Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

Pancreatic Cancer

Ali Shamseddine MDProessor of Medicine

AUBMC

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

GITSG1

Survival advantage for chemoradiation followed by 5-FU for 1 year, but

Early termination, andSlow accrual (43 patients in 8 years)

EORTC2

No survival benefit for chemoradiation, but no maintenance chemotherapy

1. Kaiser MH, et al. Arch Surg. 1985;120:899-903.2. Klinkenbijl JH. Ann Surg. 1999;230:776-782.

Adjuvant Therapy: Historical Lack of Consensus

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

1. Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.2. Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

Two recent randomized clinical trials demonstrated benefit ESPAC-11

N = 289 (4-arm study also evaluating chemoradiation) Observation vs 5-FU/LV (Mayo) 5-year survival: 8% vs 21% (P = .009)

CONKO-0012

N = 368 Observation vs gemcitabine (Days 1, 8, and 15 of 4-

week cycle x 6 months) Disease-free survival: 6.9 vs 13.4 months 5-year disease-free survival: 5.5% vs 16.5%

Adjuvant Chemotherapy

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

ESPAC-1: SurvivalCONKO-001: Disease-Free Survival

Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

Adjuvant Chemotherapy:Outcomes

Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.Oettle H, et al. J Am Med Assoc. 2007;297:267-277.

Months

Cu

mu

lati

ve D

isea

se F

ree

Su

rviv

al

100%

75%

50%

25%

0%0

100%

75%

50%

25%

0%12 24 36 48 60 72

Chemotherapy

No chemotherapy

Months

Su

rviv

al (

%)

847260483624120

observation

gemcitabine

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001: Previous Analysis

Previously reported data indicated that the median DFS was 13.4 and 6.9 mos in the gemcitabine and control groups, respectively

Estimated DFS at 3 and 5 yrs was 23.5% and 16.5% in the gemcitabine group and 7.5% and 5.5% in the control group, respectively

Subgroup analyses showed the effect of gemcitabine on DFS was significant in patients with either R0 and R1 resection

No difference in OS between the gemcitabine and control groups

Oettle H, et al. JAMA. 2007;297:267-277.

CONKO*-001: Final results of the randomized,

prospective, multicenter phase III trial of adjuvant chemotherapy with

gemcitabine versus observation in patients with resected pancreatic

cancer (PC)

U.P. Neumann P. Neuhaus, H.Riess, S. Post, K. Gellert, K. Ridwelski, H.

Schramm, C. Zülke, G. Fahlke, J. Langrehr, H. OettleCharitè - Universitätsmedizin Berlin - Campus Virchow Klinikum;

Ruprecht-Karls-Universität, Mannheim; Oskar-Ziethen-Krankenhaus, Berlin; Otto-von-Guericke-Universität, Magdeburg; Wald-Klinikum, Gera;

Universität Regensburg, Regensburg; AIO; CAO; Deutsche Krebsgesellschaft e.V.

*CHARITÉ ONKOLOGIE:Clinical studies in GI cancers

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

Disclosure

I have Consultant or Advisory Role to disclose:Lilly OncologyRocheSanofi-Aventis

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Study Design and Patient Disposition

* 7 excluded Patients:

4 pts. withdrew consent

1 pt. no histologic verification

1 pt. persistent disease after resection

1 pt. another malignant disease

* 7 excluded Patients:

4 pts. withdrew consent

3 pts. another malignant disease

Resected pancreatic cancer 368 patients enrolled 7/98 - 12/04

Stratification R; T; N

182 pts. for Observation

179 eligible* pts. (96%)for Intent-to-Treat Analysis

175 eligible* pts. (96%) for Intent-to-Treat Analysis

186 pts. for Gemcitabine

Date of Analysis: March 2008

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Endpoints

Primary Endpoint Disease free survival (DFS)

Secondary Endpoint Overall survival (OS) Toxicity

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Inclusion Criteria

Histologically proven resected pancreatic carcinoma Standard operation No measurable disease No prior chemo- or radiotherapy No active infection Karnofsky performance status 50% Adequate hematologic, renal and hepatic function CA 19-9, CEA < 2.5 ULN Start with adjuvant therapy within 6 weeks after resection Written informed consent

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Treatment Schedule

Gem

Obs

Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks

Observation: d1; q 4 weeks

Randomisati

on

Follow up every 8weeks

Gem

Ultrasoundafter week 8

Ultrasoundafter week 16

CT Scanafter week 32

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Patient Characteristics

Characteristic Chemotherapy(N=179)

Observation(N=175)

Days to randomisation

Median (interquartile range) 22 (15 - 32) 24 (15 - 34)

Age - years

Median (range) 62 (34 - 82) 61 (36 - 81)

Sex – no. (%)

Female 74 (41%) 77 (44%)

Male 105 (59%) 98 (56%)

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Tumor Characteristics

Characteristic Chemotherapy(N=179)

Observation(N=175)

1 + 2 25 (14%) 24 (14%)T

3 + 4 154 (86%) 151 (86%)

negative 52 (29%) 48 (27%)N

positive 127 (71%) 129 (73%)

1 10 (6%) 9 (5%)

2 103 (58%) 95 (54%)

3 63 (35%) 68 (39%)G

unknown 3 (2%) 3 (2%)

R0 145 (81%) 149 (85%)R

R1 34 (19%) 28 (15%)

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Disease Free Survival (DFS)

We already demonstrated safety data and superior DFS for adjuvant treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer.

