Transcript Pancreatic Cancer Recent Treatment Advances

ASCO 2009 – GI Highlights
Eileen M. O’Reilly, M.D.
Associate Member
Memorial Sloan-Kettering Cancer Center
Associate Professor
Weill Medical College of Cornell University
CONKO-004
A Randomized Prospective Trial of
Chemotherapy +/- LMWH,
Enoxaparin, in Patients with
Advanced Pancreas
Adenocarcinoma (LBA #4506)
H. Riess, U. Pelzer. G. Deutschinoff, B. Opitz,
M. Stauch, P. Rietzig, S. Hahnfeld, A. Hilbig,
J. Stieler, H. Oettle
Cancer, PC & Thromboses
• VTE in malignancy related to poor prognosis
– 12% vs 36% I-yr OS for VTE vs no VTE in Ca pts
• Data suggest improved outcome in PC with
the addition of anticoagulation to systemic tx
• Retrospective review in metastatic PC
– Addition of LMWH to chemotherapy improved
survival from 3.8 → 6.6 mths (p= 0.006)
Sorensen, et al. NEJM, 2000. Chew, et al. Arch Int Med, 2006.
Von Delius, et al. Thromb Haemost, 2007
Study Endpoints
• Primary endpoint
– Symptomatic venous thromboembolism (VTE)
within the first 3 months of chemotherapy
• Secondary endpoints
–
–
–
–
VTE in the first 6, 9 and 12 mths
Major bleeding within 3, 6, 9 and 12 mths
PFS, OS, RR
Toxicity
Riess, et al. ASCO, 2009 (LBA #4506)
CONKO-004 (LBA #4506)
Stratify N= 540 (planned)
•Locally advanced vs M1
•Primary vs Relapsed
•PS 80- 100% vs 60- 70%
•Creatinine level ≤/ > ULN
R
A
N
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Systemic Therapy
+
Enoxaparin*
Systemic Therapy
*Enoxaparin 1 mg/kg/day for 3 mths → 40 mg/day until POD
Riess, et al. ASCO, 2009 (LBA #4506)
Study Treatment
• Treatment allocation based on PS + creatinine
– For pts with PS ≥ 80% and creat ≤ ULN
• Gemcitabine, 5FU/LV, Cisplatin (GFFC); d 1,8,22
– For pts with PS of 60 - < 80% or creat > ULN
• Gemcitabine (G); d 1,8, 5, q 28
• Experimental arm
– Enoxaparin 1 mg/kg for 12 weeks → 40 mg SQ
El Rayes, et al. J Clin Oncol, 2003. Araneo, et al. Can Invest, 2003.
Riess et al. ASCO, 2009 (LBA #4506)
Eligibility
•
•
•
•
•
•
•
•
•
Histologically proven PC
Measurable disease
No prior systemic therapy
KPS ≥ 60%
Adequate hematologic, hepatic function
No VTE within previous 2 years
No major haemorrhage, no aspirin > 500mg
Calculated creatinine clearance > 30 ml/min
No indication for anticoagulation
Riess, et al. ASCO, 2009 (LBA #4506)
Biostatistics
• Hypothesis: Significant decrease in
symptomatic VTE from 10% → 3% with LMWH
• Sample size: N= 540, 1: 1 ratio,15% dropout
or 24 pts with VTE
