Malcolm MooreProfessor of Medicine and Pharmacology,

Princess Margaret Hospital, University of Toronto, Toronto, Canada

Director of the Bras Family New Drug Development Program, Princess Margaret Hospital, University of Toronto, Canada

Head of Division of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto

Senior Scientist in the Division of Experimental Therapeutics at the Ontario Cancer Institute, Canada

He is the author of more than 160 peer- reviewed publications and has given over 140 invited lectures worldwide

Princess Margaret Hospital

Charting a new landscape in advanced pancreatic cancer

Malcolm MoorePrincess Margaret Hospital

University of TorontoToronto, Canada

Pancreatic cancer: a major therapeutic challenge

Major health burden

– fourth leading cause of cancer death in the USA

– fifth leading cause of cancer death in the EU

Fatal disease with 98% mortality rate1,2

– OS rate is among the shortest of any solid tumour

Poor prognosis

– usually locally advanced or metastatic at diagnosis

– most patients unsuitable for surgery

– current treatment options are limited

1Parkin DM, et al. CA Cancer J Clin 2005;55:74–1082Michaud DS. Minerva Chir 2004;59:99–111OS = overall survival

Gemcitabine(n=63)

5-FU(n=63) p value

Median survival (months) 5.65 4.41 0.0025

0 2 4 6 8 10 12 14 16 18 20

100

80

60

40

20

0

5-FU

Gemcitabine

Months

Pat

ien

ts s

urv

ivin

g (

%)

Burris H, et al. J Clin Oncol 1997;15:2403–13

Gemcitabine: a standard of care in pancreatic cancer

5-FU = 5-fluorouracil

Lack of progress in therapy for advanced pancreatic cancer

Treatment options remained limited over last decade despite promising phase II results with gemcitabine plus various different agents

More than 10 phase III trials of new drug versus gemcitabine or in combination with gemcitabine– none demonstrated a survival benefit

Increased toxicity with several combination regimens

Randomised phase III trials in pancreatic cancer (median OS in months)

Gem Gem + X p value

Gem ± marimastat (Bramhall, Br J Cancer 2002)

Gem ± tipifarnib (Van Cutsem, J Clin Oncol 2004)

Gem ± exatecan (Abou-Alfa, J Clin Oncol 2006)

Gem ± CPT-11 (Rocha-Lima, J Clin Oncol 2006)

Gem ± pemetrexed (Oettle, Ann Oncol 2006)

5.5

6.0

6.2

6.6

6.3

5.5

6.4

6.7

6.3

6.2

NS

NS

NS

NS

NS

Gem ± 5-FU bolus (Berlin, J Clin Oncol 2002)

Gem ± capecitabine (Herrmann, J Clin Oncol 2007)

Gem ± 5-FU/LV (Riess, J Clin Oncol 2005)

Gem ± capecitabine (Cunningham, ECCO 2005)(preliminary results)

Gem ± cisplatin (Heinemann, J Clin Oncol 2006)

Gem ± oxaliplatin (Louvet, J Clin Oncol 2005)

Gem ± oxaliplatin (Poplin, ASCO 2006)

5.4

7.3

6.2

6.0

6.0

7.1

4.9

6.7

8.4

5.9

7.4

7.5

9.0

5.9

NS

NS

NS

0.026

NS

NS

NS

Gem ± erlotinib (Moore, J Clin Oncol 2007)

Gem ± bevacizumab (Kindler, ASCO 2007)

Gem ± cetuximab (Philip, ASCO 2007)

5.9

6.1

5.9

6.4

5.8

6.4

0.011

NS

NS

Gem = gemcitabine; Gem + X = combination regimen being investigated LV = leucovorin; NS = not significant

Gemcitabine/cetuximab versus gemcitabine alone: phase III study (n=735)

Philip PA, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):s199 (Abstract 4509)

