Anticorpi monoclonali nel trattamento del
carcinoma colorettale
IL TRATTAMENTO DI PRIMA LINEA
NELLA MALATTIA AVANZATA
New Drugs in CRC
9
Irinotecan
9
Oxaliplatin
9
Oral Fluoropyrimidines (CAP-UFT)
9
Bevacizumab
9
Cetuximab
First-Line: Questions
9
Folfox o Folfiri?
9
Fluoropyrimidines?
9
Doublet or triplet?
9
Doublet or single-drug
Ædoublet?
9
Continuous or intermittent therapy?
GOIM Protocol 9901 Objective response
53 (30.8)
48 (29.2)
PR
9 ( 5.2)
8 ( 4.8)
CR
44 (25.7)
40 (24.4)
PD
66 (38.3)
68 (41.6)
SD
0.71
p
172
164
Evaluable
182
178
Entered
ORR:
62
56
CR + PR
Response:
FOLFIRI
FOLFOX4
(26.9-41.4)
(28.9-43.2)
(95% C.I.)
34
36
Evaluable
34
(27.2-41.5)
31
(24.6-38.3)
ITT
(95% C.I.)
G.Colucci et al.,JCO 2005p 0,60
Kaplan-Meier survival estimates, by cdArm
analysis time 0 12 24 36 48 0.00 0.25 0.50 0.75 1.00 Arm - A Arm - B Chi-Square = 1.17 p< 0.28Arm - A Median = 14 Range (1 - 48) Arm - B Median = 15 Range (1 - 43)
COLORECTAL CANCER
9901
Results
n 109 81 111 69 RR 56% 15% 54% 4% Median PFS (months) 8.5 4.2 8.0 2.5 Median PFS (months) 14.2 10.9 for sequenceMedian overall survival 21.5 20.6 (months)
Arm A
FOLFIRI
→ FOLFOX6
Arm B
FOLFOX6
→ FOLFIRI
FOLFIRI vs
FOLFOX: no difference in first-line efficacy
Incidence % of NCI-CTC grade 3 - 4
FOLFIRI FOLFOX Tournigand n=109 Colucci N=138 Tournigand n=111 Colucci N=167 Neutropaenia 22 10 40 10 Febrile neutropaenia 6 1 - -Diarrhoea 13 10 10 5 Neurotoxicity** (grade 3) 0 0 31 Alopecia (grade 2) 24 42 9 19 Nausea/vomiting 12 4 3 3 Stomatitis Cholinergic syndr (gr. 2) Hypersensivity Cardiac 9 1 10 * -1 1 -1 1 * 1 toxicity death** Specif. modified Levy-scale ‡ +19% neurotoxicity grade 3 with FOLFOX in first-line
1
First-Line: Questions
9
Folfox o Folfiri?
9
Fluoropyrimidines?
9
Doublet or triplet?
9
Doublet or single-drug
Ædoublet?
9
Continuous or intermittent therapy?
