2013 ASCO CRC Poster Discussion (Old Dog, New Tricks) Weijing Sun, MD, FACP University of...
-
Upload
lydia-wiggins -
Category
Documents
-
view
232 -
download
0
Transcript of 2013 ASCO CRC Poster Discussion (Old Dog, New Tricks) Weijing Sun, MD, FACP University of...
2013 ASCO CRC Poster Discussion(Old Dog, New Tricks)
Weijing Sun, MD, FACPUniversity of Pittsburgh
• Bevacizumab in CRC Therapy: Doses, efficacy, maintenance, and impact of ages
- 3515, 3516, 3517, 3521 • S-1 in CRC: the un-replaceable role of fluoropyrimidines
in CRC therapy, and equivalence of different analogs : -3518, 3519• Early response is critical and an indicator for the overall
outcome: 3520
• What can we learn from these studies?• What is the potential impact of these studies
on clinic practice?
3516: FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer who have failed first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study Hiroshi Tamagawa, et al
Evaluated the optimal dose of Bevacizumab (2nd-line):A long-time question since the first day of bevacizumab in clinical practice: 5mg/kg vs. 10 mg/kg vs. 7.5 mg/kg (commonly used in q3wks regimen with XELOX)
Oxaliplatin based CTx + bevacizumab 5mg/kg R
Arm A: FOLFIRI + bevacizumab 5mg/kg
Arm B: FOLFIRI + bevacizumab 10mg/kg
Primary End Point: PFSSecondary end points: Toxicity, RR, TTF, OS, OS from the first-line, duration from the start of the first-line
N=367
PFS100
80
60
40
20
0 6 12 18 24 30 36
Hazard ratio: 0.95 (95% CI: 0.75-1.21)p= 0.676 (log-rank test)Median PFS: A = 6.1 month (95% CI: 5.3-7.0); B = 6.4 month (95% CI: 5.6-7.4)
AB
Months
PFS
Prob
abili
ty (%
)
Subgroup Analysis of PFS
LY metastasis no
yes
Peritoneal metastasis no
yes
Age <65 years
≥65 years
Pretreatment <180 days
≥180 days
CEA <20 ng/mL
≥20 ng/mL
CA 19-9 <35 ng/mL
≥35 ng/mL
Sum of <50 mm
target lesions ≥50 mm
Arm B better
0.99(0.75-1.29)
1.08(0.71-1.66)
0.93(0.72-1.20)
1.31(0.78-2.20)
1.02(0.73-1.41)
1.00 (0.73-1.38)
0.75(0.46-1.24)
1.14(0.88-1.48)
1.25(0.88-1.77)
0.82(0.60-1.13)
1.09(0.77-1.55)
0.96(0.70-1.33)
1.22(0.87-1.71)
0.81(0.59-1.12)
Arm A better
Hazard Ratio (95% CI)
No differences: - dose intense of chemotherapy- subgroup analysis: sex, age, PS, primary site (rectal vs. colon)
metastatic characteristics (location, numbers, peritoneal mets), CEA, CA19-9…
Arm A(n=180)
Arm B(n=187)
PR, No. (%) 20 (11.1) 20 (10.7) p=1.00
SD, No. (%) 127 (70.6) 132 (70.6)
PD, No. (%) 25 (13.9) 22 (11.8)
NE, No. (%) 8 ( 4.4) 13 ( 7.0)
PFS RR
IFL + Placebo 6.2 months 35 %
IFL + Bev. 5 mg/kg 10.6 months 45%
PFS RR
FOLFOX 4.8 months 9.2%
FOLFOX + Bev. 10 mg/kg 7.2 months 21.8%
(Bev. 10 mg/kg) (2.8 months) (3.0%)
The Potential Impact of Bevacizumab Dose on the CRC Chemotherapy Efficacy
First line: AVF 2107g
Second line: E3200
PFS RR
5FU/LV 5.2 months 17 %
5-FU/LV + Bev. 5mg /Kg 9.0 months 40 %
5-FU/LV + Bev 10 mg /Kg 7.2 months 24 %
Initial Phase II: Kabbinavar
Conclusion• No significant difference was found in PFS between Arm A and Arm B. • No Surprise - dose of Bevacizumab was based on neither the Tumor
mass (size or numbers) nor the biologics (VEGF, or VEGFR levels) of Cancer.
