Transcript Biomarkers in mCRC

“Enfermedad limitada al hígado en
cáncer colorrectal metastásico RAS WT:
¿qué aporta Panitumumab?”.
Dr. Carles Pericay Pijaume
Oncología Médica,
Hospital Universitari de Sabadell,
Corporació Sanitària Parc Taulí (Sabadell)
Madrid, 12 de Febrero de 2015
CRC liver metastases are common and predict a
poor prognosis if untreated
• In 2012, CRC was the 2nd most common cancer in Europe:1
– 447,000 new cases
– 215,000 deaths
•
~ 50% of CRC patients develop liver metastases2
– Liver metastases responsible for 2/3 of CRC patient deaths2
•
0 - 6% 5 year survival for untreated CRC liver metastases3
1. Ferlay J et al. Eur J Cancer. 2013;49(6):1374–403; 2. Van den Eynde M, and Hendlisz A. Rev
Recent Clin Trials. 2009;4(1):56–62; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99.
CRC, colorectal cancer.
Resection of liver metastases improves survival
Median 5-year survival, %
70
60
50
40
30
32%
30%
20
10
7%
0%
0
R0 resected
(16 studies)
Resected,
R0/R1 unclear
Non-radical
resection
(19 studies)
(11 studies)
Not resected
(6 studies)
Surgical series published after 1980
Simmonds PC et al. Br J Cancer. 2006;94(7):982–99
Error bars indicate range.
Current definition of liver metastases resectability
•
The criteria for liver metastasis resectability have not been standardized1-3
Oncological
considerations
e.g.
• Resectable extrahepatic
disease
• Number of lesions ≥ 5
• Tumour progression
•
Medical fitness for
surgery
Technical
considerations
e.g.
• R0 with ≥ 25%–30% FLR
• Complex procedure
Resectability1-5
NCCN Guidelines criteria for resection suitability6
“... the likelihood of achieving complete resection of all evident disease with negative
surgical margins and maintaining adequate liver reserve”
1. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 2. Spolverato G et al. World J Gastrointest Oncol. 2013;5(12):207–21;
3. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 4. Adams RB et al. HPB. 2013;15(2):91–103;
5. Adam R et al. Oncologist. 2012;17(10):1225–39; 6. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer
[v.3.2014]. www.nccn.org (accessed 20/02/2014).
FLR, functional liver remnant;
R0, resection with microscopically
negative margins
ESMO 2012 Clinical Guidelines
Stratification of mCRC patients for 1st-line treatment
Metastatic colorectal cancer
Group 0
Group 1
Group 2
Group 3
Yes
Group 0
Initially R0 resectable
No
Potentially R0 resectable with CT
& patient can tolerate CT and surgery
Yes
Group 1
No
Yes
Group 2
Symptomatic or aggressive disease
No
Yes
Far advanced/bulky disease
No
Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516
Patient can tolerate
CT
No
Yes
Group 2
Group 3
CT, chemotherapy; R0, resection with microscopically negative margins.
mCRC patient distribution between ESMO guideline
first-line treatment stratification groups
Metastatic colorectal cancer
~15%1,2
~85%1,2
Initially R0
resectable
Non-resectable at clinical presentation
70-90%2
10-30%2
Potentially
resectable
Group 0
Group 1
Never resectable
Group 2*
Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 1. Van den Eynde M, and Hendlisz A. Rev
Recent Clin Trials. 2009;4(1):56–62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037–45.
Group 3
*Some patients may become resectable following
exceptional response to treatment. CT, chemotherapy;
R0, resection with microscopically negative margins.
mCRC patient distribution between ESMO guideline
first-line treatment stratification groups
Metastatic colorectal cancer
~15%1,2
~85%1,2
Initially R0
resectable
Non-resectable at clinical presentation
70-90%2
10-30%2
Potentially
resectable
Group 0
Group 1
Never resectable
Group 2*
Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516; 1. Van den Eynde M, and Hendlisz A. Rev
Recent Clin Trials. 2009;4(1):56–62; 2. Nordlinger B et al. Eur J Cancer. 2007;43(14):2037–45.
