ASCO 2009 – GI Highlights Eileen M. O’Reilly, M.D. Associate Member Memorial Sloan-Kettering Cancer Center Associate Professor Weill Medical College of.

ASCO 2009 – GI Highlights

Eileen M. O’Reilly, M.D.

Associate MemberMemorial Sloan-Kettering Cancer CenterAssociate ProfessorWeill 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 ≤/ > ULNSystemic Therapy

RANDOMIZE

Systemic Therapy +

Enoxaparin*

*Enoxaparin 1 mg/kg/day for 3 mths → 40 mg/day until POD

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


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


Study Conduct

• Open-label, randomized phase II

• Recruitment 4/04- 1/09, 33 centers

• Date of analysis 4/09


Demographics (N= 312)

Observation(N= 152)

Enoxaparin(N= 160)

Age (median) 63 yrs 62 yrs

Male 62% 57%

Metastatic Disease 75% 74%

Primary Disease 87% 84%

KPS 80-100% 85% 84%

Creatinine ≤ ULN 95% 96%


Recruitment ceased 1/09 (24 VTE episodes)


CONKO-004 (N= 312)

Gemcitabine, Cis, 5-FU(N= 255)

PS ≥ 80% and creat ≤ ULN

Gemcitabine(N= 57)

PS 60-70% or creat > ULN

Gemcitabine(N= 27)

Gemcitabine + Enoxaparin(N= 30)

Gem, Cis, 5-FU, LV(N= 125)

Gem, Cis, 5-FU + Enoxaparin(N= 130)

VTE in the first 3 Months

Observation(N= 152)

Enoxaparin(N= 160)

Total

Pulmonary embolism 2 - 2

Proximal leg DVT 9 2 11

Distal leg DVT 2 - 2

Upper extremity DVT 3 - 3

All VTE events 16 2 18


1 pt had DVT + PE. 18 events in 17 pts

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


Major Bleeding Events (3 months)

Observation(N= 152)

Enoxaparin(N= 160)

P-Val

VTE in first 3 mths *2.63% 3.75% 0.6


9 non-fatal, *1 fatal upper GI haemorrhage (observation arm)

Overall Results (Med f/up 34 wks)

Observation(N= 152)

Enoxaparin(N= 160)

P-Val

VTE 22 (15.5%) 8 (5%) < 0.05

Bleeding 15*# (9.9%) 10* (6.3%) 0.6

TTP (preliminary) 19 weeks 22 weeks

OS (preliminary) 29 weeks 31 weeks


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)

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 Arnoldfor 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 non-

functioning NET’s• Anti-proliferative value not well established• No well-designed phase III trials to answer

question in midgut NET’s

Midgut NET‘sN= 85

Placebo IM q 4 wks(N= 43)

Promid Study (Abst #4508)

Octreotide LAR 30mg IMq 4 wks (N= 42)

Randomized phase III, placebo-controlled, double-blindMidgut NET’s: Jejunem, ileum, appendix, right colon

Primary Endpoint: TTPSecondary Endpoints: RR (WHO), OS

RANDOMIZE

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

• 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


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%

Time from Diagnosis 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%

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

Octreotide LAR 30mg Significantly Increases Time to Tumor Progression

Octreotide LAR vs placebo P=0.000017HR= 0.33 [95% CI: 0.19–0.55]

Based on Intention to treat analysis

Pro

po

rtio

n w

ith

ou

t p

rog

ress

ion

Time (months)

Octreotide LAR: 42 patients / 27 events Median 15.6 months [95% CI: 11.0–29.4]

Placebo: 43 patients / 41 events Median 5.9 months [95% CI: 5.5–9.1]

PROMID: TTP

Arnold,et al. ASCO, 2009 (Abst #4508)

Octreotide(N= 42)

Placebo(N= 43)

P-value

TTP (Overall) 15.6 mths 5.9 mthsHR 0.33

p= 0.000017

TTP (Liver ≤10%)28.8 mths(N= 32)

6.1 mths(N= 32)

HR 0.21p< 0.0001

TTP (Liver >10%)10.3 mths(N= 10)

4.5 mths(N= 11)

PROMID: Response Rates


Octreotide Placebo

Complete Response - -

Partial Response 1 1

Stable Disease 28 (67%) 16 (70%)

Progressive Disease 10 (24%) 23 (54%)

• 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

Is the Treatment Effect Homogenous across Subgroups?

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 900

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

Based on the per protocol analysis

P= 0.0008; HR= 0.27 [95% CI: 0.12–0.61]

Pro

po

rtio

n w

ith

ou

t p

rog

res

sio

n

P= 0.0007; HR= 0.23 [95% CI: 0.09–0.57]

Pro

po

rtio

n w

ith

ou

t p

rog

res

sio

n

Octreotide LAR Lengthens TTP in Patients with Functioning and Non-Functioning Midgut NETs

Patients with non-functioning tumors Patients with functioning tumors

Time (months)Time (months)

Octreotide LAR: 17 patients / 11 events

Median TTP 10.35 months

Placebo: 16 patients / 14 events


Octreotide LAR: 25 patients / 9 events


Placebo: 27 patients / 24 events


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, double-blinded, 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

Advanced Carcinoid

(progressive)N= 390 Octreotide LAR + Placebo

RADIANT 2 Trial

Octreotide LAR + Everolimus

Primary Endpoint: PFS

Accrual completed – Results awaited

RANDOMIZE

Yao, et al (PI)

