Transcript Essentials of Oncology

Randomized multicenter study of
cetuximab plus FOLFOX or cetuximab plus FOLFIRI in
neoadjuvant treatment of
non-resectable colorectal liver metastases
(CELIM study)
G. Folprecht1, T. Gruenberger2, J.T. Hartmann3, F. Lordick4,
J. Stoehlmacher1, W. Bechstein5, D. Ockert6, T. Herrmann4,
T. Liersch7, C.-H. Köhne8
1University
Hospital Carl Gustav Carus, Dresden, Germany, 2University Hospital Vienna, Austria,
3University Hospital Tübingen, Germany, 4National Center for Tumor Diseases, Heidelberg, Germany,
5University Hospital Frankfurt, Germany, 6Krankenhaus der Barmherzigen Brüder, Trier, Germany,
7University Hospital Goettingen, Germany, 8Klinikum Oldenburg, Oldenburg, Germany
Abstract
BACKGROUND
Resectability of colorectal liver metastases (mets) can be induced by an effective chemotherapy regimen.
Combinations of cetuximab with FOLFIRI or FOLFOX have been shown to increase response and resection
rates.
METHODS
Patients (pts) with non-resectable liver mets were randomized to receive FOLFOX6 or FOLFIRI plus
cetuximab in this multicenter, randomized phase II study. Pts were stratified according to the reason for nonresectability (technically non-resectable vs. ≥ 5 liver mets), the use of PET scans at initial staging, and EGFR
status. Preoperative treatment was planned for 8 cycles. In case of persistent non-resectability,
multidisciplinary evaluation was planned every 4 cycles.
RESULTS
From December 2004 to March 2008, 124 pts were screened for the study. 111 pts were randomized to
receive FOLFOX plus cetuximab (56 pts) or FOLFIRI plus cetuximab (55 pts). Median age was 63 years. Out
of the 111 pts, 60 pts (54%) were judged as technically non-resectable, 20 pts (18%) were staged with PET,
and 81 pts (73%) were EGFR detectable.
At the interim analysis in March 2008, response and resection data were available from 81 pts. Best response
was 75.3% (61/81 pts, 95%CI 64.5-84.2%, combined analysis for both arms) and confirmed response was
59.3% (48/81 pts, 95% CI 47.7-70.0%). KRAS status was available for 86 pts; best response rate in KRAS
wild-type pts was 85.4% (41/48 pts, 95%CI 72.2-93.9%), and 50% (7/14 pts) in KRAS mutant pts. Sixteen
resections were performed in pts with ≥ 5 liver mets, 18 resections in technically non-resectable pts. In total,
34/81 pts were resected (42.0%, 95%CI 31.1-53.5%), 29 with microscopically free margins (R0).
Interim data on toxicity of 98 pts demonstrated acne-like rash (32%), neutropenia (20%), diarrhea (15%),
allergic reaction (6%), and neurologic toxicity (5%) to be the most common preoperative grade ≥3 toxicities in
both arms. One patient had a fatal pulmonary embolism (2.9%).
CONCLUSION
In the interim analysis, the combination of cetuximab with standard chemotherapy has demonstrated high
activity and an encouraging rate of liver resection.
Mature resection and response data per treatment arm and KRAS status will be reported at the meeting.
Background
•
Resection of liver metastases provides favorable long-term survival (Adam Ann Surg 2004)
•
Resectability of colorectal liver metastases depends on:
- technical resectability
- prognostic factors
•
Number of liver metastases is regarded as an important prognostic factor and is an
exclusion criterion in neoadjuvant trials for resectable liver metastases
(Nordlinger, Lancet 2007)
•
Standard systemic chemotherapy regimens for colorectal cancer include FOLFOX and
FOLFIRI
•
For both regimens, high response rates were reported in phase II studies and – more
recently – in randomized trials such as CRYSTAL (Van Cutsem ASCO 2008) and OPUS
(Bokemeyer ASCO 2008)
•
Multi-institutional randomized trials investigating patients with isolated liver metastases are
lacking
Patient selection
Patients with non-resectable, histologically confirmed colorectal liver metastases
Definition of non-resectability:
– ≥ 5 liver metastases and/or
– liver metastases that are technically non-resectable (local surgeon in cooperation with
local radiologist defined non-resectability based on the amount of functional liver tissue
remaining, infiltration of all liver veins, and infiltration of both hepatic arteries, both
portal branches, or both bile ducts)
Patients with simultaneous liver metastases were eligible if the primary tumor was resected ≥1
month prior to chemotherapy.
