Transcript 2005_files/Seymour - FOCUS PD #3518

Fluorouracil, Oxaliplatin, CPT-11: Use and
Sequencing (MRC FOCUS)
- a 2135-patient randomised trial in advanced
colorectal cancer
Matt Seymour, on behalf of the UK NCRI Colorectal Clinical
Studies Group and FOCUS Trial Investigators
(Enquiries: [email protected])
Background and rationale for study
•Both oxaliplatin and irinotecan are well-established active agents in
metastatic colorectal cancer. Each can be used in combination with
fluoropyrimidines in 1st-line therapy or as 2nd-line therapy. Irinotecan may also
be used as single-agent 2nd-line therapy.
•Phase III trials reported in 1999-2000 gave proof of improved RR and PFS, but
also some additional toxicity, with 1st-line combination therapy. OS advantage
was seen in irinotecan but not oxaliplatin trials, a difference which was
thought to have arisen from differing usage of effective 2nd-line/cross-over
therapy.
•From 2002, UK Health Service guidance recommended 1st-line FU alone
followed by 2nd-line single-agent irinotecan for most patients (but 1st-line
FU/Ox combination for patients where a response may potentially allow liver
resection).
•QUESTION: does 1st-line combination therapy improve overall survival and/or
quality of life compared with 1st-line FU plus a consistent policy of 2nd-line
combination therapy or 2nd-line irinotecan?
Aims
•To determine if there is an advantage to the use of
combination chemotherapy for colorectal cancer
compared with the UK standard approach of sequential
FU then Ir (“staged single agents”)
•To determine if combination therapy is best used 1stline, or reserved for 2nd-line after single-agent FU
(“staged combination”).
•To compare the efficacy and toxicity of an irinotecancontaining combination vs the equivalent oxaliplatincontaining combination
Design
2100
patients
A:(700 pts) FU until it fails, then change to Ir
Ox+fluoropyrimidine
B(ir): (350) FU until it fails, then add Ir
Ox+fluoropyrimidine
B(ox): (350) FU until it fails, then add Ox
Ir +fluoropyrimidine
C(ir): (350) FU+Ir from the start until it fails
Ox +fluoropyrimidine
C(ox): (350) FU+Ox from the start until it fails
Ir +fluoropyrimidine
3rd drug salvage
molecular pathology
to find predictive variables
(Adlard et al ASCO‘04 #9506)
time to failure
of first 2 drugs.
Power: 80% (α = 0.01) to detect a difference of 22.5% vs
15% in 2-year overall survival of each plan against Plan A.
introduced Feb 03; prior
to that “no crossover”
salvage with
Mitomycin/FU
Endpoints
•Primary - Overall survival
•Secondary - PFS, RECIST response, Time to
failure of first two drugs
•Other – Quality of Life & Economic evaluation
Drug Regimens
FU
“MdG”
• dexamethasone 8 mg iv
• l-LV 175 mg 2hr ivi
• 5FU 400 mg iv bolus
• 5FU 2800 mg 46-hr ivi
oral dexamethasone d2-4
cycle repeat 14 days
Ref: Cheeseman et al,
