI + cetuximab
N 77 74
Response rate 43% 45%
Median PFS 8.6 m 8.3 m
Median OS 17.4 m 18.9 m
ASCO 2009 Koza #4055ASCO 2009 Koza #4055
FOLFOX + cetuximab
FOLFIRI + cetuximab
KRAS status WT mutant WT mutant
N 34 23 28 32
Median PFS 9.1 m * 7.2 m 8.4 m 8.1 m
Median OS 22.5 m * 15.2 m 19.9 m 18.9 m
ASCO 2009 Koza #4055ASCO 2009 Koza #4055
Choice of chemotherapy in combination with cetuximab: randomized phase II study FOLFOX vs FOLFIRI
* statistically significant versus KRAS mutant group
Chemotherapy + anti-EGFR antibodiesquestions
3) Is there a preference for anti-EGFR therapy in KRAS wildtype patients with potentially resectable metastases?
Cross-study comparisons show higher response rates for anti-EGFR therapy compared to bevacizumab. Whether this results in a higher proportion of patients that become resectable, and whether this subsequently results in an improved outcome has never been demonstrated in a prospective trial
Chemotherapy + anti-EGFR antibodiesquestions
4) Is there a preference for capecitabine over 5FU in combination with oxaliplatin?
Pooled analysis of randomized trials does not show a relevant difference between FOLFOX and CAPOX1
In 2 phase III studies with targeted therapy, the results with FOLFOX are slightly better than with CAPOX. Any benefit of FOLFOX, if at all, should be balanced against the use of infusional devices and more frequent patient visits
1Arkenau et al. J Clin Oncol 2008
Chemotherapy + anti-EGFR antibodiesquestions
5) Do patients with KRAS wildtype and BRAF mutated tumors benefit at all from systemic treatment?
BRAF mutation is a negative prognostic marker, results of CAIRO2 study in control arm (CAPOX+bevacizumab):
BRAF mutationn = 17
BRAF wildtypen = 243
P value
Median PFS (m) 5.9 12.1 0.003
Median OS (m) 15.0 24.6 0.002
Tol et al. NEJM 2009
Cetuximab group No cetuximab group
BRAF: HR 2.2 (1.3-3.8)KRAS: HR 1.05 (0.8-1.4)
BRAF and KRAS wild typeKRAS mutatedBRAF mutated
BRAF: HR 2.1 (1.6-3.2)KRAS: HR 1.5 (1.1-2.0)
Tol et al. NEJM & ECCO/ESMO 2009
CAIRO2: Progression-free survival-BRAF and KRAS-
Chemotherapy + anti-EGFR antibodiesquestions
6) Are there other markers that may predict the efficacy of anti-EGFR therapy within the group of KRAS wildtype patients?
Several candidate markers (EGFR FISH, PIK3CA, PTEN, EGFR ligands, FcγR polymorphisms, etc), but to date none of them have shown results that may be used in the clinic
First-line treatment options for chemotherapy in metastatic colorectal cancer
- potentially resectable mets- relief of symptoms- salvage treatment unlikely
- all other patients (majority)1
combination chemotherapysequential - or
combination chemotherapy
• Choice between irinotecan and oxaliplatin should be made on an individual basis• Capecitabine may replace 5FU as monotherapy or in combination schedules
1CAIRO study: Koopman et al. Lancet 2007 FOCUS study: Seymour et al. Lancet 2007
• In first-line, the results with anti-EGFR antibodies do not appear superior to bevacizumab
• Absolute benefit of anti-EGFR antibodies appears to increase in late-line treatment, while this appears to decrease with bevacizumab
• Bevacizumab is better tolerated than anti-EGFR agents in most patients
Current data suggest a preference for bevacizumab in first-line, and a role for cetuximab/panitumumab in salvage treatments
Choice of targeted drug in patients with KRAS wildtype tumors
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