• However, patients with first-line treatment <180 days, CEA ≥20 ng/mL, sum of target lesions ≥50 mm seem to benefit from bev 10 mg/kg.
• May make sense as larger tumor burden may be benefit with more Bev.
• The results from study suggest that the optimal dose of continuous bev as second-line treatment is 5 mg/kg.
• With the efficacy from this and other studies and cost-effective ration—Agree!
No need to have any further debate regarding the appropriate dose of Bevacizumab in CRC therapy (in the 2nd line setting)
3517: Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the ITACa randomized clinical trial
Alessandro Passardi, et al
Alessandro Passardi et al
Baseline CharacteristicsPatient Characteristics CT+bevacizumab N=176 CT N=194
Age: median years (range) 66 (34-83) 66 (33-82)Male % 61 59Performance Status (ECOG) % 0 82 79 1-2 18 21Tumor localization % rectum 23 26 colon 77 74Stage at diagnosis % I-III 17 17 IV 83 83CT regimen % folfox 59 61 folfiri 41 39KRAS % wild type 59 55 mutant 41 45Prior cancer therapy % surgery 76 75 radiotherapy 10 10 Adjuvant chemotherapy 19 13
0.00
0.20
0.40
0.60
0.80
1.00P
FS
0 6 12 18 24 30 36months
Events / n (%) Median PFS(95% CI)
-------- CT + B 159 / 176 (90.3) 9.6 (8.2-10.3)
-------- CT 178 / 194 (91.8) 8.4 (7.2-9.0)
= 1.2 months
HR = 0.87, 95% CI (0.70-1.08), p = 0.212
OS: 20.6 months in both arms [p=0.278, HR 1.18 (0.88-1.58)]
RR: 48.9 (CT +B) vs. 47.9 % (p=0.371)
CT + B CT
Treatment cycles (N) 2083 1945Treatment cycles per patient median (range)
8 (1-43) 6 (1-28)
Cycles with reduction of CT: N (%)
291 (14.0)
404 (20.8)
CT Cumulative dose: median (range)
90 (44-100)
87 (48-100)
- A relative small study with diverse CT regimens (60% FOLFOX)
- Appeared as ‘NO16966’ Data
- No data in 2nd and 3rd line therapy
- Will not change current practice
PFS
3515: Maintenance therapy with bevacizumab with or without erlotinib in metastatic CRC according to KRAS: Results of the GERCOR DREAM phase III trial. C. Tournigand, et al
mFOLFOX7 bevacizumab
XELOX2 bevacizumab
FOLFIRI bevacizumab
Bevacizumab (7.5 mg/kg q3w)
+ erlotinib (150 mg/d)
until PD
RANDOMIZATION
NoProg
N=222
N=224
INDUCTION, N=700 MAINTENANCE, N=446
Bevacizumab (7.5 mg/kg q3w)
until PD
REGISTRATION
Primary end point: PFS on maintenance therapySecondary endpoints : OS, OS from maintenance, Duration without chemotherapy, RR, Survival according to KRAS mutational status
OPTIMOX 1
FOLFOX4(n=312)
FOLFOX7(n=313)
6 cycles
FOLFOX7
6 cycles
LV5FU2
12 cycles
Clinic Chemptherapy Goal: Increasing the efficacy, minimize/delay the toxicity- Optimox 1: maintain the efficacy and decreasing the toxicity with ‘stop
and go’ strategy- Biological agents benefit in combination with chemotherapy - VEGF inhibitors vs. EGFR inhibitor(s) and combination? Maintenance?
The impacts of Kras status?