Group 3
*Some patients may become resectable following
exceptional response to treatment. CT, chemotherapy;
R0, resection with microscopically negative margins.
What is conversion chemotherapy?
mCRC with initially non-resectable liver metastases
Conversion chemotherapy*
Tumour
shrinkage
Resection
1. Adam R, et al. Oncologist 2012;17:1225–39; 2. Nordlinger B, Benoist S. J Clin Oncol 2006;24:4954–5;
*Chemotherapy to convert unresectable
3. Nordlinger B, et al. Clin Colorectal Cancer 2010;9:212–8; 4. Schmoll HJ et al. Ann Oncol. 2012;23(10):2479–516.
liver metastases to resectable.
Conversion CT + surgery for treatment of mCRC with
unresectable liver metastases
Single centre study of consecutive patients
mCRC with
unresectable
liver metastases
(n = 184)
Conversion
chemotherapy*
Response evaluated
every 2 months
Surgery
F
O
L
L
O
W
U
P
Minimum
follow-up 5 years
• Study objectives: evaluation of possibility of cure, determination of
predictive factors of disease cure
Adam R, et al. J Clin Oncol 2009; 27:1829-35.
*Last preoperative regimen, FL (18%), FOLFOX (62%),
FOLFIRI (6%), FOLFOXIRI (9%), Other (5%)
An oncosurgical approach offers the chance of cure to
a subgroup of initially non-resectable patients
Survival probability
1.0
OS
(n = 184)
DFS
(n = 184)
0.8
0.6
5-year survival
0.4
10-year survival
33%
27%
0.2
19%
15%
0
0
1
2
3
4
5
6
Time (years)
7
8
9
10
• Cure was achieved in 16% of CRC patients with liver metastases who
became eligible for surgery after response to conversion chemotherapy
Adam R, et al. J Clin Oncol 2009; 27:1829-35.
Cure = disease-free ≥ 5 years after last hepatectomy / last resection of extrahepatic metastases;
CRC, colorectal cancer; DFS, disease-free survival; OS, overall survival.
Response to CT correlates with liver resectability
Rate of liver resection following CT
0.6
Resection rate
0.5
Selected patients, r = 0.96 P = 0.002
0.4
Non-selected patients, r = 0.74 P < 0.0001
0.3
Phase III trial data, r = 0.67 P = 0.024
0.2
0.1
0.0
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Response rate
• Patient selection and efficacy of pre-operative CT were strong
predictors for resectability of liver metastases
Folprecht G, et al. Ann Oncol 2005;16:1311–9.
CT, chemotherapy
Response rate (%)
NO16966: BEV + CT significantly improves PFS but not
RR or OS in combination
with XELOX/FOLFOX4 (ITT)
70
RR
p=0.99
60
50
40
30
38
38
20
10
0
Placebo +
FOLFOX4/XELOX
BEV +
FOLFOX4/XELOX
AVF2107g: Bevacizumab significantly improves RR,
PFS and OS in combination with IFL (ITT)
Response rate (%)
RR
Months
70
p=0.004
60
50
40
30
45
35
20
Months
10
0
Placebo + IFL
BEV + IFL
CRYSTAL: Cetuximab + FOLFIRI significantly
improves RR, PFS and OS vs FOLFIRI (KRAS wt)
RR
Response rate (%)
70
p<0.001
60
57
50
40
30
40
20
10
0
FOLFIRI Cetuximab + FOLFIRI
OPUS: Cetuximab + FOLFOX4 significantly improves
RR and PFS vs FOLFOX4 (KRAS wt)
70
Response rate (%)
RR
p=0.0027
60
57
50
40
30
34
20
10
0
FOLFOX4
Cetuximab +
FOLFOX4
PRIME: Panitumumab + FOLFOX4 significantly
improves RR and PFS vs FOLFOX4 (KRAS wt)
Response rate (%)
RR
70
p=0.018
60
57
50
40
48
30
20
10
0
FOLFOX
Pani + FOLFOX
Liver limited
All patients