Br J Cancer 87:393-9, 2002
Ir + FU
“IrMdG”
•dexamethasone 8 mg iv
•irinotecan 180mg/m2 30
mins ivi, then
•l-LV 175 mg, 2hr ivi
•FU 400 mg/m2 iv bolus
•FU 2400 mg/m2 46hr ivi
oral dexamethasone d2-4
cycle repeat 14 days
Ox + FU
“OxMdG”
•dexamethasone 8 mg iv
•oxaliplatin 85mg/m2 plus
l-LV 175 mg, 2hr ivi
(concurrent), then
•FU 400 mg/m2 iv bolus
•FU 2400 mg/m2 46hr ivi
oral dexamethasone d2-4
cycle repeat 14 days
Ref: Leonard et al,
Ref: Cheeseman et al,
Br J Cancer 87:1216-20, 2002 Br J Cancer 87:393-9, ‘02
Ir
single-agent Ir
•dexamethasone 8 mg iv
•irinotecan 350 mg/m2,
90 mins ivi (300 mg/m2
if PS2 or age >70)
oral dex d2-4
cycle repeat 21 days
Reference: SPC
Eligibility Criteria
•Histologically confirmed adenocarcinoma of the colon
or rectum
•Inoperable metastatic of locoregional disease
•No previous chemotherapy for established metastatic
disease
•WHO performance status 0, 1 or 2
BUT:
•Patients with with metastases which may potentially
become operable after a chemotherapy response were
not entered (eligible for 1st-line Ox+FU combination
under national guidance)
Results
2135 patients were entered between May 2000 and December 2003
at 61 participating oncology centres in the UK and Cyprus
Pre-treatment characteristics
Plan
male
female
Age: median
(interquartiles)
PS = 0
PS = 1
PS = 2
A
B(ir)
B(ox)
C(ir)
C(ox)
n=701
n=356
n=356
n=356
n=357
70%
30%
69%
31%
66%
34%
67%
33%
69%
31%
63
(56-69)
64
(57-70)
64
(56-69)
64
(57-69)
64
(56-69)
41%
50%
9%
41%
51%
8%
41%
50%
9%
41%
50%
8%
41%
50%
8%
Chemotherapy delivery
Plan
A
B(ir)
B(ox)
C(ir)
C(ox)
first two
drugs on
FOCUS
plan
1st line regimen
(mean cycles)
MdG
10
MdG
9.7
MdG
9.7
IrMdG
10.5
OxMdG
10.6
2nd line regimen
(mean cycles
Ir
4.9
IrMdG
7.7
OxMdG
7.7
-
-
salvage:
third and
further
drugs
received any
salvage chemo
24%
27%
25%
46%
41%
received crossover drug (Ox/Ir)
13%
(Ox)
12%
(Ox)
17%
(Ir)
27%
(Ox)
26%
(Ir)
Tolerability of 1st-line therapy: CTC grade3 toxicity
A,B(ir) & B(ox)
C(ir)
C(ox)
MdG
(1316)
IrMdG
(339)
OxMdG
(340)
neutrophils
8.6%
19.5%
27.7%
platelets
0.4%
1.2%
2.4%
vomiting
3.0%
7.7%
7.7%
diarrhoea
5.5%
12.4%
10.6%
neuropathy
0.7%
2.7%
11.2%
lethargy
13.0%
21.3%
23.8%
alopecia
0.2%
2.7%
2.4%
Treatment regimen
(n)
Tolerability of 2nd-line therapy: CTC grade3 toxicity
A
B(ir)
B(ox)
Treatment regimen
(n)
Ir
(337)
IrMdG
(175)
OxMdG
(200)
neutrophils
13.1%
19.4%
23.9%
vomiting
5.9%
4.6%
5.1%
diarrhoea
15.7%
8.6%
8.0%
neuropathy
0.6%
1.1%
3.0%
lethargy
17.2%
19.9%
19.1%
alopecia
9.5%
2.9%
0.0%
Overall survival (1556 events)
Months
Overall survival (1556 events)
Months
Plan
First 2 drugs schedule
A
B(ir)
B(ox)
FU then Ir
FU then FU/Ir
FU then FU/Ox
13.9
14.8
15.2
C(ir)
C(ox)
1st-line FU/Ir
1st-line FU/Ox
16.3
15.2
Comparison
Median OS
n
p
.
1066
1066
1422
Logrank HR (95%ci)
0.92 (0.60 – 1.07)
0.95 (0.82 – 1.10)
0.93 (0.82 – 1.05)
0.275
0.456
0.247
.