(Expected resectability after response to chemotherapy was NOT an inclusion criterion)
No extrahepatic disease
Karnofsky PS ≥ 80% and adequate hepatic, renal, and bone marrow function
No prior chemotherapy (except adjuvant chemotherapy ≥ 6 months ago); no concurrent
immunotherapy, chemotherapy or hormone therapy; no previous malignancy other than
colorectal cancer, basal cell carcinoma, or pre-invasive carcinoma of the cervix; no
inflammatory bowel disease; no relevant coronary heart disease
Informed consent
Methods
•
Patients were randomized to:
1) FOLFOX6 (oxaliplatin 100 mg/m², 5-FU 400 mg/m² [bol], 5-FU 2400 mg/m², FA 400 mg/m²)
plus cetuximab (400 mg/m², then 250 mg/m²)
2) FOLFIRI (irinotecan 180 mg/m², 5-FU 400 mg/m² [bol], 5-FU 2400 mg/m², FA 400 mg/m²)
plus cetuximab (400 mg/m², then 250 mg/m²)
3) FOLFOX6 (patients with negative immunohistochemistry for EGFR)
This arm was closed after the third patient and all subsequent patients were randomized
to arm (1) or (2)
•
Patients were evaluated for response every fourth cycle (every 8 weeks)
•
Resection was planned in case of resectability after 8 cycles
If patients were non-resectable, resectability was further evaluated with each CT scan
•
Patients were regarded to have a confirmed response if confirmed according to RECIST or if
the confirmation CT scan was not performed because the patient underwent resection
•
Central surgical review is being performed
(data not yet available)
Patients with non-resectable colorectal liver metastases
(technically non-resectable / ≥ 5 liver metastases)
without extrahepatic metastases
Biopsy:
EGFR screening
Randomization
FOLFOX6 + cetuximab
FOLFIRI + cetuximab
Therapy: 8 cycles (~ 4 months)
Evaluation of resectability
Technically non-resectable
Technically resectable
4 additional CTX cycles
Resection
Primary endpoint: Response
Therapy continuation
for 6 cycles
(~ 3 months)
Enrollment and analysis
•
From December 2004 to March 2008, 114 patients were randomized into the study
•
17 centers participated actively in the trial
– 43% of patients were randomized at 3 study sites, 75% at 7 study sites
•
3 patients were randomized to FOLFOX6 (arm closed early)
– These patients are not included in the current analysis
•
111 patients were randomized to FOLFOX6 plus cetuximab or FOLFIRI plus cetuximab
•
2 patients did not receive planned treatment:
– 1 patient withdrew consent
– 1 patient retrospectively revealed known extrahepatic disease
•
105 patients were evaluable for response
•
Presented data are based on an interim analysis as of August 15, 2008
Patient characteristics
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=56
n=55
n=111
65.1 y
62.0 y
63.3 y
male
64%
64%
64%
≥5 metastases
45%
46%
45%
Technically non-resectable
55%
55%
55%
Staged using PET *
16%
20%
18%
EGFR-positive (IHC)
71%
75%
73%
Median age
Sex
Stratified characteristics
* PET is not generally reimbursed in Germany
Patient characteristics
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=56
n=55
n=111
wild-type
70%
71%
71%
Rectal cancer
36%
52%
44%
T3/4
89%
83%
86%
yes
9%
23%
16%
yes
4%
15%
8%
KRAS (n=99)
Primary tumor site
Primary tumor stage
Adjuvant chemotherapy
Adjuvant radiotherapy
Patient characteristics
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=56
n=55
n=111
I-II
17%
10%
13%
III
4%
16%
10%
IV
79%
74%
77%
yes
17%
9%
13%
yes
72%
70%
71%
Primary UICC stage
Prior liver resection
Synchronous liver
metastases
UICC, International Union Against Cancer
Patient characteristics
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=56
n=55
n=111
<5
23%
31%
27%
5-10
55%
49%
52%
>10
20%
15%
17%
NA
2%
5%
4%
0-1
17%
10%
13%
2
17%
31%
24%
3
34%
38%
36%
4-5
32%
21%
27%
Number liver metastases
Fong score (n=83)*
* Fong score is evaluated for resectable liver metastases
Fong score data not available for all pts.