CRYSTAL y OPUS (KRAS WT)
CRYSTAL
FOLFIRI + ERBITUX
FOLFIRI
OPUS
FOLFOX + ERBITUX
FOLFOX
FOLFIRI + ERBITUX
FOLFIRI
FOLFOX + ERBITUX
FOLFOX
n
RR (%)
R0 resections (%)
316
350
57
40
5.1
2.0
p<0.001
p=0.03
57
34
7.3
3.1
p<0.003
p=0.22
71
44
13.2
5.6
p=0.002
p=0.15
76
39
16.0
4.3
p=0.018
p=0.35
82
97
68
72
25
23
Van Cutsem ASCO-GI 2011
PRIME: Increased R0 resection rate in LLD
KRAS wt: LLD
30%
30%
25%
25%
20%
20%
15%
10%
7.0%
8.3%
Patients (%)
Patients (%)
KRAS wt
10%
5%
0%
0%
Pani +
FOLFOX4
(n=325)
17.5%
15%
5%
FOLFOX4
(n=331)
27.8%
FOLFOX4
(n=56)
Pani +
FOLFOX4
(n=60)
Douillard J-Y, et al. J Clin Oncol 2010;28:4697–4705;
Petrelli F, et al. Int J Colorectal Dis 2012;27:997–1004
Conceptualizing the relevance of
DpR for survival
OS
Lethal
tumor load
No tumor shrinkage
Baseline
tumor load
PFS
Tumor shrinkage
PFS
PFS
Time under treatment
Mansmann UR, et al. ASCO GI 2013 (Abstract no. 427)
CRYSTAL and OPUS: More patients
demonstrate ETS when treated with cetuximab
Cetuximab + FOLFIRI
CRYSTAL
62%
≥20%* (n=184)
<20%* (n=115)
Probability of OS
Cetuximab + FOLFIRI
38%
≥20%* (n=184)
<20%* (n=115)
1.0
0.8
mOS 30.0 mo
0.6
0.4
0.2
HR 0.53
p<0.001
mOS 18.6 mo
0.0
0
n=299
OPUS
Cetuximab + FOLFOX4
10
20
30
≥20%* (n=54)
<20%* (n=24)
n=78
*Radiologic evaluation reported by the
investigator and reviewed by an IRC
Probability of OS
69%
50
60 (months)
Cetuximab + FOLFOX4
≥20%* (n=54)
<20%* (n=24)
1.0
31%
40
0.8
mOS 26.0 mo
0.6
HR 0.43
0.4
mOS 15.7 mo
p=0.006
0.2
0.0
0
10
20
30
40 (months)
Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)
PRIME: More patients had RECIST response or
ETS at week 8 with panitumumab + CT than with
CT alone
80
Patients with
RECIST response
80
70
Patients with ETS
70
69
60
50
51
40
38
30
39
Patients (%)
Patients (%)
60
50
40
30
20
20
10
10
0
0
FOLFOX
Pani
+ FOLFOX
(n = 298)
(n=286)
56
39
FOLFOX
Pani
+ FOLFOX
(n = 298)
(n=284)
Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P)
OS was significantly longer in patients
achieving RECIST response or ETS in both
arms
FOLFOX
ETS
Median OS, months
(95% CI)
HR, p-value
RECIST response
Median OS, months
(95% CI)
HR, p-value
FOLFOX + pani
<20%
(n=130)
≥20%
(n=158)
<20%
(n=87)
≥20%
(n=197)
16.6
(12.4–18.8)
25.1
(22.1–32.8)
10.7
(9.4–16.1)
30.0
(27.2–33.1)
HR=0.52, p<0.0001
HR=0.43, p<0.0001
FOLFOX
FOLFOX + pani
<30%
(n=130)
≥30%
(n=112)
<30%
(n=141)
≥30%
(n=145)
17.6
(15.4–20.2)
29.5
(22.5–34.5)
18.0
(14.0–21.7)
30.3
(26.6–36.8)
HR=0.54, p<0.0001
HR=0.53, p<0.0001
● Patients demonstrating ETS who received pantitumumab plus FOLFOX showed a
greater OS benefit compared with those receiving FOLFOX alone (30.0 vs 25.1
months)
Douillard J-Y, et al. ESMO 2012 (Abstract No. 558P)
Downsizing initially unresectable metastases offers
similar 5-year survival as initially resectable patients
CRC liver metastases
Initially resectable
Initially non-resectable
Conversion CT
Resection
5-year survival* 38%
(range)
(30 - 68%)2
Resection
Untreated
37%
0%
(8 - 79%)2
(0 - 6%)3
1. Van den Eynde M, and Hendlisz A. Rev Recent Clin Trials. 2009;4(1):56–62; 2. Kanas GP, et
al. Clin Epidemiol 2012;4:283–301; 3. Simmonds PC et al. Br J Cancer. 2006;94(7):982–99.