• Stratify: KPS 60- 70% vs 80- 100%; M0 vs
M1; Primary vs Recurrent; Creat ≤ / > ULN
Riess, et al. ASCO, 2009 (LBA #4506)
Study Conduct
• Open-label, randomized phase II
• Recruitment 4/04- 1/09, 33 centers
• Date of analysis 4/09
Riess, et al. ASCO, 2009 (LBA #4506)
Demographics (N= 312)
Age (median)
Male
Metastatic Disease
Primary Disease
KPS 80-100%
Creatinine ≤ ULN
Observation
(N= 152)
63 yrs
62%
75%
87%
85%
95%
Enoxaparin
(N= 160)
62 yrs
57%
74%
84%
84%
96%
Recruitment ceased 1/09 (24 VTE episodes)
Riess, et al. ASCO, 2009 (LBA #4506)
CONKO-004 (N= 312)
Gemcitabine
(N= 57)
PS 60-70% or creat > ULN
Gemcitabine, Cis, 5-FU
(N= 255)
PS ≥ 80% and creat ≤ ULN
Gemcitabine
(N= 27)
Gemcitabine + Enoxaparin
(N= 30)
Gem, Cis, 5-FU, LV
(N= 125)
Gem, Cis, 5-FU + Enoxaparin
(N= 130)
Riess, et al. ASCO, 2009 (LBA #4506)
VTE in the first 3 Months
Observation Enoxaparin
(N= 152)
(N= 160)
Pulmonary embolism
2
Proximal leg DVT
9
2
Distal leg DVT
2
Upper extremity DVT
3
All VTE events
16
2
1 pt had DVT + PE. 18 events in 17 pts
Riess, et al. ASCO, 2009 (LBA #4506)
Total
2
11
2
3
18
VTE in the first 3 Months
• Observation 9.9% vs 1.3% in enoxaparin arm
– p< 0.01
– Difference of 8.6% between two arms
– Relative risk reduction of 87%
• VTE according to chemotherapy
– Gemcitabine 12.4% vs 6.6% Gem,Cis,5FU,LV
– Poor PS pts – more VTE
Riess, et al. ASCO, 2009 (LBA #4506)
Major Bleeding Events (3 months)
VTE in first 3 mths
Observation
(N= 152)
Enoxaparin
(N= 160)
P-Val
*2.63%
3.75%
0.6
9 non-fatal, *1 fatal upper GI haemorrhage (observation arm)
Riess, et al. ASCO, 2009 (LBA #4506)
Overall Results
(Med f/up 34 wks)
VTE
Bleeding
TTP (preliminary)
OS (preliminary)
Observation
(N= 152)
22 (15.5%)
15*# (9.9%)
19 weeks
29 weeks
Enoxaparin
(N= 160)
8 (5%)
10* (6.3%)
22 weeks
31 weeks
P-Val
< 0.05
0.6
3 fatal haemorrhages:
*2 tumor-related lethal GI bleeds in two GFFC pts (12.4, 13.4 wks)
#1 lethal GI haemorrage in a gemcitabine-treated pt (16.7 wks)
Riess, et al. ASCO, 2009 (LBA #4506)
CONKO-004 Conclusions
1. Advanced PC high risk of symptomatic VTE
2. PS may be more powerful predictor of VTE
risk over treatment intensity
3. Enoxaparin 1mg/kg/day significant reduces
clinically relevant VTE
4. No undue safety concerns observed
5. Impacts of enoxaparin prophylaxis on RR,
PFS, OS immature
Interpretation CONKO-004
• Early data reassuring regarding safety
• Need maturity to assess impact on PFS, OS
• Low dose of enoxaparin?