XELIRI / XELOX
Patt ‘04 CPT 250, 1 + CAP 1000 bid x 14 / 3 wXELIRI
5254
7.8 16.8 N 25 HF 6 Schoffski ‘04 OXA 130, 1 + CAP 1000 bid x 14 / 3 wXELOX
9655
7.7 19.5 N 7 D 16 HF 3 NE 17 Grothey ‘04 CAPIRI CAPOX 77 41 18.8 80 51 16.8 Drugs No. % TTP OS 3-4 gr Pts OR Tox %Response Rates:
XELIRI Compares Favorably
with 5-FU /LV/Irinotecan
1Patt YZ et al. Proc ESMO Ann Onc. 2004;15:iii88 (238P); 2Bajetta E et al. Cancer 2004;100:279–87; 3Borner MM et al. Ann Onc.,2005;16:282–8; 4Saltz LB et al. N Engl J Med 2000;343:905–14; 5Goldberg R et al. J Clin Oncol 2004;22:23–30; 6Douillard JY et al. Lancet 2000;355:1041–7 7Tournigand C et al. J Clin Oncol 2004;22:229–37
60 50 40 30 20 10 0 Response (%) XELIRI (n=68)2 IFL (n=231)4 IFL (n=264)5 FOLFIRI (n=145)6 XELIRI (n=52)1 XELIRI (n=37)3 FOLFIRI (n=109)7
Phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (XELOX1*)
9
2x2 factorial,
randomized phase III trial
Previously untreated patients with MCRC (n=1920) Avastin 5mg/kg every 2 weeks (n=330) Placebo (n=330) Avastin 7.5mg/kg every 3 weeks (n=330) Placebo (n=330) FOLFOX4 (n=300) XELOX (n=300) PD PD PD PD z Primary objectives
z at least equivalent TTP with XELOX (± Avastin) versus FOLFOX4 (±
Avastin)
z superior TTP with Avastin + XELOX/FOLFOX versus XELOX/FOLFOX
Randomized Phase III study of Capecitabine plus
Oxaliplatincompared with Fluorouracil/foloinic acid plus Oxaliplatin
as First-line therapy for Metastatic colorectal cancer
J. Cassidy e al.,J Clin Oncol 2008; 26: 2006-12
2-arm design
protocol amendment 2x2 factorial design
R 634 pts R 1401 pts
XELOX (317) FOLFOX4 (317)
XELOX FOLFOX4
+plb +Beva +plb +Beva 350 350 351 349 No pts %RR PFS DOR OS FOLFOX 1017 37 8.5 7.6 19.6 XELOX 1017 37 8.0 7.5 19.8 Xelox1-NO16966A
Age 18–75 years; ECOG PS ≤2; no prior chemotherapy for MCRC (adjuvant therapy ≥6 months earlier)
Randomized Phase II Trial:
CAPIRI vs CAPOX
(Predefined Crossover in Second-Line)
C
R
O
S
S
O
V
E
R
CAPOX
CAPIRI
Disease progression n=35 n=33R
A
N
D
O
M
I
Z
A
T
I
O
N
CAPIRI
Xeloda 1000mg/m2 twice daily, d1–14, q21d Irinotecan 80mg/m2 d1, 8CAPOX
Xeloda 1000mg/m2 twice daily, d1–14, q21d Oxaliplatin 70mg/m2 d1, 8 n=79 n=82CAPOX and CAPIRI:
Similar High First-Line Efficacy
Grothey A et al. J Clin Oncol Proc ASCO 2004;22 (Suppl. 14S) (Abst 3534)
CAPOX
1st line
(n=80)
CAPIRI
2nd line
(n=34)
CAPIRI
1st line
(n=77)
CAPOX
2nd line
(n=31)
Overall response rate (%)
51
21
41
13
Median PFS (months)
6.2
5.1
7.1
4.3
Median overall survival
(months [95% CI])
16.5
(12.9–18.5)
18.8
(15.7–23.7)
First-Line CAPIRI and CAPOX:
Both Regimens Well Tolerated
Patients (%) 20 15 10 5 0 Diar rhea Nau sea Vom iting Infe ction Sens ory neur opa thy Han d-foo t syndr om e Bili rubi n CAPIRI (n=79) CAPOX (n=80)Most common (>2.5%) grade 3/4 clinical adverse events
First-Line: Questions
9
Folfox o Folfiri?
9
Fluoropyrimidines?
9
Doublet or triplet?
9
Doublet or single-drug
Ædoublet?
9
Continuous or intermittent therapy?
OR
66
41
0.0002
PR
60
34
< 0.0001
Resecability
14
6
0.05
Only liver
36
12
0.02
mPFS
9.8
6.9
0.0006
mOS
22.6
16.7
0.032
Falcone A. et al., JCO 2006; 24 (18S):3513 abs (244)
(81)
FOLFOXIRI IN ACC
First-Line: Questions
9
Folfox o Folfiri?
9
Fluoropyrimidines?
9
Doublet or triplet?
9
Doublet or single-drug
Ædoublet?
9
Continuous or intermittent therapy?