*median; CRC, colorectal cancer; CT, chemotherapy.
A meta analysis of resectability and outcomes with
anti-EGFR mAb therapy (KRAS exon 2 WT, LLD)
• Comparison of first-line CT + / - cetuximab or panitumumab
– KRAS WT initially unresectable liver-limited mCRC
• Meta analysis of RCTs:
– Primary outcome: rate of R0 resection
– Secondary outcomes: PFS, OS and ORR
• Four RCTs involving 484 KRAS WT patients were included:
– PRIME, Douillard 2010
– COIN, Maughan 2011
– CRYSTAL, Van Cutsem 2011
– OPUS, Van Cutsem 2011
Petrelli F, Barni S. Int J Colorectal Dis 2012;27:997-1004.
CT, chemotherapy; mCRC, metastatic colorectal cancer; LLD, liver
limited disease; mAb, monoclonal antibody; ORR, overall response
rate; OS, overall survival; PFS, progression-free survival.
Impact of anti-EGFR mAb therapy on outcomes
(KRAS exon 2 WT, LLD)
Response rate
20
P = 0.001
60
40
20
72
43
0
CT alone
CT+ EGFR mAb
Proportion, %
Proportion, %
80
R0 resection rate
P = 0.04
15
10
5
0
18
11
CT alone
CT + EGFR mAb
• Meta-analysis indicates EGFR inhibitors increase R0 resection rate
by 60% in mCRC patients with unresectable liver-limited disease
Petrelli F, Barni S. Int J Colorectal Dis 2012;27:997-1004.
CT, chemotherapy; mAb, monoclonal antibody;
R0, resection with microscopically negative margins.
20060314 Trial
FOLFIRI + panitumumab in 1st-line mCRC
E
N
D
mCRC
(n = 150)
FOLFIRI (Q2W) +
panitumumab 6 mg/kg
(Q2W on day 1 of each cycle)
Disease assessment every 8 weeks
until week 48, then every 3 months
until disease progression
O
F
S
A
F
E
T
Y
T
R
E
A
T
M
E
N
T
F
O
L
L
O
W
U
P
E
N
D
O
F
S
T
U
D
Y
8 weeks after
end of treatment
•
Study endpoints: ORR (1°), PFS, disease control rate, DoR, TTP,
DoSD, TTF, safety
-
The incidence of R0 resection was also reported
www.amgentrials.com; protocol ID: 20060314; ClinicalTrials.gov ID: NCT00508404.
Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138:65-72.
DoR, duration of response; PFS, progression-free survival;
TTP, time to progression; DoSD, duration of stable disease;
TTF, time to treatment failure; ORR, overall response rate.
KRAS WT tumours were more likely to respond to
treatment with panitumumab plus FOLFIRI
Objective response rate
R0 resection rate, patients with LLD
20
40
56
20
38
Proportion, %
Proportion, %
60
15
10
19
5
6
0
KRAS MT
KRAS WT
0
KRAS MT
KRAS WT
• A higher proportion of patients with KRAS WT than with KRAS MT
had an objective response and R0 resection
Köhne C-H, et al. J Cancer Res Clin Oncol 2012; 138:65-72.
CT, chemotherapy; R0, resection with microscopically negative margins.