• No change in standard practice for advanced
disease for now
Neuroendocrine
Placebo-Controlled, Double-Blind, Prospective
Randomized Study of the Effect of Octreotide LAR in
the control of tumor growth in patients with Metastatic
Neuroendocrine Midgut Tumors:
A Report from the PROMID Study Group
Rudolf Arnold
for the PROMID Study Group
Department of Internal Medicine, Philipps University, Marburg,
Germany
Octreotide LAR
• Binds somatostatin receptors 2, 5
• FDA-approved for functional tumors for
symptomatic relief
• Indicated for progressive metastatic nonfunctioning NET’s
• Anti-proliferative value not well established
• No well-designed phase III trials to answer
question in midgut NET’s
Promid Study (Abst #4508)
Midgut NET‘s
N= 85
R
A
N
D
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Octreotide LAR 30mg IM
q 4 wks (N= 42)
Placebo IM q 4 wks
(N= 43)
Randomized phase III, placebo-controlled, double-blind
Midgut NET’s: Jejunem, ileum, appendix, right colon
Primary Endpoint: TTP
Secondary Endpoints: RR (WHO), OS
Arnold, et al. ASCO, 2009 (Abst #4508)
PROMID Study
• 18 centers in Germany from 2001 to 2008
• 85 patients treated from a planned 162 accrued
• Planned Interim Analysis
– Based on 67 POD and 16 observed deaths
– Log-rank test, planned group sequential analysis at
level of 0.0122
– ASCO 2009: updated results
Patient Population
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Untreated, metastatic, well-diff midgut NET’s
Histologic confirmation
Functional or non-functional
Primary tumor located in the mid-gut
No curable therapeutic intervention feasible
Measurable disease by CT or MRI
Arnold, et al. ASCO, 2009 (Abst #4508)
Study Endpoints
• Primary endpoint
– Time-to-tumor progression
• Secondary endpoints
–
–
–
–
–
–
Survival
Objective responses (WHO)
Biochemical response
Symptom control
Quality of life
Safety
Patient Demographics
Octreotide
(N= 42)
Placebo
(N= 43)
Age
63 yrs
61 yrs
Male
48%
54%
7.5 mths
3.3 mths
Karnofsky Score ≥ 90%
83.3%
88.4%
Resection of primary
69.1%
62.8%
Functional Syndrome
41%
37%
Octreoscan Positivity
76%
72%
Ki 67 ≤ 2%
97.6%
93%
Hepatic Tumor Burden < 10%
73.2%
74%
Chromogranin elevated
61.9%
69.8%
Time from Diagnosis
Octreotide LAR 30mg Significantly Increases
Time to Tumor Progression
Octreotide LAR vs placebo P=0.000017
HR= 0.33 [95% CI: 0.19–0.55]
Proportion without progression
1
Octreotide LAR: 42 patients / 27 events
Median 15.6 months [95% CI: 11.0–29.4]
0.75
Placebo: 43 patients / 41 events
Median 5.9 months [95% CI: 5.5–9.1]
0.5
0.25
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Time (months)
Based on Intention to treat analysis
84
90
PROMID: TTP
Octreotide Placebo
(N= 42)
(N= 43)
P-value
TTP (Overall)
15.6 mths
HR 0.33
5.9 mths
p= 0.000017
TTP (Liver ≤10%)
28.8 mths
(N= 32)
10.3 mths
(N= 10)
6.1 mths
(N= 32)
4.5 mths
(N= 11)
TTP (Liver >10%)
Arnold,et al. ASCO, 2009 (Abst #4508)
HR 0.21
p< 0.0001
PROMID: Response Rates
Complete Response
Partial Response
Stable Disease
Octreotide
1
28 (67%)
Placebo
1
16 (70%)
Progressive Disease
10 (24%)
23 (54%)
Arnold, et al. ASCO, 2009 (Abst #4508)
Is the Treatment Effect
Homogenous across Subgroups?
