novel treatment strategies in metastatic colorectal cancer patients with kras wildtype tumors

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


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


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


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


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


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


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


• 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


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


median PFS (m) 12.5 8.1 0.003

median OS (m) 24.9 17.2 0.03


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


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


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


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


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


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



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




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


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


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




Hurwitz et al. 813 IFL + 4.4 * 0.54 + 4.7 * 0.66


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


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


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


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


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


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


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-


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

novel treatment strategies in metastatic colorectal cancer patients with kras wildtype tumors

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