Gemcitabine + cetuximab

Gemcitabine monotherapy

Median OS (months) 6.5 6.0

Progression-free survival (PFS) (months) 3.5 3.0

Response rate (RR) (%)* 12 14

Patients experiencing ≥1 grade 4 toxicity (%) 14 11

*Includes unconfirmed responses HR = hazard ratio; CI = confidence interval

HR=1.09(95% CI: 0.93–1.27)

p=0.14

HR=1.13(95% CI: 0.97–1.30)

p=0.058

Phase III data did not confirm promising phase II results

Gemcitabine/bevacizumab versus gemcitabine/placebo: phase III CALGB study

Kindler HL, et al. J Clin Oncol 2007;25(Suppl. 18 Pt.I):s199 (Abstract 4508)

Gemcitabine + bevacizumab (n=302)

Gemcitabine + placebo (n=300)

Median OS (months) 5.7 6.0

PFS (months) 4.8 4.3

RR (%)*

Complete response

Partial response

Stable disease

1.9

11.2

40.7

3.0

8.3

35.7*Includes unconfirmed responses

Phase III data did not confirm promising phase II results

PI3K Akt

Rationale for targeting EGFR in anticancer therapy

Extracellular

Intracellular

P P

Woodburn J. Pharmacol Ther 1999;82:241–50; Lynch TJ, et al. N Engl J Med 2004;350:2129–39Knowlden JM, et al. Endocrinology 2003;144:1032–44

Chakravarti A, et al. Cancer Res 2002;62:4307–15

Proliferation Invasion Metastasis Angiogenesis Inhibition of apoptosis

JNKMAPK

Epidermal growth factor receptor (EGFR)

Rationale for targeting EGFR in pancreatic cancer

EGFR overexpression is common (30–95%)1,2

Elevated EGFR and EGF is thought to be associated with3–5 – more aggressive disease – increased tumour size– late clinical stage – poor prognosis – reduced sensitivity to chemotherapy

1Tobita K, et al. Int J Mol Med 2003;11:305–9 2Srivastava A, et al. Hum Pathol 2001;32:1184–9

3Ueda S, et al. Pancreas 2004;29:1–8 4Nicholson R, et al. Eur J Cancer 2001;37:S9–S15

5Xiong H, et al. Semin Oncol 2002;29:31–7

Data overview: PA.3 study

Gemcitabine 1,000mg/m2 i.v. weekly

+placebo 100/150mg/day p.o.

(n=284)

PA.3: study schemaGemcitabine 1,000mg/m2 i.v.

weekly+

erlotinib 100/150mg/day p.o.(n=285)

Moore M, et al. J ClinOncol 2007;25:1960–6

Stratified by Centre ECOG PS (0/1 vs 2) Stage of disease

(locally advanced/ distant metastases)(n=569)

*1:1 randomisationECOG = Eastern Cooperative Oncology Group; PS = performance status; i.v. = intravenous; p.o. = oral

Primary endpoint = overall survival

Secondary endpoints include progression-free survival (PFS), quality of life (in selected countries), response rate (RR), toxicity, biomarkers

RANDOM I SE*

PA.3: key eligibility criteria

Locally advanced or metastatic adenocarcinoma of the pancreas

Age 18 years

PS 0–2

Measurable or non-measurable disease

Prior radiotherapy for local disease allowed

No prior chemotherapy, except for 5-FU or gemcitabine as a radiosensitiser

EGFR-positive status not required

Moore M, et al. J Clin Oncol 2007;25:1960–6

Gemcitabine + erlotinib (n=285)

Gemcitabine + placebo (n=284)

Median age (years) 64 64

Female/male (%) 52/48 43/57

PS 0/1/2 (%) 30/51/19 30/52/18

Locally advanced/metastatic (%) 24/76 25/75

Pain score 20/>20/unknown (%) 46/51/3 45/53/2

Measurable disease (%) 94 92

PA.3: patient characteristics* 569 patients randomised

– 521 patients at 100mg/placebo

– 48 patients at 150mg/placebo

*Baseline characteristics of the 100mg cohort did not differ substantially from the whole population

Moore M, et al. J Clin Oncol 2007;25:1960–6Data on file, OSI Pharmaceuticals Inc.