• Benefit of octreotide LAR versus placebo seen
irrespective of
– Functioning or non-functioning NETs
– Elevated or non-elevated CgA
• Most favorable outcome in patients with
– Hepatic tumor load ≤10%: HR= 0.21
– Resected primary: HR= 0.16
Octreotide LAR Lengthens TTP in Patients with
Functioning and Non-Functioning Midgut NETs
Patients with functioning tumors
Patients with non-functioning tumors
Octreotide LAR: 17 patients / 11 events
Median TTP 10.35 months
Octreotide LAR: 25 patients / 9 events
Median TTP 27.14 months
Placebo: 27 patients / 24 events
Median TTP 7.21 months
0.75
0.5
0.25
0
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Placebo: 16 patients / 14 events
Median TTP 5.45 months
1
Proportion without progression
Proportion without progression
1
0.75
0.5
0.25
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90
Time (months)
Time (months)
P= 0.0008; HR= 0.27 [95% CI: 0.12–0.61]
P= 0.0007; HR= 0.23 [95% CI: 0.09–0.57]
Based on the per protocol analysis
Safety Consistent with
Established Octreotide LAR Profile
• No treatment-related deaths
• Treatment was discontinued because of AE’s in 5 of 42
octreotide LAR recipients and no placebo recipients
• Most frequent serious AEs affected
– GI tract (octreotide LAR n= 6; placebo n= 8)
– Hematopoietic system (octreotide LAR n= 5; placebo n=1 )
– General health status, e.g. fatigue, fever (octreotide LAR n= 8;
placebo n= 2)
• Serious AE’s in 11 octreotide LAR and 10 placebo pts
Summary
• Octreotide LAR 30mg significantly improves TTP in
metastatic well-differentiated midgut NETs
– 67% reduction in POD for octreotide LAR pts
– Regardless of functional status
• Overall survival – difficult to assess given cross-over
from placebo to octreotide LAR at progression
• Observed safety findings similar to those seen in
previous studies of octreotide LAR in NETs
Interpretation
• Strengths – placebo-controlled, doubleblinded, central radiology review,
homogenous NET’s
• Limitations – small numbers, cross-over, not
powered for survival, imbalance in time prior
to enrollment
• An option to initiate octreotide LAR for newly
diagnosed NET’s
RADIANT 2 Trial
Advanced
Carcinoid
(progressive)
N= 390
R
A
N
D
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E
Octreotide LAR + Everolimus
Octreotide LAR + Placebo
Primary Endpoint: PFS
Accrual completed – Results awaited
Yao, et al (PI)
SWOG 0518
Advanced Poor
Prognosis
Carcinoid
N= 287
R
A
N
D
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E
Octreotide LAR +
Bevacizumab
Octreotide LAR + IFN α-2b
Primary Endpoint: PFS
Ongoing recruitment
Yao, et al (PI)
ESPAC-3
ESPAC-3(v2)
A Multicentre, International, Open-label,
Randomised Controlled Phase III Trial of
Adjuvant 5-Fluorouracil/Folinic acid (5FU/FA) vs Gemcitabine (GEM) in Patients
with Resected Pancreatic Ductal
Adenocarcinoma
European Study Group for Pancreatic Cancer
CR-UK Liverpool Cancer Trials Unit
LCTU
Liverpool Cancer Trials Unit
Background
ESPAC-1 compared chemotherapy [5FU/FA ] with
chemoradiation
Using a 2x2 factorial design
Observation