PRIME study
FOLFOX4 ± panitumumab in 1st-line treatment of
metastatic CRC
FOLFOX4 (Q2W) +
panitumumab 6 mg/kg
mCRC
KRAS* WT
(n = 1183)
(Q2W)
O
F
R
1:1
FOLFOX4 (Q2W)
Disease assessment
every 8 weeks
•
E
N
D
T
R
E
A
T
M
E
N
T
L
O
N
G
T
E
R
M
F
O
L
L
O
W
U
P
Study endpoints: PFS (1°), OS, ORR, TTR, DoR, safety and tolerability
-
Primary Analysis: pre-specified; after >50% of KRAS exon 2 WT patients had died1,2
-
Updated OS Analysis: exploratory; after >80% of KRAS exon 2 WT & MT patients died2
www.amgentrials.com: ID: 20050203; ClinicalTrials.gov ID: NCT00364013;
1. Douillard JY, et al. J Clin Oncol 2010; 28:4697-705;
2. Douillard JY, et al. N Engl J Med 2013; 369:1023-34.
*KRAS status was prospectively analysed;
FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin;
DoR, duration of response; ORR, objective response rate;
OS, overall survival; TTR, time to response; Q2W, every 2 weeks.
PRIME study RAS analysis
Post-hoc analysis objective
Post-hoc analysis to evaluate tumour shrinkage,
resection rates and PFS and OS outcomes for
patients with RAS WT and LLD treated in
the 1st-line PRIME study
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).
RAS WT, KRAS & NRAS exons 2/3/4;
LLD, liver-limited disease
PRIME study RAS analysis
Patient population and objective
(RAS WT LLD patients, updated analysis)
First-line mCRC RAS WT
(n = 505)
FOLFOX4
(n = 252)
FOLFOX4 + Panitumumab
(n = 253)
Liver plus other mets
(n = 169)
Liver plus other mets
(n = 172)
Other only mets
(n = 36)
Other only mets
(n = 39)
LLD
(n = 48)
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).
LLD
(n = 41)
CLM, colorectal liver metastases; LLD, liver-limited disease;
RAS, KRAS & NRAS exons 2/3/4.
PRIME study RAS analysis
Objective response and tumour shrinkage
(RAS WT LLD patients, updated analysis)
Tumour shrinkage
≥ 30% at wk 8#
Objective response
Panitumumab + FOLFOX4
FOLFOX4
100
100
100
P = 0.015
80
60
40
66
79
Proportion, %
80
60
20
20
0
0
n = 41 n = 48
79
40
51
P = 0.270
Median shrinkage, %
P = 0.231
Proportion, %
Maximum tumour
shrinkage§
80
60
40
65
73
20
0
n = 35 n = 43
assessed at baseline and week 8; §Patients assessed at
baseline and at least one other time point; LLD, liver-limited disease;
RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive.
#Patients
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).
n = 39 n = 46
Metastasectomy (all resections)
Complete resection*
P = 0.349
P = 0.216
15
15
10
10
15
5
9
0
FOLFOX4 Panitumumab
(n= 41)
+ FOLFOX4
(n= 48)
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).
Patients, n
Patients, n
PRIME study RAS analysis
Metastasectomy and complete resection rates
(RAS WT, LLD patients, updated analysis)
14
5
7
0
FOLFOX4
(n= 41)
Panitumumab
+ FOLFOX4
(n= 48)
*Subgroup of patients with metastasectomy; LLD, liver-limited disease;
RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive.
PRIME study RAS analysis
PFS, OS
(RAS WT, LLD patients, updated analysis)
OS
PFS
100
100
HR (95% CI) = 0.75 (0.48, 1.19)
P = 0.2223
80
70
60
50
40
30
20
10
90
Kaplan-Meier estimate
Kaplan-Meier estimate
90
80
HR (95% CI) = 0.71 (0.43, 1.16)
P = 0.1737
70
60
50
40
30
20
10
0
0
0
4
8 12 16 20 24 28 32 36 40 44 48 52
Months
Events
n (%)
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64
Months
Median OS
months
Panitumumab +
FOLFOX4 (n = 48)
38 (79)
11.3
Panitumumab +
FOLFOX4 (n = 48)
FOLFOX4 (n = 41)
37 (90)
9.9
FOLFOX4 (n = 41)
Peeters M, et al. EJC 2013; 49 (suppl 4):abstract MC13-0022 (and poster).