PA.3: OS in the total population* (ITT)

100

80

60

40

20

0

*Includes patients with locally advanced and metastatic disease at both 100mg/day and 150mg/day doses of erlotinibITT = intent to treat; HR = hazard ratio; CI = confidence interval

0 6 12 18 24Months

p=0.038 HR=0.82 (95% CI: 0.69–0.99)

Su

rviv

al p

rob

abil

ity

(%)

Median survival (months)

1-year survival

Gemcitabine + erlotinib 6.24 23

Gemcitabine + placebo 5.91 17

Moore M, et al. J Clin Oncol 2007;25:1960–6

PA.3: overall survival in the 100mg cohort

100

80

60

40

20

00 6 12 18 24

Months

p<0.028HR=0.81 (95% CI: 0.68–0.97)

Su

rviv

al p

rob

abil

ity

(%)

Median survival (months)

1-year survival

Gemcitabine + erlotinib (n=261) 6.4 23.8

Gemcitabine + placebo (n=260) 6.0 19.4

Moore M, et al. J Clin Oncol 2007;25:1960–6

*HR adjusted for PS and extent of disease at baseline

30% increase in PFS

100

75

50

25

00 6 12 18 24

Months

Su

rviv

al p

rob

abil

ity

(%)

Erlotinib + gemcitabine (n=261)

Placebo + gemcitabine (n=260)

p=0.006HR=0.76* (95% CI: 0.64–0.92)

Data on file, OSI Pharmaceuticals Inc.

PA.3: PFS in the 100mg cohort

PA.3: all subgroups benefit from treatment with erlotinib plus gemcitabine

*Stratified by PS and extent of disease**No prior chemotherapy allowed, other than as a radiosensitiser

0 0.50 1.00 1.50 2.00 2.50

Factors n HR 95% CI

HR

Erlotinib: placebo* 521 0.81 0.7–1.0

PS 0–1PS 2

43289

0.870.70

0.7–1.10.5–1.1

Locally advancedDistant metastases

124397

0.930.80

0.6–1.30.7–1.0

Pain intensity 20Pain intensity >20

238268

0.721.00

0.6–0.90.8–1.3

EGFR positiveEGFR negativeEGFR unmeasured

7066

385

0.820.750.86

0.5–1.30.5–1.20.7–1.1

MaleFemale

273240

0.741.00

0.6–0.90.8–1.3

Age <65 yearsAge 65 years

274247

0.780.94

0.6–1.00.7–1.2

CaucasianBlackAsian

4561334

0.880.670.61

0.7–1.10.2–2.20.3–1.3

Prior radiosensitisingchemotherapy**No prior radiosensitisingchemotherapy**

42

479

0.62

0.86

0.3–1.2

0.7–1.0

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):s1 (Abstract 1)Genentech: Tarceva® full prescribing information

Importance of stable diseaseMedian duration of SD >5 months

0 10 20 30 40 50 60

Gemcitabine+ erlotinib

Gemcitabine+ placebo

Data on file, OSI Pharmaceuticals Inc.

Disease control rate (CR + PR + SD): gemcitabine plus erlotinib 59%; gemcitabine plus placebo 49.4%; p=0.036

Patients (%)

SD

SD

CR/PR

CR/PR

CR = complete responsePR = partial response; SD = stable disease

Acceptable safety profile with addition of erlotinib: no synergistic toxicities

Serious adverse drug reactions are infrequent

Gemcitabine + erlotinib

Gemcitabine + placebo

Grade 3/4 AEs

Pat

ien

ts (

%)

20

15

10

5

0 Rash Diarrhoea Infections Weight loss

Tarceva® Summary of Product CharacteristicsAE = adverse event

Significance of PA.3

First randomised trial to show significantly prolonged survival with any regimen versus single-agent gemcitabine in advanced pancreatic cancer – first demonstration of OS benefit with EGFR

inhibitor in combination with chemotherapy Results led to– FDA approval of the combination in patients with

locally advanced and metastatic pancreatic cancer– EMEA approval of the combination in patients with

metastatic pancreatic cancer

EGFR = epidermal growth factor receptorFDA = Food and Drug Administration; EMEA = European Medicines Agency

Erlotinib in the routine clinical setting: a case study

Case study: patient history

20-year-old university student

History of abdominal pain for 6 months and gradually increasing abdominal distension