Sequential Compared to
Combination Chemotherapy
CAP 2500
IRI 350
CAPOX 2000 + 130
CAPIRI
CAPOX
R
All-cause-60-day mortality = 3% vs 4.5% (=30 pts)
Treatment-related death 11 pts: 8A and 3B !
mOS 16.3 vs 17.4 (p 0.32, HR: 0.92)
Koopmann M et al. Lancet 2007, 370: 135-142
PTS R / T
820 / 803
410/410 401/402First-line: questions
9
Folfox o Folfiri?
9
Fluoropyrimidines?
9
Doublet or triplet?
9
Doublet or single-drug
Ædoublet?
9
Continuous or intermittent therapy?
“Stop and Go”
OPTIMOX1: FOLFOX7 x 6
LV5FU
U.PD
FOLFOX7
OPTIMOX2: FOLFOX7 x 6
REST
at PRO, FOLFOX7
R
63
8.3
10.8
--
24.6
61
6.7
9.0
4.6
18.9
p 0.04
p 0.05
%RR
mPFS
mDDC
mCFI
mOS
“Maintenance LV5FU therapy prolongs PFS and OS, especially in pts with poor prognosis (14.5 vs 20.9). CFI can be recommended only in selected pts without adverse prognostic factors”
F. Maindrault-Goebel et al., ASCO 2007; 25:4013
29 studi di fase III: 13498 pazienti
PFS e RR sono significativamente correlate
(p <0.0001)
PFS (m)=0,1xRR% + 3,2
Correlazione più debole tra % di RO e OS
OS (m)= 0,088 RR% + 10,45
Survival associated with use of 3 drugs
Combination first-line % with 3 drugs Overall survival (months) Author IFL 5% 14.8 Saltz IFL 24% 14.8 Goldberg FOLFIRI 16% 17.4 Douillard FOLFOX FOLFOX 30% 58% 16.2 18 DeGramont Colucci FOLFOX 60% 19.5 Goldberg FUciOX 60% 19.4 Giacchetti FOLFOX 62% 20.6 Tournigand FUFOX 68% 19.7 Grothey AIO/IRI 54% 20.1 Köhne FOLFIRI 74% 21.5 TournigandFirst-Line: Questions
9
Folfox o Folfiri?
9
Fluoropyrimidines?
9
Doublet or triplet?
9
Doublet or single-drug
Ædoublet?
9
Continuous or intermittent therapy?
Cetuximab as Single Agent in 2
ndLine
Treatment of Irinotecan-Refractory mCRC
* ~ 40% of pts received Cetuximab as a 3rd or higher line treatment ♦IRN/OHP-refractory pts ♠ IRN/FU/OHP-refractory pts Pts RR Dis Con mTTP mS Saltz JCO 2004 57 9% 37% 1.4 mths 6.4 mths Cunningham NEJM 2004* 111 11% 34% 1.5 mths 6.9 mths -11% 12% 46% 34% -29 Mirtsching ASCO 2004♠ -235 Lenz ASCO 2004♦ 10,9%
Response Rate/TTP: IRC
Combination
Monotherapy
p-value
(N=218) [95% CI] (N=111) [95% CI]
PR
[17.5–29.1]
10.8%
[5.7–18.1]
0.0074
Disease control* 55.5%
[48.6–62.2]
32.4%
[23.9–42.0] 0.0001
Median TTP
4.1 months
1.5 months
<0.0001
*CR+PR+SD
22.9%
CRYSTAL
Trial:
Study Design
Stratification factors: z Regions z ECOG PS Populations z Randomized patients n=1217 z Safety population n=1202 z ITT population: n=1198 FOLFIRI irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeksCetuximab + FOLFIRI
Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks R EGFR-expressing metastatic CRCOPUS Study Design
Cetuximab + FOLFOX-4
400 mg/m2 initial IV infusion (day 1) then 250 mg/m2 weekly + oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks FOLFOX-4 oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks EGFR-expressing metastatic CRC Stratification factors: ECOG PS 0-1, 2