R
PACCE: PFS and OSOx-CT + BEV
(n=410)Ox-CT + BEV + Pmab
(n=413)HR
(95% CI)
PFS (mos) 11.1 months 9.6 months 1.27 (1.05-1.53)
OS ( mos) >24 months 19.4 months 1.43 (1.11-1.83)
ORR 46% 45%
Iri-CT + BEV(n=115)
Iri-CT + BEV + Pmab(n=115)
HR(95% CI)
PFS (mos) 11.7 10.1 1.21 (0.80-1.82)
OS (mos) 20.5 20.7 NR
ORR 39% 43% 1.15 (OR)
CAPOX/ Bev CAPOX/BEV/Cet p value
n = 368 n = 368
Median PFS (months)
(HR; 95% CI)
10.7
(9.7-12.5)
9.6
(8.5-10.7)
0.018
(1.21;1.03-1.45)
Median OS (months)
(HR; 95% CI)
20.4
(18.1-26.1)
20.3
(17.9-21.6)
0.21
(1.15;0.93-1.43)
Response rate
(CR + PR)44% 44% 0.88
Disease control rate
(CR + PR + SD)83% 81% 0.39
CAIRO2
Bev alone(N=228)
Bev + erlotinib(N=224)
HR[95% CI]
P value
Maintenance PFS(from randomization)
4.6 [4.1-5.7]
5.9[4.5-6.4]
HR 0.76[0.61-0.94]
0.0096
PFS(from registration)
9.3 [8.7-10.1]
10.2 [9.5-11.5]
HR 0.75[0.61-0.93]
0.0088
OS(from registration)
27.9 [24.1-31.1]
28.4 [25.1-33.9]
HR 0.89[0.70-1.12]
0.8857
Survivals
BevacizumabN=228
Bevacizumab + ErlotinibN=224
Diarrhea 2 (1) 20 (9)Skin toxicity 0 (0) 46 (20)
Grade 3/4 Toxicity (%)
Maintenance PFS(randomized population, from randomization)
B B + E
No. of patients 228 224
Events 183 159
Censored 45 65
Median maint. PFS
4.6 5.9
HR [95% CI] 0.76 [0.61-0.94]
P value 0.0096
CAIRO2: KRAS genotyping (n=501)Kras WT (n=305) 61%
Kras Mutated (N=196) 39%
p
PFS (months)
CAPOX +B 10.7 12.5 0.92CAPOX +B+C 10.5 8.6 0.47
p 0.10 0.043OS (months)
CAPOX +B 23.0 24.9 0.90CAPOX +B +C 22.2 19.1 0.52
p 0.49 0.35
SurvivalsKras WT Bev alone
(N=111)Bev + erlotinib
(N=129)HR
[95% CI]
P value
m PFS(from randomization)
5.9[4.0-6.5]
6.0[4.5-7.8]
HR 0.86[0.64-1.15]
0.3153
PFS(from registration)
9.7 [8.7-11.0]
10.9 [9.7-12.6]
HR 0.82[0.61-1.11]
0.1974
OS(from registration)
31.5 [27.5-38.1]
31.8 [26.6-37.9]
HR 0.92[0.66-1.30]
0.6443
Kras Mut Bev alone(N=89)
Bev + erlotinib(N=91)
HR[95% CI]
P value
Maintenance PFS(from randomization)
4.4 [3.8-5.3]
4.7[3.6-7.1]
HR 0.77[0.54-1.08]
0.124
PFS(from registration)
9.9 [8.6-10.8]
9.8 [8.4-12.2]
HR 0.80[0.57-1.13]
0.212
OS(from registration)
26.9 [22.4-33.2]
26.3 [21.0-34.4]
HR 1.06[0.72-1.55]
0.767
Maintenance PFSWT KRAS Mut KRAS
- The addition of erlotinib to bevacizumab following induction therapy with bevacizumab-based chemotherapy significantly increases the maintenance PFS.
- In contrast to anti-EGFR Mabs, KRAS tumor status does not select patients with mCRC benefiting from erlotinib
However: Will the results change the practice?• Bevacizumab alone is not standard, and without clear benefit
(SAKK 41/06, abs 3503); and after OPTIMOX 1, 5-FU (or Capecitabine)+ bevacizumab is already the maintenance therapy in many practices (which is supported by CAIRO3, abs 3502).