Events
n (%)
Median OS
months
32 (67)
40.7
31 (76)
33.4
LLD, liver-limited disease; PFS progression-free survival; OS, overall survival;
RAS, KRAS and NRAS exons 2/3/4; P-values are descriptive.
NEOADJUVANT BEVACIZUMAB IN LIVER METASTASES
Study
Treatment
Selected
patients
n
TR (%)
R0 (%)
AVF 21071
B-IFL
IFL
No
402
45
<2
NO 169662
B-FOLFOX
B-XELOX
No
700
701
38
38
6.3
4.9
First-BEAT3
B-CT (oxali/CPT)
No
1914
-
9 (12/7)
GONO4
B-FOLFOXIRI
No (LLD)
57
(30)
77 (80)
(26)
TRIBE5
b-FOLFOXIRI
FOLFIRI
No (LLD)
252
256
65
53
15 (32)
12 (28)
Gruenberger7
B-XELOX
Resectable
56
73
92
BOXER6
B- XELOX
non-resectable
and borderline
46
78
10-40
OLIVIA8
B-FOLFOXIRI
B-FOLFOX6
non- resectable
disease
41
39
80
61
49%
23%
LLD CRC patients
1- Hurwitz 2004, 2- Saltz 2008, 3- Okines 2009, 4- Masi 2010, 5- Falcone 2012, 6- Wong 2011, 7Gruenberger 2008, 8- Gruenberger 2013
CELIM: Tasas de Respuesta y Resección R0
All
patients
Cetuximab
+ FOLFOX6
Cetuximab
+ FOLFIRI
KRAS wt
KRAS mt
n=106
n=53
n=53
n=67
n=27
CR/PR
62%
68%
57%
70%
41%
95% CI
52–72%
54–80%
42–70%
58–81%
22–61%
34%
38%
30%
33%
30%
25–44%
25–52%
18–44%
22–45%
14–50%
R0 resections
95% CI
Folprecht G, et al. Lancet Oncol 2010; 11: 38–47
Folprecht G, et al. EMCC 2011 (Abstract-Poster No. 6009)
POCHER:
Alta tasa de respuestas y resecciones
Response rate
50
40
30
Patients (%)
Patients (%)
60
79%
80
80
70
70
60
60
50
40
30
60%
Patients (%)
80
70
2-year OS rate
R0 resection rate
50
68%
40
30
20
20
20
10
10
10
0
0
0
Garufi C, Br J Cancer, 2010
▼Panitumumab in 1st-line mCRC
Phase II trial of panitumumab plus FOLFOX4 or
FOLFIRI in subjects with KRAS wild-type
colorectal cancer and liver-limited disease: The
PLANET study
A. Abad1*, B. Massuti2, C. Grávalos3, P. Escudero4, C. Guillén-Ponce5, J.L. Manzano1, A.
Gomez6, Mª J. Safont7, J. Gallego8, J. Sastre9, C. Pericay10, R. Dueñas11, C. LópezLópez12, F. Losa13, M. Valladares14, E. González15, A. Yuste2, A. Carrato5, Enrique Aranda6
On behalf of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
1.Germans Trias i Pujol Hospital –ICO, Badalona, Spain; 2. General Hospital, Alicante, Spain; 3. Doce de Octubre Hospital, Madrid, Spain; 4. Clínico
Lozano Blesa Hospital, Zaragoza, Spain; 5. Universitario Ramón y Cajal Hospital, Madrid, Spain; 6. Maimonides Institute of Biomedical Research,
IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba. Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Spain; 7. General
Hospital, Valencia, Spain; 8. General Universitario de Elche Hospital, Alicante, Spain; 9. Hospital Clínico San Carlos, Madrid; Center affiliated to the
Red Temática de Investigación Cooperativa, RD06/0020/0021, Spain, Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid; 10.