Felt a lump in upper abdomen

Past medical health was good but there was a strong family history of cancer

CT scan was performed in December 2005

CT = computerised tomography

Case study: imaging at baseline

Liver biopsy found well-differentiated adenocarcinoma of pancreatic or biliary tract origin

Case study: initial treatment

Patient commenced treatment with gemcitabine plus erlotinib 100mg/day

Two days after starting erlotinib, the patient developed pustular rash that increased in intensity– stopped erlotinib and came to clinic

On examination, confirmed as grade 3 rash

Erlotinib-related rash: NCI-CTC grade 3

Definition Severe, generalised

erythroderma (generalised reddening and scaling of skin)

Macular, papular or vesicular eruption (small fluid-filled blisters)

Desquamation covering >50% of BSA– OR <50% of BSA, but very

symptomatic with vesicular eruption

NCI-CTC = National Cancer Institute-CommonToxicity Criteria; BSA = body surface area

Management recommendations for symptomatic rash

Hydrocortisone1% or 2.5% cream

AND/OR

Clindamycin 1% gel

Treat as moderate

AND

Systemic steroids†

AND

Consider dose interruption

Hydrocortisone2.5% cream

OR

Clindamycin 1% gel

OR

Pimecrolimus 1% cream

Synthetic tetracycline*

AND

*Doxycycline or minocycline 100mg b.i.d.†Prednisone, methylprednisolone 30mg once daily (tapered over 30 days)b.i.d. = twice daily

2-weekly assessments

Lynch TJ, et al. Oncologist 2007;12:610–21

No treatment

OR

ModerateMild Severe

Case study: rash management

Erlotinib stopped for 1 week while rash treated with oral minocycline and topical steroids

Restarted erlotinib at 100mg/day

Grade 3 rash recurred by week 7 at which point erlotinib was temporarily halted, then restarted at a reduced dose of 50mg/day

Case study: continuing status

Repeat CT scan after 8 weeks showed stable pancreatic mass and reduction in liver metastases

Patient continued on gemcitabine plus 50mg/day erlotinib

After 6 months of treatment, the patient had chronic grade 1 rash and diarrhoea– CT scan showed further improvement in

liver lesions

Case study: imaging at 6 months

Case study: current status

September 2006: patient underwent resection of pancreatic tail mass and liver lesions– confirmed well-differentiated

cystic adenocarcinoma

Patient remained well until May 2007 when two new liver lesions were observed– treated with radiofrequency ablation

December 2007 – three new liver lesions observed– restarted gemcitabine plus erlotinib

Future developments

Identifying patients most likely to benefit from gemcitabine plus erlotinib

Prior to treatment– molecular markers – demographic/clinical characteristics (e.g. age,

gender, histology, PS)

During treatment– RR; disease control rate– other surrogate markers (e.g. presence of rash)

PA.3: significant improvement in OS in PS 2 patients

Su

rviv

al p

rob

abili

ty (

%)

100

80

60

40

20

0 0 6 12 18 24Months

p≤0.001HR=0.47 (95% CI: 0.31–0.71)

Gemcitabine + erlotinib (n=53)Median: 4.16 months95% CI: (4.37–6.34)

Gemcitabine + placebo (n=52)Median: 3.20 months95% CI: (2.63–4.11)

Data on file, OSI Pharmaceuticals Inc.

PA.3: skin rash associated with erlotinib 72% of patients developed skin rash

Significantly higher likelihood of skin rash in

– patients younger than 65 years (p=0.01)

– patients with a good PS (p=0.03)

Presence of rash was associated with

– higher rate of disease control (p=0.05)

– longer survival (HR=0.74, p=0.037)

Generally develops within 7–10 days of starting therapy and may spontaneously resolve and reappear

No correlation with duration of therapy

Reversible following drug discontinuation

PA.3: degree of rash correlates with OS (100mg cohort)

p<0.0001, HR=0.71

Grade 0Grade 1Grade 2

100

80

60

40

20

0

Su

rviv

al p

rob

abili

ty (

%)

0 5 10 15 20Months

Grade 0(n=79)

Grade 1(n=108)

Grade 2(n=103)

Median survival (months) 5.29 5.75 10.51

1-year survival (%) 16 11 43

Data on file, OSI Pharmaceuticals Inc.