P. Neuhaus et al., ASCO 2005H. Oettle et al., JAMA 2007

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 DFS

Gemcitabine Median: 13.4 months (95% CI. 11.3-15.4) (21.2% censored)

Observation Median: 6.9 months (95% CI. 6.2-7.5) (7.4% censored)

Log Rank P<0.001(14.4% censored)

Median DFS (months)Arm A Arm B P*

All pts n=179 n=17513.4 6.9 <.001

R0 n=145 n=14813.1 7.3 <.001

R1 n=34 n=2715.4 5.5 <.001

N– n=52 n=4822.4 10.4 <.006

N+ n=127 n=12712.1 6.3 <.001

T1-2 n=25 n=2427.5 10.0 <.05

T3-4 n=154 n=15113.1 6.6 <.001

*Log-rank test

Date of Analysis: March 2008

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 DFS Hazard Ratios

0.59 [0.46, 0.76] 0.33 [0.18, 0.58]

Test for heterogeneity: Chi² = 3.54, df = 1 (P = 0.06), I² = 71.7%

0.53 [0.34, 0.84] 0.53 [0.41, 0.69]

Test for heterogeneity: Chi² = 0.00, df = 1 (P = 0.96), I² = 0%

0.52 [0.27, 1.00] 0.55 [0.43, 0.70]

Total (95% CI) 0.55 [0.44, 0.69]

Test for heterogeneity: Chi² = 0.02, df = 1 (P = 0.87), I² = 0%

0.2 0.5 1 2 5

Favours gemcitabine Favours control

R Status R0 R1

N stage N- N+

T stage T1-2 T3-4

DFS (fixed) 95% CI

Hazard ratio 95% CISub-category

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Overall Survival (OS)

Gemcitabine Median: 22.8 months (95% CI. 18.5-27.2) (23.5% censored)

ObservationMedian: 20.2 months (95% CI. 17.7-22.8) (10.9% censored)

Log Rank P=0.005(17.2% censored)

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Longterm Survival

ITT OS 1 year (%) 2 years (%) 3 years (%) 5 years (%)

Gemcitabine 72.0 48.5 36.5 21.0

Observation 72.5 40.0 19.5 9.0

Δ Gem-Obs -0.5 8.5 17.0 12.0

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 OS Resection Margin

R0 n=293

Gemcitabine Median: 22.8 months (95% CI. 18.0-27.6) (24.8% censored)

ObservationMedian: 20.3 months (95% CI. 17.9-22.7) (11.5% censored)

Log Rank P=0.018(18.1% censored)

R1n=61

Gemcitabine Median: 22.1 months (95% CI. 9.4-34.9) (17.6% censored)

ObservationMedian: 14.1 months (95% CI. 12.2-16.0) (7.4% censored)

Log Rank P=0.088 n.s.(13.1% censored)

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 OS Primary Tumor

T1+T2n=49

Gemcitabine Median: 40.6 months (95% CI. 26.6-54.5) (44.0% censored)

Observation Median: 27.0 months (95% CI. 21.4-32.7) (20.8% censored)

Log Rank P= 0.12 n.s.(32.7% censored)

T3+T4n=305

Gemcitabine Median: 21.0 months (95% CI. 16.2-25.8) (20.1% censored)

Observation Median: 19.0 months (95% CI. 16.3-21.7) (9.3% censored)

Log Rank P= 0.018(14.8% censored)

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 OS Hazard Ratios

OS (fixed) 95% CI

Hazard ratio 95% CISub-category

R Status R0 R1

0.74 [0.57, 0.95] 0.62 [0.36, 1.08]

Test for heterogeneity: Chi² = 0.30, df = 1 (P = 0.59), I² = 0%

N stage N- N+

0.57 [0.36, 0.91] 0.80 [0.61, 1.04]

Test for heterogeneity: Chi² = 1.50, df = 1 (P = 0.22), I² = 33.5%

T stage T1-2 T3-4

0.58 [0.29, 1.16] 0.74 [0.58, 0.95]

Total (95% CI) 0.72 [0.57, 0.91]

Test for heterogeneity: Chi² = 0.44, df = 1 (P = 0.50), I² = 0%

Test for overall effect: Z = 2.74 (P = 0.005)

0.2 0.5 1 2 5

Favours gemcitabine Favours control

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

CONKO-001 Conclusions

Treatment with gemcitabine as compared to observation in patients with resected pancreatic cancer results in improved disease free survival and overall survival

Adjuvant treatment with gemcitabine doubles the longterm survival rate after 5 years compared to observation

Gemcitabine should be the standard of care for adjuvant treatment of pancreatic cancer