Preoperative toxicity
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=54
n=55
n=109*
All grade 3/4
72%
73%
73%
n.s.
Neutropenia
24%
22%
23%
n.s.
Thrombopenia
9%
0
5%
0.02
Allergic reaction
11%
4%
7%
n.s.
Skin toxicity
28%
38%
33%
n.s.
Diarrhea
9%
18%
14%
n.s.
Nausea/Vomiting
7%
0
4%
0.04
0
9%
5%
0.02
Neuropathy*
20%
0
10%
0.001
Other neurologic toxicity
6%
4%
5%
n.s.
0
7%
4%
0.04
Infection
Alopecia*
* grade >1
p-value
One patient died from pulmonary embolism
*Two randomized pts did not receive therapy
Efficacy: Response
CR/PR
95% CI
SD
PD
FOLFOX6 +
FOLFIRI +
KRAS
All
cetuximab
cetuximab
wild-type
patients
n=52
n=53
n=67
n=105*
85%
66%
79%
75%
(44 pts)
(35 pts)
(53 pts)
(79 pts)
71.9-93.1%
51.7-78.5%
67.4-88.1%
65.9-83.1%
11%
23%
13%
17%
(6 pts)
(12 pts)
(9 pts)
(18 pts)
4%
11%
8%
8%
(2 pts)
(6 pts)
(5 pts)
(8 pts)
Responses are not yet confirmed
Data regarding response confirmation are still pending for 14 pts
* 105 pts evaluable for efficacy
Resections
All resections
R0 resections
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=52
n=53
n=105*
40%
43%
42%
(21 pts)
(23 pts)
(44 pts)
37%
34%
35%
(19 pts)
(18 pts)
(37 pts)
* 105 pts evaluable for efficacy
Time to intervention
Time to intervention
0.60
0.50
Probability
0.40
All pts
FOLFOX 6 + Cetuximab
0.30
FOLFIRI + Cetuximab
0.20
0.10
0.00
0
2
4
6
8
10
12
14
Months
44 patients were resected, 5 patients had exploratory laparotomy
Median time to intervention (resection/laparotomy): 5.0 months
Median number of cycles prior to intervention: 8
16
Resections according to tumor response
Best responses
PR/CR
SD
PD
n=79
n=18
n=8
R0 resections
35 pts
2 pts
0
Without R0 resection
44 pts
16 pts
8 pts
35/37 of resected pts (95%) had a tumor response
The 2 remaining pts had minor responses
Resections by patient subgroup
All resections
R0 resections
Technically
≥ 5 liver
KRAS
non-resectable
metastases
wild-type
n=57
n=48
n=67
40%
44%
43%
(23 pts)
(21 pts)
(29 pts)
32%
40%
34%
(18 pts)
(19 pts)
(23 pts)
Comparison of R0 resections between strata technically non-resectable and ≥ 5 liver mets: p=0.4
Conclusions
•
Among patients with initially non-resectable liver metastases, 42% had a liver
resection and 35% had an R0 resection
•
FOLFOX6 plus cetuximab and FOLFIRI plus cetuximab are highly active
regimens and induced high response rates
– 79% unconfirmed CR/PR in KRAS wild-type patients
•
The current data do not allow us to draw conclusions regarding differences
between FOLFOX6 and FOLFIRI in the preoperative setting as final data are still
pending
•
There were no major differences in resection rates between patients who
entered the study with technically non-resectable disease and those who had
≥ 5 liver metastases
•
Tumor response is a precondition for resection of liver metastases,
as nearly all patients achieved a tumor response before resection
•
Median time to intervention (resection/laparotomy) was 5.0 months
•
Data for progression-free survival and surgical review of resectability are not
yet mature and will be presented at a later meeting
We thank...
• All patients
• All investigators at the study sites
University Hospital Dresden, Klinikum Oldenburg, University Hospital Vienna,
University Hospital Tübingen, University Hospital Göttingen, University
Hospital München Rechts der Isar, Krankenhaus der Barmherzigen Brüder
[Trier], University Hospital / NCT Heidelberg, University Hospital Würzburg,
Klinikum Passau, University Hospital Frankfurt, Klinikum Celle, University
Hospital Essen, Klinikum Magdeburg, Klinikum Aschersleben, University
Hospital Mannheim, Klinikum Essen-Mitte
• The study was supported by:
Merck KGaA, Sanofi-Aventis, and Pfizer