Sabadell Hospital, Corporación Sanitaria Parc Taulí, Barcelona, Spain; 11. Complejo Hospitalario de Jaén Hospital, Jaén, Spain; 12. Marqués de
Valdecilla Hospital, Santander, Spain; 13. General de L´Hospitalet Hospital, Barcelona, Spain; 14. Complejo Hospitalario Universitario Hospital, La
Coruña, Spain; 15. Virgen de las Nieves Hospital, Granada, Spain; *actual address: Oncology Unit, Campus CIMA, Barcelona, Spain
▼ This medicinal product is subject to additional monitoring. All suspected adverse reactions should be reported
PLANET study
Objectives
To evaluate the efficacy and safety of the addition
of Pmab to standard CT regimens, either FOLFIRI
or FOLFOX4, as first-line treatment in WT KRAS
CCR patients with liver-only metastases.
To explore possible differences in outcomes
according to other RAS mutations.
PLANET study
Study design
FOLFOX4 (Q2W) +
panitumumab 6 mg/kg
WT KRAS liveronly mCRC
not suitable for
initial surgery
(Q2W)
Response Rate,
Resectability Rate,
Safety, PFS,OS
R
1:1
N=80
FOLFIRI (Q2W) +
panitumumab 6 mg/kg
(Q2W))
• Sponsor: Spanish Cooperative Group for Digestive Tumour Therapy (TTD)
• Principal investigators: Dr. Albert Abad & Dr. Alfredo Carrato
• ClinicalTrials.gov identifier:
NCT00885885
PLANET study
Endpoints
•
•
•
Primary Endpoint:
• Objective response rate (ORR) over the entire Pmab+CT
treatment period
Secondary Endpoints:
• Resection rate (R0+R1) of liver metastases
• Time to resection
• Progression-free survival (PFS)
• Overall survival (OS)
• Adverse Events (AEs) and peri-operative safety
Exploratory Endpoints:
• Response according to molecular biomarkers (RAS status)
PLANET study
Key eligibility criteria
• >18 years of age
• WT KRAS CRC
• Synchronous or metachronous liver-only metastases deemed
resectable or unresectable, meeting one of the following criteria
– ≥4 liver metastases
– ≥1 metastasis >10 cm in diameter
– Liver metastases not resectable
• No prior anti-EGFR therapy
• Karnofsky performance status ≥70%
• Adequate haematologic, renal and metabolic function
Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).
EGFR, epidermal growth factor receptor
PLANET study
Patient disposition and characteristics
•
77 patients were analyzed
–
–
38 received Pmab-FOLFOX4
39 received Pmab-FOLFIRI
PmabFOLFOX4
(N = 38)
PmabFOLFIRI
(N = 39)
31 (81.6)
28 (71.8)
59 (76.6)
65 (32, 79)
63 (37, 83)
64 (32, 83)
27.4 (4.4)
25.9 (3.6)
26.7 (4.0)
Median time since CCR diagnosis, months
(Q1, Q3)
3.4 (1.3,
22.7)
1.6 (0.6,
11,5)
1.9
(0.6, 22.2)
Technically resectable liver metastases, n (%)
12 (31.6)
12 (30.8)
24 (31.2)
Prior surgery for primary tumor, n (%)
26 (68.4)
22 (56.4)
48 (62.3)
Prior adjuvant/neoadjuvant CT and/or
radiotherapy, n (%)
6 (15.8)
4 (10.3)
10 (13.0)
3 (7.9)
3 (7.7)
6 (7.8)
Male, n (%)
Median age, years (min, max)
Mean body mass index, kg/m2 (SD)
Prior FOLFOX, n (%)
Abad et al. Presented at the 16th World Congress on Gastrointestinal Cancer, June 25-28, 2014, Barcelona (Spain); Abstract nº PD-0006
TOTAL
(N = 77)
PLANET study
Response rate and resectability – presented a ESMO
PLANET study
OS
WT RAS
100
100
90
90
Proportion event-free (%)
Proportion event-free (%)
WT KRAS exon 2
80
70
60
50
40
30
20
P log rank = 0.848
P Wilcoxon = 0.915
10
80
70
60
50
40
30
20
P log-rank = 0.935
P Wilcoxon = 0.634
10
0
0
0
10
20
30
Months
40
50
60
0
10
20
30
Months
Median, months
(95% CI)
40
50
Median, months
(95% CI)
Panitumumab + FOLFOX4
32.5 (20.6–NA)
Panitumumab + FOLFOX4
39.0 (26.4–NA)
Panitumumab + FOLFIRI
42.4 (17.8–51.5)
Panitumumab + FOLFIRI
45.8 (32.8–51.5)
Abad A, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3560 (and poster).