R
Treatment until progression, symptomatic deterioration or unacceptable toxicity
Efficacy: Response Rate All Patients
and ECOG 0-1 Stratum
Response
rate, %
Cetuximab +
FOLFOX-4
FOLFOX-4
All
45.6
(n=169)
35.7
(n=168)
ECOG 0-1*
49.0
(n=153)
36.8
(n=152)
*
p=0.032**,
Odds ratio: 1.648 [95% CI:1.043, 2.604]OR [95% CI]
Favors FOLFOX Favors Cetuximab + FOLFOX
Subgroup (number of patients)
Efficacy by Subgroups
2.00 [1.02, 3.93] 1 (74 vs69) One metastatic site 2.11 [0.88, 5.07] Livermetastasis only Yes (50 vs39)
≤10 000 / mm3 (124 vs131)
Leucocytes 2.00 [1.19, 3.35]
2.07 [1.03, 4.14]
>upper normal limit (82 vs63)
LDH Alkaline phosphatase <300 U/L (128 vs128) 2.04 [1.22, 3.42] 1.82 [1.03, 3.21] 1.14 [0.57, 2.31] <65 years (96 vs109) ≥65 years (73 vs59) Age 2.29 [1.18, 4.46] 1.12 [0.61, 2.04] Western Europe (72 vs 75) Eastern Europe (97 vs 93) Region
All ITT subjects (n= 169 vs 168)
0.1 1
10 5 2
ECOG 0/1 1.648 [1.043, 2.604]
Enrolled : 70 Sex Male: 43 (61,4%) Female: 27 (38,6%) Age (yrs) Median: 62 Range: 36-74 PS (Ecog) Median: 0 Range: 0-2 Primary tumor site:
Colon: 48 (68.6%) Rectum: 22 (31,4%) Main sites: Liver: 53 (75.7%) Lung: 23 (32.9%) Lymphnodes: 9 (12.9%) Others: 19 (27.1%) Single site: 44 (63%) Multiple sites: 26 (37%) Sinchronous: 59 (84%) Metacronous: 11 (16%) Adjuvant therapy: yes: 7 (10%) no: 63(90%)
Patients’polulation: 70 unselected
Only liver metastases:
33
pts (47%); with bulky disease: 25/33(
76%)
Enrolled/Screened 70/82 (85%) Evaluable 67 CR 4 (6%) PR 39 (58.2%) SD 20 (29.8%) PRO 4 (6%) ORR COR 43/67 (64%) 95%IC (51-74) 42/67 (62,7%) TGCR 63/67 (94%) 95%IC (88-99)
ITT analysis OR 43/70 (61%) 95%IC (48-71)
TGCR 63/70 (90%) 95%IC (83-97)
Objective Responses
3 pts NED: 1 suicide; 1 refused treatment; 1 allergic reaction
Cetuximab + Oxaliplatin
Based Regimen
Author
Ev
Pts
RR
(%)
TGC
(%)
PFS
(mo)
OS
(mo)
G3-4 skin
toxicity
Tabernero, 2007
43
72
95
12.3
30
30%
Seufferlein, 2005
41
54
nr
nr
nr
17%
Colucci, 2006
67
64
94.0
10
22
20%
Dakhil, 2006
67
61.2
89.6
8
nr
17%
Venook, 2006*
58
60
86
8.2
nr
nr
* part of randomized phase II
OPUS, 2007 169 45,6 81
VEGF VEGF recept or Antibodies inhibiting VEGF
Inhibiting antibodies Soluble VEGF
receptors (VEGF-Trap) – P – P P– P– – P – P Angiogenesis Small-molecules inhibiting VEGF receptors (TKIs)
TKIs = tyrosine kinase inhibitors
Phase III Trial:
Efficacy Summary
Median survival (mo)
PFS (mo)
ORR (%)
CR
PR
Duration of response (mo)
15.6
6.24
35
2.2
32.5
7.1
20.3
10.6
45
3.7
41.2
10.4
IFL + Placebo IFL + Avastin
P value
(n=412) (n=403)
0.00003
<0.00001
0.0029
Phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (XELOX1*)
9
2x2 factorial,
randomized phase III trial