• Erlotinib is not indicated in CRC
May help future investigation of anti-VEGF mAb + Anti-EGFR TKI in mCRC
Conclusions
3521: Results according to age in AVEX, a randomized phase 3 trial of bevacizumab with capecitabine for elderly patients with mCRCMark P. Saunders, et al
Previously untreated mCRC, age 70 years
N=280
Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d
Bevacizumab 7.5 mg/kg day 1, q21d
+Capecitabine 1000 mg/m2 b.i.d.
days 1–14, q21d
Stratification factors:• ECOG PS (0–1 vs 2)• Geographic region
Randomize 1:1
Are elderly patients at increased risk for toxicity secondary to Bevacizumab, and how old is old?
Progression-free and overall survival*
*Overall population. 113 PFS events in the BEV + cape arm; 127 PFS events in the cape arm; 75 OS events in each treatment arm. BEV = bevacizumab; cape = capecitabine; CI = confidence interval; OS = overall survival; PFS = progression-free survival
140 99 68 41 23 13 8 2 2 1 0
140 82 38 13 6 4 1 1 1 1 0
Number at riskBEV + cape
Cape
Time (months)
PFS
estim
ate
1.0
0.8
0.6
0.4
0.2
0.0
0 4 8 12 16 20 24 28 32 36 40
5.1 mo
9.1 mo
HR=0.53 (95% CI: 0.41–0.69)P<0.001
Time (months)
1.0
0.8
0.6
0.4
0.2
0.0
0 4 8 12 16 20 24 28 32 36 40 44O
S es
timat
e
16.8 mo 20.7 mo
HR=0.79 (95% CI: 0.57–1.09), P=0.182
Number at riskBEV + cape
Cape
2
1
140 120 95 81 60 44 34 16 12 8 5
140 108 85 62 49 33 19 11 9 6 5
Bevacizumab + Capecitabine (n=140) Capecitabine (n=140)
A. Progression-free survival B. Overall survival
Progression-free and overall survival
Outcome
70 – 74 years 75 – 79 years ≥80 years
Bev + Capen=55
Capen=46
Bev + capen=57
Capen=66
Bev + capen=28
Capen=28
Median PFS, mos(95% CI)
7.6(6.0–11.8)
5.0 (4.0–6.5)
9.8(7.1–11.4)
5.1(4.1–7.4)
10.5(5.0–14.5)
5.1(2.2–7.1)
Hazard ratio (95% CI)Log-rank P
0.52 (0.32–0.83)<.001
0.60 (0.40–0.89).016
0.36 (0.19–0.71).003
Median OS, months(95% CI)
20.7 (13.7–26.1)
22.2(9.7–42.7)
19.8(13.8–27.3)
17.4(11.9–23.0)
19.7(7.5–26.9)
12.6(6.6–17.0)
Hazard ratio (95% CI)Log-rank P
0.91 (0.50–1.66) .55
0.79 (0.48–1.30).37
0.62 (0.31–1.24).24
AE, %
70 – 74 years 75 – 79 years ≥80 years
Bev + Capen=54
Capen=46
Bev + capen=53
Capen=64
Bev + capen=27
Capen=26
Any AE 96 94 96 95 93 100
Grade ≥3 AE 63 41 55 41 59 58
SAE 35 28 26 30 30 46
Grade 5 AE* 7 11 8 9 11 19
AE leading to dose interruption/modification 61 33 49 47 52 54
Any AE leading to discontinuation 22 7 30 17 22 19
AE, %
70 – 74 years 75 – 79 years ≥80 years
Bev + Capen=54
Capen=46
Bev + capen=53
Capen=64
Bev + capen=27
Capen=26
Bleeding/hemorrhage 20 11 30 6 26 –
Hypertension 15 2 26 6 15 8
VTE 11 7 13 6 11 –
Proteinuria 13 – 4 2 4 –
ATE 4 – 2 2 11 12
No major difference of AEs comparing with other Bevacizumab studies
Conclusions• A statistically significant improvement in PFS with the addition of
bevacizumab to capecitabine (HR, 0.53; P<.001)
– Patients grouped according to age (70–74 years, 75–79 years, ≥80 years) had a similar PFS benefit
• The safety profile was consistent with previously reported data and consistent across age subgroups
• Suggests that the combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly with good PS
- Age is ‘relative’, even with anti-angiogenic agent, (however, data here is only for Bev… ).