WT RAS, WT KRAS & NRAS exons 2/3/4;
NA, not achieved
ESMO Clinical Groups for 1st-line treatment
Definition of Group 0 (initially resectable) patients
Initially R0
resectable
Group 0
Non-resectable at clinical presentation
Group 1
Group 2
Group 3
• Metastases are:
– Limited to liver and / or lung
– Clearly R0-resectable, even without preoperative chemotherapy
• Treatment aim is curative and to decrease risk of relapse
Schmoll HJ, et al. Ann Oncol 2012; 23:2479-516.
R0, resection with microscopically negative margins.
EORTC intergroup study 40983 [EPOC]
Surgery ± FOLFOX4 for resectable liver metastases
from colorectal cancer
Open label, phase 3 study
mCRC with
initially
resectable
LLD
(n = 364)
•
FOLFOX4
6 cycles
R
1:1
None
S
U
R
G
E
R
Y
FOLFOX4
6 cycles
None
Study endpoints: PFS (1°), OS, resectability, tumour response, safety
ClinicalTrials.gov identifier: NCT00006479
Nordlinger B, et al. Lancet 2008; 371:1007-16; Nordlinger B, et al. Lancet 2013; 14:1208-14.
mCRC metastatic colorectal cancer; LLD, liver limited disease;
OS, overall survival; PFS, progression free survival.
EORTC intergroup study 40983 [EPOC]
Progression free survival
All eligible patients
All resected patients
100
HR (96% CI) = 0.77 (0.60, 1.00)
P = 0.041
80
60
40
20
0
Proportion event-free (%)
Proportion event-free (%)
100
HR (96% CI) = 0.73 (0.55,
0.97)
P = 0.025
80
60
40
20
0
0
1
2
3
4
5
6
0
1
2
3
5
6
Years
Years
3-year PFS, %
3-year PFS, %
•
4
Surgery + FOLFOX4
(n = 171)
36.2
Surgery + FOLFOX4
(n = 151)
42.4
Surgery (n = 171)
28.1
Surgery (n = 152)
33.2
Perioperative FOLFOX4 reduced the risk of PFS events by ~25%
Nordlinger B, et al. Lancet 2008; 371:1007-16.
PFS, progression free survival.
20100086 EORTC BOS-2 study
Patients with resectable liver metastases
Open label, phase 2 study
mFOLFOX6
KRAS WT
mCRC
with
resectable
LLD
(n = 360)
R
mFOLFOX6 +
bevacizumab
mFOLFOX6 +
panitumumab
6 cycles
•
mFOLFOX6
S
U
R
G
E
R
Y
mFOLFOX6 +
bevacizumab
mFOLFOX6 +
panitumumab
F
O
L
L
O
W
U
P
6 cycles
Study endpoints: PFS (1°), pathological response rate, resection
rate, OS, safety
ClinicalTrials.gov identifier: NCT01508000.
BOS, biologics, oxaliplatin and surgery, OS, overall survival.
Conclusiones
• El CCRm tiene mal pronóstico si no se trata.
• La cirugía hepática ofrece posibilidad de curación (15%)
• Hasta un 30% de los tumnores inicialmente irresecables se
convierten en resecables tras QT de conversión
• Las combinaciones de quimioterapia con tratamientos biológicos
ofrecen tasas de respuestas superiores a 50% en pacientes no
seleccionados, y superiores a 70% en pacientes con enfermedad
limitada al hígado.
• Los datos de los estudios fase III (PRIME), y los estudios de los
estudios fase II con pacientes seleccionados (PLANET), permiten
emular los resultados de otras combinaciones
Conclusiones
• Cuando hablemos del tratamiento de conversión
en pacientes afectos de CCRm potencialmente
resecables, las combinaciones con panitumumab
han demostrado ser igualmente eficaces que
otras combinaciones de tratamiento estudiadas
con anterioridad.