Previously untreated patients with MCRC (n=1920) Avastin 5mg/kg every 2 weeks (n=330) Placebo (n=330) Avastin 7.5mg/kg every 3 weeks (n=330) Placebo (n=330) FOLFOX4 (n=300) XELOX (n=300) PD PD PD PD z Primary objectives
z at least equivalent TTP with XELOX (± Avastin) versus FOLFOX4 (±
Avastin)
z superior TTP with Avastin + XELOX/FOLFOX versus XELOX/FOLFOX
Study/regimen Endpoint
TTP/PSS (mo) OS (mo) ORR (%)
TREE (phase II)
mFOLFOX 8.7 19.2 41 mFOLFOX+bev 9.9 26 52 bFOL 6.9 17.9 20 bFOL+bev 8.3 20.7 39 CapeOx 5.9 17.2 27 CapeOx+bev 10.3 27 46
NO16966 (phase III)
FOLFOX or XELOX 8 19.9 38
FOLFOX or XELOX+bev 9.4 21.3 38
Efficacy Results for Selected Studies of
1st line Chemotherapy
Panitumumab
PD
Follow-up
6.0 mg/kg Q2W
+ BSC
BSC
PD
Follow-up
R
R
A
A
N
N
D
D
O
O
M
M
I
I
Z
Z
E
E
Optional Optional Panitumumab Panitumumab Crossover Study Crossover Study Randomization stratification • ECOG score: 0-1 vs 2• Geographic region: Western EU vs
Central & Eastern EU vs Rest of World
Randomized Controlled Phase 3 Trial in mCRC
1:1
ENDPOINTS
Primary PFS
Secondary OS, ORR, Duration of & time to response Safety adverse events, antibody formation
Event Event --fr e e Probability fr e e Probability 0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0
Weeks from Randomization
Weeks from Randomization
0
0 88 1616 2424 3232 4040 4848 5656
Hazard ratio=0.54 (95% CI: 0.44, 0.66) Stratified log-rank test
p < 0.000000001
Progression-Free Survival
Panitumumab + BSC BSC alone Patients at risk: Patients at risk: Panitumumab Panitumumab BSC alone BSC alone 231 231 118118 4949 3131 1313 55 11 232 232 7575 1717 77 33 11 11Progression
Progression
-
-
Free Survival for
Free Survival for
Panitumumab
Panitumumab
-
-Treated Patients by
Treated Patients by
KRAS
KRAS
Status
Status
_
Median (95% CI) in Weeks Mutant: 7.4 (7.1–8.0)
--
Wild-type: 16.2 (8.3–23.7) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion with PFS 55 50 45 40 35 30 25 20 15 10 5 0 24 38Patients at Risk:Mutant Wild-type 24 38 6 25 6 25 4 17 3 14 2 13 2 7 6 3 3
Biologicals as first-line therapy in advanced CRC:
ORR from key randomised trials
31 45 38 46 47 43 34 35 38 36 39 39 ORR (%) 50 40 30 20 10 0
FOLFIRIFOLFOX AvastinPlacebo AvastinPlacebo CetuximabControl CetuximabControlPanitumumab + Avastin
Avastin
IFL XELOX/FOLFOX FOLFOX FOLFIRI Irinotecan-based CTx p=0.60 p=0.004 p=0.99 p=0.064 p=0.0038 n.s. Colucci et al. JCO 2005 Hurwitz et al. NEJM 2004 Saltz et al.
JCO. In press al. ECCO 2007Bokemeyer et
Van Cutsem ASCO 2007
Hecht et al. ASCO GI 2008
Guidelines: Current Treatment Algorithms in
Advanced CRC
1st-line 2nd-linePatients suitable for combination CTx
FOLFIRI/(XELIRI) + Avastin FOLFOX/ XELOX Erbitux mono FOLFOX/XELOX + Avastin Irinotecan + ERBITUX FOLFIRI (XELIRI) 3rd-line Irinotecan + Erbitux Irinotecan + erbitux FOLFOX/ XELOX