- Key issue is careful patient selection.
3518: Non-inferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer: A randomized phase III trial (ACTS-CC)
Yoshihiko Nakamoto, et al. ACTS-CC study group
S-1: 80, 100, 120 mg/day according to BSA in 2 divided doses daily Day 1-28, q6w x 4 cycles (24w)
S-1UFT: 300-600 mg/day according to BSALV: 75mg/dayin 3 divided doses dailyDay 1-28, q5w x 5 cycles (25w)
UFT/ LV
pStage IIIColon Cancer (C-RS) ・ Curatively resected ・ Age: 20 - 80 y.o. ・ PS: 0-1
Control armTest arm
Stratification factors ・ LN metastasis (N1/N2) ・ Institution
R
Primary End Point: 3-yr DFS, Non inferiority margin of HR in DFS: 1.29Target sample size : 1,480 pts. with one-sided α=0.05, β=0.20
Biochemical action of S-1 and UFT/LVEffector Modulator ① Modulator ②
S-1CDHP
DPD inhibition( strong )
oteracilDecreasing GI toxicity
UFT/LVuracil
DPD inhibition ( moderate )
LVPotentiation of
TS inhibition
DPD : Dihydropyrimidine dehydro- genase TS : thymidylate synthetaseCDHP : 5-chloro-2,4-dihydroxypyridine
tegafurProdrug of 5-FU
- Potent DPD inhibitory activity - Easy administration (Twice-daily p.o.)- Low price (1/2 of UFT/LV, 1/3 of mFOLFOX6 in Japan)
DFS and OSMedian follow-up: 41.3 months (1.8-52.2)
EAS : n=1,518
88.2%
80.1% 75.5%
71.8%
86.5%
77.6% 72.5%
66.1%
S-1
UFT/LV
HR 0.85 [95%CI: 0.70-1.03], p=0.1003
One-sided p<0.0001 (non-inferiority)
No. at risk
0y 1y 2y 3y 4y 5y
S-1 758 658 594 533 167
UFT/LV
760 649 573 476 77
98.8%96.8%
93.6% 88.3
%98.9% 96.6%
92.7%86.1%
HR 0.86 [95%CI: 0.62-1.19]P=0.3600
No. at risk
0y 1y 2y 3y 4y 5y
S-1 758 743 723 666 144
UFT/LV
760 741 713 658 147
S-1
UFT/LV
Conclusions
- Adjuvant chemotherapy using S-1 will be a treatment option for stage III colon cancer in Japan
- S-1 for stage III CRC is non-inferior in DFS to that of UFT/LV. - AEs were acceptable, and the completion rate of the protocol Tx. was high.