1066
1067
1423
0.86 (0.74 – 1.00)
0.96 (0.83 – 1.11)
0.90 (0.80 – 1.02)
0.043
0.563
0.109
C vs B
C(ir) vs B(ir)
C(ox) vs B(ox)
C(ir)+C(ox) vs B(ir)+B(ox)
712
713
1425
0.93 (0.78 – 1.12)
1.03 (0.90 – 1.29)
0.98 (0.88 – 1.14)
0.441
0.712
0.695
IrMdG vs OxMdG
B(ir) vs B(ox)
C(ir) vs C(ox)
B(ir)+C(ir) vs B(ox)+C(ox)
712
713
1425
0.97 (0.82 – 1.16)
0.88 (0.74 – 1.05)
0.93 (0.82 – 1.05)
0.771
0.165
0.220
B vs A
B(ir) vs A
B(ox) vs A
B(ir)+B(ox) vs A
C vs A
C(ir) vs A
C(ox) vs A
C(ir)+C(ox) vs A
Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)]
Age
Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)]
Performance Status
Subgroup OS analysis – [C(ir)+C(ox)] versus [B(ir)+B(ox)]
Prior Adjuvant Chemo
Response to 1st line chemotherapy (RECIST) criteria
A,B(ir) & B(ox)
C(ir)
C(ox)
Treatment regimen
(n)
MdG
(1157)
IrMdG
(284)
OxMdG
(299)
CR+PR
28.5%
51.4%
56.2%
SD
47.9%
37.0%
30.1%
PD
23.6%
11.6%
13.7%
(Measurable patients with 1 follow-up assessment)
PFS, 1st line (1969 events)
Response to 2nd line chemotherapy
A
B(ir)
B(ox)
Ir
(259)
IrMdG
(141)
OxMdG
(155)
CR+PR
11%
21%
23%
SD
42%
44%
48%
PD
47%
35%
28%
Treatment
regimen
(n)
PFS, 2nd line (659 events)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
Plan A
Plan B(ir)
Plan B(ox)
regimen
Ir
IrMdG
OxMdG
18
Events
310
163
186
Total
355
182
209
Time to failure of the first two drugs (1505 events)
A
B(ir)
B(ox)
C(ir)
C(ox)
Months
Median FFS
10.5
11.3
11.6
9.0
9.2
HR (95%CI), p-value (versus A)
0.90 (0.78, 1.06) p=0.203
0.90 (0.77, 1.04) p=0.163
1.25 (1.08, 1.45) p=0.003
1.19 (1.03, 1.38) p=0.020
QoL - EORTC QLQ-C30 - mean global QL scores over time
6
5.8
5.6
5.4
5.2
5
4.8
4.6
4.4
4.2
4
baseline
3 months
FU then Ir
1st-line FU/Ir
6 months
FU then FU/Ir
1st-line FU/Ox
9 months
12 months
FU then FU/Ox
Conclusions:
Overall survival:
• No major differences: no comparisons reached p<0.01 level.
• “Staged single agents” (FU then Ir) tends towards inferiority
compared to any other plan (reaches p=0.043 against 1st-line FU+Ir).
• “Staged combination” (FU then combination) is non-inferior to 1stline combination chemotherapy (HR 0.98 [0.86-1.10]).
• Trend toward OS benefit for 1st-line combination in PS2 subgroup.
Secondary endpoints:
• We confirm higher RR, PFS and toxicity of combination therapy.
• 1st-line combination “uses up” first 2 drugs earlier.
• The higher RR/PFS of 1st-line combinations does not give better QoL.
•
Questions and issues:
•Many of the best prognosis patients (“potentially down-stageable”
liver metastases) were not included in this trial:
•explains why median OS is lower than in some other trials.
•conclusions don’t apply to potentially down-stageable patients.
•Low rate of “3rd drug salvage” in this trial (non-crossover policy up
to Feb 2003).
•would more cross-over have affected the result?
•The “MdG” FU regimen is highly active (RR 28.5%, PFS >7 months).
•success of staged combination may depend on this high efficacy.
•Non-inferiority of the staged combination permits consideration of
1st-line “MdG+novel therapy” arms in future trials.