PA.3: observed skin rash

Potential reasons

– variability of drug absorption

– variability of metabolism

– ability of rash to predict a more immunocompetent individual

– pharmacogenomic basis

Further study in this area is necessary to understand the value of rash in predicting survival in individual patients

– some patients with no rash do obtain clinical benefit from erlotinib

– some patients who develop grade 2 rash had grade 1 rash initially

Phase II trial: assessing potential predictive markers and dose escalation according to skin reactions

Primary endpoint: OS Mandatory tissue collection for biomarker testing Secondary endpoints: PFS, disease control, safety, correlation of

EGFR-related biomarkers with outcome (EGFR, EGF, TGF-α, KRAS, pAkt, pMAPK)

No rash or grade 1

rashAdvanced pancreatic

cancer: gemcitabine +

erlotinib 100mg(n~400)

PD

Gemcitabine + erlotinib 100mg

PD

PD4 weeks

Gemcitabine + erlotinib 100mg

Gemcitabine + erlotinib dose escalation to

grade 2 rash or DLT

Grade 2 rash

DLT = dose-limiting toxicity; PD = progressive disease

EGFR: a predictive factor? In NSCLC, EGFR IHC and EGFR FISH status have not yet

been demonstrated to correlate with benefit from EGFR inhibitors in a prospective, randomised trial

In NSCLC, activating mutations of EGFR (exons 18–21) may be correlated with increased benefit from EGFR TKIs such as gefitinib or erlotinib

These appear to be the most promising candidate biomarkers for EGFR-targeted therapy, e.g. erlotinib

HOWEVER, incidence of activating mutations in pancreatic cancer = 1.5%

Results from one tumour type can not be extrapolated to another tumour type

NSCLC = non-small cell lung cancer; IHC = immunohistochemistryFISH = fluorescence in-situ hybridisation; TKIs = tyrosine-kinase inhibitors

PA.3: survival by EGFR IHC status (100mg cohort)

EGFR IHC+ (n=70)EGFR IHC– (n=66)

1.00

0.75

0.50

0.25

00 6 12 18 24

Months

Su

rviv

al p

rob

abili

ty

1.00

0.75

0.50

0.25

00 6 12 18 24

Months

Su

rviv

al p

rob

abili

ty

Erlotinib (n=34)

Placebo (n=32)

HR=0.75

95% CI: 0.46–1.23 (p=NS)

Erlotinib (n=41)

Placebo (n=29)

HR=0.82

95% CI: 0.50–1.32 (p=NS)

Data on file, OSI Pharmaceuticals Inc.

PA.3: implications of EGFR gene copy number for survival

EGFR FISH+

(n=50)

EGFR FISH–

(n=57) HRp

value

Number of partial responses 5/48 4/53 1.36 0.68

Median OS (months) 5.3 7.8 1.24 0.32

Median PFS (months) 3.6 4.2 1.85 0.004

Moore M, et al. J Clin Oncol 2007(Suppl. 18 Pt I):s203(Abstract 4521)

Gemcitabine+ erlotinib

Gemcitabine + placebo HR p value

HR + p value for interaction

Survival (months)

EGFR FISH+ 5.2 5.2 0.90 0.73 1.41 (p=0.31) EGFR FISH– 8.4 6.7 0.60 0.08

N.B. results are irrespective of treatment received

KRAS: a predictive factor?