NSABP C-06 3 yr. DFS 5 yr DFS 5 yr. OS
5-FU/LV 74.5 % 68.2 % 78.7 %UFT 74.5 % 67.2 % 78.5 %
- Might fit in US pts, based on NSABP C-06 data, however, not available in USA
3519: A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: the SOFT study. D. Takahari, et al SOFT Study Group
Stratification factors:• With vs. without adjuvant chemotherapy
•Institutions
n=512
mFOLFOX6+Bev (n=256)L-OHP: 85 mg/m2 d1
Bev: 5 mg/kg d1l-LV: 200mg/m2 d1
5-FU: 400mg/m2 bolus d15-FU: 2,400mg/m2 46 hr civ d1,2
repeated every 2 wks
SOX+Bev (n=256)L-OHP: 130 mg/m2 d1
Bev: 7.5 mg/kg d1S-1: 80, 100, 120 mg*/body d1-14
repeated every 3 wks
mCRC1st lineAge: 20 - 80
PS: 0-1
*According to body surface area, BSA < 1.25 m2, 1.25=<BSA <1.5, BSA >=1.5
Non-inferiority
Control arm Test arm
R
PFS and OS
0 6 12 18 24 30 36 420
0.25
0.5
0.75
1
mFOLFOX6+BevSOX+Bev
mFOLFOX6+Bev : 10.2 M (95% CI:9.5-11.3)SOX+Bev: 10.2 M (95% CI:9.4-11.1)
PFS HR=1.021 (95% CI:0.847-1.232)
Best overall response mFOLFOX6+Bev (n=233) No. of pts*
SOX+Bev (n=234)No. of pts*
p value
NE 16 21
RR (%) 62.7 61.5 0.8026
DCR (%) 89.3 89.3 0.9872
R0 resection rate 22 24
R0-R (%) 22 (8.6%) 24 (9.4 %) 0.7678
0 6 12 18 24 30 36 420
0.25
0.5
0.75
1
mFOLFOX6+Bev : 30.9 M (95% CI:28.6-33.1)SOX+Bev : 29.6 M (95% CI:25.8- …)
Median follow-up duration: 23.4 M (0.3 to 37.8)
mFOLFOX6+BevSOX+Bev
OS
HR=1.052 (95% CI:0.805-1.376
Sex MaleFemale
Age <65
65≦Primary lesion Colon
RectosigmoidRectum
Histology tub1,2por1,2
Other
History of surgery for No
colorectal cancer YesHistory of adjuvant Notherapy for CRC Yes
Target lesions NoYes
Liver metastases NoYes
Lung metastases No
Yes
BSA(m2) < 1.25
1.25 < 1.50≦
1.50 ≦
SOX+Bev better mFOLFOX6+Bev better
P value for interactionSub-group No. of pts329182
273
238
25785
166
437
21
53
119
392433
78
44467
197
314395
116
14
175
322
0.1880
0.2592
0.5409
0.3367
0.3285
0.9947
0.8514
0.3837
0.0419
0.9150
Subgroup analysis of PFS(FAS)
0.25 2.5
D.Takahari, et al. ASCO 2013; Abstract #3519
Conclusions
SOX + Bev can replace with mFOLFOX6 + Bev as a first-line treatment for mCRC in Japan with a more convenient regimen
D.Takahari, et al. ASCO 2013; Abstract #3519
3520: Prognostic value of early objective tumor response (EOTR) to 1stline systemic therapy in mCRC: Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD (Aide et Recherche en Cancérologie Digestive) database
Dirkje W Sommeijer, et al, the ARCAD Group
Available Data 15 Studies 42 Arms
13,949 Patients
Response Data 15 Studies 42 Arms
11,987 Patients w/RR
1962 patients missing status or dates
EOTR8 5 Studies 10 Arms
3,037 Patients
EOTR6 5 Studies 16 Arms
4,632 Patients
EOTR12 10 Studies 32 Arms
6,688 Patients
Target 4 Studies 8 Arms
1,833 Patients
Non-Target 5 Studies 8 Arms
2,799 Patients
Target 3 Studies 6 Arms
1,828 Patients
Non-Target 4 Studies 4 Arms
1,209 Patients
Target 5 Studies 14 Arms
2,382 Patients
Non-Target 9 Studies 18 Arms
4,306 Patients
15 Studies: N9741, OPTIMOX 1, FOCUS, AVF2192g, AVF2107g, HORG,
HORIZON H, FOCUS 2, NO16966, OPTIMOX 2, PACCE, MAX,
Macco, PRIME, HORIZON IH
OS and PFSEOTR at 6 weeks EOTR at 12 weeks
EOTR at 8weeks
PFS PFS PFS
EOTR at 6, 8, 12 weeks, overall response rate and PFS and OS
(adjusting with age, gender, PS, Mets in liver and lung)
PFS OS
Discussion- Clinic investigation: EORT warrants further consideration
as a potential surrogate endpoint to detect early signals for future trials, particularly randomized studies .
- Clinic Practice: EORT as a ‘clinic surrogate prognostic factor’ in mCRC treatment
- Questions:a) Early response vs. Duration of responseb) Tumor biologyc) Early response brings more treatment options
(resection, local-regional therapy, more lines of therapy), improved quality of life.