Chemotherapy (CT)
Chemoradiotherapy (CRT)
CRT
LCTU
Liverpool Cancer Trials Unit
CT
ESPAC-1 Lancet, 2001
No benefit for Chemoradiation – Potential benefit for Chemotherapy
LCTU
Liverpool Cancer Trials Unit
Lancet,
2001;358(9293):1576-85
ESPAC-3(v1) Trial Design
Patients with ductal adenocarcinoma
undergoing ‘curative’ resection
Target N=990
RANDOMISE
OBSERVATION
Target N=330
5FU/ FA
5-FU 425mg/m2 &
FA 20mg/m2 for 5
days every 28 days
for 6 cycles
Target N=330
GEMCITABINE
1000mg/m2 once a
week for 3 of 4
weeks for 6 cycles
Target N=330
330 per arm to detect 10% difference in 2y survival rate (= 5%, 1-b= 80%)
LCTU
Liverpool Cancer Trials Unit
Trial opened July 2000
Eligibility
• Complete macroscopic resection for pancreatic ductal
adenocarcinoma (WHO Classification)
• R0 or R1 resection
• No: ascites, liver or peritoneal metastasis, or any other
distant abdominal or extra-abdominal organ spread
• No previous or concurrent malignancy diagnoses
• WHO performance status < 2
• Life-expectancy of more than 3 months
• Fully informed written consent
LCTU
Liverpool Cancer Trials Unit
ESPAC-1
ESPAC-1 NEJM 2004: No benefit for Chemoradiation confirmed
Survival rates 2-year 5-year
No CRT:
41.4% 19.6%
CRT:
28.5% 10.0%
HR=1.28 (0.99, 1.66), p=0.053
NEJM 2004;
350:1200-10
ESPAC-1
ESPAC-1 NEJM 2004: Benefit for Chemotherapy confirmed
Survival rates 2-year 5-year
No CT:
30.0% 8.4%
CT:
39.7% 21.1%
HR=0.71 (0.55, 0.92), p=0.009
NEJM 2004;
350:1200-10
Impact
• OBSERVATION arm closed on DMC advice June 2003
(n=61)
• Target recruitment updated to detect 10% difference in
survival at 2-years with 90% power, DMC July 2005
• Updated Target: 515 pancreatic ductal adenocarcinoma
patients (275 events) per chemotherapy group
LCTU
Liverpool Cancer Trials Unit
ESPAC-3(v2) Trial Design
Patients with ductal adenocarcinoma undergoing ‘curative’ resection
Target N=1030*
RANDOMISE
5FU/ FA
Target N=515
Actual=551
GEMCITABINE
Target N=515
Actual N=537
3-monthly follow-up to death
515 per arm to detect 10% difference in 2y survival rate ( = 5%, 1-b = 90%)
LCTU
Liverpool Cancer Trials Unit
*Actual N=1088
Patient Demographics
5FU/FA
n=551
Age (years)
GEM
n=537
TOTAL
n=1088
63 (34-85)
63 (31-81)
63 (31-85)
Sex
Male
Female
301 (55%)
250 (45%)
297 (55%)
240 (45%)
598 (55%)
490 (45%)
Baseline PS †
0
1
2
200 (36%)
286 (52%)
64 (12%)
167 (31%)
303 (57%)
64 (12%)
367 (34%)
589 (54%)
128 (12%)
Smoking † Never
Past
Present
207 (43%)
192 (39%)
87 (18%)
189 (40%)
207 (44%)
78 (16%)
396 (41%)
399 (42%)
165 (17%)
Surgery to Rand (days)
45 (4-114)
45 (5-98)
45 (4-114)
†
Significant prognostic variable
Tumor Pathology
5FU/FA
n=551
GEM
n=537
TOTAL
n=1088
Stratification factor:
R Status † R0
R1
356 (65%)
195 (35%)
348 (65%)
189 (35%)
704 (65%)
384 (35%)
Max Tumour Size (mm) †
30 (2-350)
30 (2-105)
30 (2-350)
Grade †
Well
Mod
Poor
Undiff
81 (15%)
327 (60%)
135 (25%)
2 (0%)
66 (13%)
336 (63%)
125 (24%)
2 (0%)
147 (14%)
663 (62%)
260 (24%)
4 (0%)
Nodes †
Neg
Pos
161 (29%)
387 (71%)
144 (27%)
391 (73%)
305 (28%)
778 (72%)
†
Significant prognostic variable