KRAS point mutations in codon 12

KRAS mutations associated with resistance to cetuximab in CRC

KRAS mutations associated with shorter survival in pancreatic cancer compared with wild-type KRAS

Lee J, et al. Cancer 2007;109:1561–9CRC = colorectal cancer

Gemcitabine + erlotinib

Gemcitabine + placebo HR p value

HR + p value for interaction

Survival (months)

KRAS mutant 6.0 7.4 1.07 0.78 1.71 (p=0.29) KRAS WT 6.1 4.5 0.66 0.34

PA.3: implications of KRAS mutations for survival

N.B. results are irrespective of treatment received

KRAS mutant(n=92)

KRAS WT(n=25) HR

p value

Number of partial responses 9/90 0/21 – 0.20

Median OS (months) 6.7 5.4 0.63 0.37

Median PFS (months) 3.8 3.7 0.86 0.53

Moore M, et al. J Clin Oncol 2007(Suppl. 18 Pt I):s203:(Abstract 4521)WT = wild-type

Limitations of PA.3 biomarker data

Data are from retrospective analyses and include only small numbers of patients– no data as yet from prospective, randomised study

designed to investigate biomarkers for predicting clinical benefit with erlotinib plus gemcitabine

– studies are planned but are in early stages

No studies or guidelines to date suggest use of a specific biomarker to select patients to receive

erlotinib plus gemcitabine

Randomised phase II biomarker study

Primary endpoint: PFS

– biomarkers: EGFR IHC, EGFR FISH, EGF, TGF-α, amphiregulin, KRAS mutations, EGFR mutations, RANTES

Secondary endpoints: response, disease control, OS, CA19-9, safety

BSC = best supportive care

Subsequent treatment at

investigators’ discretion

Advanced pancreatic

cancer failing previous

chemotherapy or unsuitable for

first-line chemotherapy PS

0–2, n=200

Erlotinib 150mg or other active

treatment

PD

PD

Erlotinib 150mg

Placebo + BSC

Challenges of finding predictive biomarkers in pancreatic cancer

Practical difficulties of tissue acquisition in pancreatic cancer

– numbers of patients with samples often small

Current status of translational research

– EGFR FISH positivity (only in 5–10% of patients)

– EGFR mutations (no activating mutations)

– KRAS mutation status (90% tumours positive, simulations suggest benefit in PA.3 highly unlikely to be driven by wild-type carriers only)

Recent analyses inconclusive

– NCIC

• EGFR FISH

• KRAS

False results have major implications

– may deny patient access to life-extending treatment

– patients may receive a therapy they are unlikely to benefit from

Randomised phase III trial: adding bevacizumab to erlotinib plus gemcitabine

Primary endpoint of OS not met Secondary endpoints were met, however, demonstrating that the

combination has some clinical activity Confirmed efficacy of gemcitabine plus elotininib control arm, in line

with PA.3 Data will be presented at an upcoming congress in 2008

PD

PDPreviously untreated metastatic

pancreatic cancer(n=600)

Erlotinib (100mg) +gemcitabine +

bevacizumab (5mg/kg every 2 weeks)

Standard regimen used in PA.3., i.e. erlotinib

(100mg) +gemcitabine

+ placebo

Bevacizumab plus gemcitabine pluserlotinib or cetuximab

R

Kindler HL, et al. J Clin Oncol 2006;24(Suppl. 18 Pt I):s188 (Abstract 4040)

Preliminary results (n=51)

BGC (n=27)

BGE (n=24)

RR 19% 21%

SD 59% 67%

Median PFS (months) 3.6 3.6

6-month survival rate 41% 38%

Previously untreated advanced

pancreatic cancer (measurable

disease), PS 0–2

Bevacizumab +gemcitabine +

erlotinib

Bevacizumab +gemcitabine +

cetuximab

Randomised phase III trial: erlotinib plus concurrent/sequential gemcitabine/capecitabine

PI: Prof V Heinemann (Germany)

Primary endpoint = time to second progression n=132/250

Erlotinib +capecitabine

Advanced pancreatic

cancer

Gemcitabine

Erlotinib + gemcitabine

Capecitabine

R

PD

PD

PD

PD

Erlotinib plus gemcitabine: conclusions

Erlotinib plus gemcitabine = a new treatment option for patients with advanced pancreatic cancer

Further research underway to establish if patients who will obtain greatest benefit from this regimen can be identified– also investigating relationship between rash and

clinical benefit

Erlotinib and gemcitabine now provides a backbone of therapy for pancreatic cancer– future trials will evaluate addition of other novel

agents, e.g. bevacizumab, to further extend survival