Advanced Poor Prognosis CarcinoidN= 287 Octreotide LAR + IFN α-2b

SWOG 0518

Octreotide LAR + Bevacizumab

Primary Endpoint: PFS

Ongoing recruitment

RANDOMIZE

Yao, et al (PI)

ESPAC-3

LCTU

Liverpool Cancer Trials Unit

ESPAC-3(v2)A Multicentre, International, Open-label, Randomised Controlled Phase III Trial of Adjuvant 5-Fluorouracil/Folinic acid (5-

FU/FA) vs Gemcitabine (GEM) in Patients with Resected Pancreatic Ductal

Adenocarcinoma

European Study Group for Pancreatic Cancer

CR-UK Liverpool Cancer Trials Unit

LCTU


Background

ESPAC-1 compared chemotherapy [5FU/FA ] with chemoradiation

Using a 2x2 factorial design

LCTU


Lancet, 2001;358(9293):1576-85

ESPAC-1 Lancet, 2001No benefit for Chemoradiation – Potential benefit for Chemotherapy

LCTU


ESPAC-3(v1) Trial Design

Patients with ductal adenocarcinomaundergoing ‘curative’ resection

Target N=990

RANDOMISE

5FU/ FA5-FU 425mg/m2 &FA 20mg/m2 for 5

days every 28 days for 6 cycles

Target N=330

GEMCITABINE1000mg/m2 once a

week for 3 of 4 weeks for 6 cycles

Target N=330

OBSERVATIONTarget N=330

330 per arm to detect 10% difference in 2y survival rate (= 5%, 1-= 80%)

Trial opened July 2000

LCTU


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

Survival rates 2-year 5-yearNo CRT: 41.4% 19.6%CRT: 28.5% 10.0%HR=1.28 (0.99, 1.66), p=0.053

ESPAC-1ESPAC-1

NEJMNEJM 2004 2004; ; 350:1200-10 350:1200-10

ESPAC-1 NEJM 2004: No benefit for Chemoradiation confirmed

Survival rates 2-year 5-yearNo CT: 30.0% 8.4%CT: 39.7% 21.1%HR=0.71 (0.55, 0.92), p=0.009

ESPAC-1ESPAC-1

NEJM 2004; NEJM 2004; 350:1200-10 350:1200-10

ESPAC-1 NEJM 2004: Benefit for Chemotherapy confirmed

LCTU


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


ESPAC-3(v2) Trial DesignPatients with ductal adenocarcinoma undergoing ‘curative’ resection

Target N=1030*

RANDOMISE

5FU/ FATarget N=515Actual=551

GEMCITABINETarget N=515Actual N=537

3-monthly follow-up to death

515 per arm to detect 10% difference in 2y survival rate ( = 5%, 1-= 90%)

*Actual N=1088

Patient Demographics

† Significant prognostic variable

Tumor Pathology

† Significant prognostic variable

On-Study Data

LCTU Liverpool

Cancer Trials Unit

χ2LR = 24.2, p<0.001 χ2

LR = 31.8, p<0.001

χ2LR = 52.7, p<0.001

χ2LR = 16.3, p<0.001

LCTU


Follow-Up

5FU/FA GEM Total

N=551 N=537 N=1088

Survival Status:AliveDead

163388

(30%)(70%)

172365

(32%)(68%)

335753

(31%)(69%)

Follow-up of alive patients:N

Median (months)Range

Inter-quartile RangeN (%) with >24 month FU

16334

0.4-7926-44

133 (82%)

17234

0.4-8628-43

149 (87%)

33534

0.4-8627-43

282 (84%)

LCTU


Reported Toxicity

5FU/FA GEM

CTC 3-4 (% of 551 pts) CTC 3-4 (% of 537 pts)WBC 32 (6%) 53 (10%)

Neutrophils 121 (22%) 119 (22%)

Platelets - 8 (1.5%)

Nausea 19 (3.5%) 13 (2.5%)

Vomiting 17 (3%) 11 (2%)

Stomatitis 54 (10%) 1 (0%)

Alopecia 1 (0%) 1 (0%)

Tiredness 45 (8%) 32 (6%)

Diarrhea 72 (13%) 12 (2%)

Other 67 (12%) 43 (8%)

Number of patients with at least one NCI CTC v2. grade 3-4 event

* Exploratory analysis: sig level p<0.005 using Bonferroni adjustment

p=0.013

p=0.94

p=0.0034

p=0.37

p=0.34

p<0.001*

p=1.0

p=0.16

p<0.001*

p=0.027

LCTU


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

40 (7.5%)* GEM patients reported 52 SAE

*Exploratory analysis: Fishers Exact test p<0.001

LCTU


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)

2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)

LCTU


PFS by TreatmentMedian PFS(t)= 14.1months (95%CI:12.5, 15.3)Median PFS(t)= 14.3months (95%CI:13.5, 15.7)

2LR=0.59, p=0.44, HRGEM VS 5FU/FA=0.95 (95%CI: 0.83, 1.09)

LCTU


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

Resected PCN= 1,080

Gemcitabine + Capecitabine

ESPAC-4: Phase III

Gemcitabine

Primary Endpoint: Overall Survival

RANDOMIZE

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

ASCO 2009 – GI Highlights Eileen M. O’Reilly, M.D. Associate Member Memorial Sloan-Kettering Cancer Center Associate Professor Weill Medical College of.

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