On-Study Data
5FU/FA
n=551
GEM
n=537
TOTAL
n=1088
Diabetic
No
388 (75%)
Non-insulin dep 54 (11%)
Insulin dep
72 (14%)
375 (75%)
51 (10%)
73 (15%)
763 (75%)
105 (10%)
145 (14%)
Surgery
Whipples
Pylorus Pres
Total Panc
Distal Panc
286 (56%)
158 (31%)
27 (5%)
40 (8%)
295 (59%)
147 (30%)
14 (3%)
39 (8%)
581 (58%)
305 (30%)
41 (4%)
79 (8%)
Local Invasion † No
Yes
297 (58%)
213 (42%)
284 (57%)
215 (43%)
581 (58%)
428 (42%)
Post-op Comps No
Yes
396 (78%)
112 (22%)
364 (74%)
130 (26%)
760 (76%)
242 (24%)
χ2LR = 24.2, p<0.001
χ2LR = 52.7, p<0.001
LCT
χ2LR = 31.8, p<0.001
χ2LR = 16.3, p<0.001
Follow-Up
5FU/FA
GEM
Total
N=551
N=537
N=1088
163 (30%)
388 (70%)
172 (32%)
365 (68%)
335 (31%)
753 (69%)
163
34
0.4-79
26-44
133 (82%)
172
34
0.4-86
28-43
149 (87%)
335
34
0.4-86
27-43
282 (84%)
Survival Status:
Alive
Dead
Follow-up of alive patients:
N
Median (months)
Range
Inter-quartile Range
N (%) with >24 month FU
LCTU
Liverpool Cancer Trials Unit
Reported Toxicity
Number of patients with at least one NCI CTC v2. grade 3-4 event
WBC
Neutrophils
Platelets
Nausea
Vomiting
Stomatitis
5FU/FA
GEM
CTC 3-4 (% of 551 pts)
CTC 3-4 (% of 537 pts)
32 (6%)
53 (10%)
p=0.013
121 (22%)
-
p=0.94
p=0.0034
119 (22%)
8 (1.5%)
19 (3.5%)
p=0.37
13 (2.5%)
17 (3%)
p=0.34
11 (2%)
54 (10%)
p<0.001*
1 (0%)
Alopecia
1 (0%)
p=1.0
1 (0%)
Tiredness
45 (8%)
p=0.16
32 (6%)
Diarrhea
72 (13%)
p<0.001*
12 (2%)
Other
67 (12%)
p=0.027
43 (8%)
LCTU
Liverpool Cancer Trials Unit
* Exploratory analysis: sig level p<0.005
using Bonferroni adjustment
Serious Adverse Events
612 patients reported 892 SAE
304 5FU/FA patients
reported 458 SAE
308 GEM patients
reported 434 SAE
117 (11%) patients reported 149 Treatment Related SAE
77 (14%)* 5FU/FA patients
reported 97 SAE
LCTU
Liverpool Cancer Trials Unit
40 (7.5%)* GEM patients
reported 52 SAE
*Exploratory analysis:
Fishers Exact test p<0.001
Survival by Treatment
Median S(t)= 23.0 months (95%CI:21.1, 25.0)
Median S(t)= 23.6 months (95%CI:21.4, 26.4)
c2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)
LCTU
Liverpool Cancer Trials Unit
PFS by Treatment
Median PFS(t)= 14.1months (95%CI:12.5, 15.3)
Median PFS(t)= 14.3months (95%CI:13.5, 15.7)
c2LR=0.59, p=0.44, HRGEM VS 5FU/FA=0.95 (95%CI: 0.83, 1.09)
LCTU
Liverpool Cancer Trials Unit
Conclusions
• No difference in survival between adjuvant
gemcitabine and 5-FU/FA in patients with resected
pancreatic cancer
• The safety profile of gemcitabine was better than
that of 5-FU/FA
•
Data reinforce the perfect design of the ESPAC-4
trial comparing gemcitabine with the combination of
gemcitabine with capecitabine
LCTU
Liverpool Cancer Trials Unit
ESPAC-4: Phase III
Resected PC
N= 1,080
R
A
N
D
O
M
I
Z
E
Gemcitabine
Gemcitabine +
Capecitabine
Primary Endpoint: Overall Survival
Neoptolemos, J (PI)
Interpretation ESPAC-3
• Adjuvant therapy works!
• Gemcitabine or 5-Flurouracil both valid options
for adjuvant therapy for resected pancreas ca
• Taking efficacy and toxicity into account –
gemcitabine probably the superior choice
• No new data regarding adjuvant chemoradiation