Clinical benefits with Tarceva combination therapy in

pancreatic cancer

Malcolm J. MoorePrincess Margaret Hospital,

University of Toronto

Burden of disease in pancreatic cancer

The incidence of pancreatic cancer is rising

Screening or early detection not developed

Vast majority of patients will die less than a year after diagnosis

– fourth-leading cause of cancer-related deaths

– overall survival is shortest of any solid tumour

The disease is debilitating and there is a need to improve patient symptoms and QoL as well as survival

Trends in the incidence of pancreatic cancer*

0

1

2

3

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5

6

1983 1985 1987 1989 1991 1993 1995 1997

Hong Kong

0

1

2

3

4

1978 1982 1986 1990 1994 1998

Mumbai, India

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2

4

6

8

10

12

1958 1968 1978 1988 1998

Sweden

0

1

2

3

4

5

6

7

8

9

1983 1985 1987 1989 1991 1993 1995 1997

Kuwait

0

1

2

3

4

5

6

7

8

1968 1973 1978 1983 1988 1993

Singapore Chinese

0123456789

10

1978 1982 1986 1990 1994

Ontario, Canada

Parkin DM et al, Cancer Incidence in Five Continents, Vol. I to VIII IARC CancerBase No. 7, Lyon, 2005

*Age standardised rates, per 100,000

Pancreatic cancer: a major therapeutic challenge

Most patients are not able to have surgery

Gemcitabine has been the standard of care for patients with advanced disease

1

Little progress in improving clinical outcomes over the last decade

Treatment options remain limited

1Burris H, et al. J Clin Oncol 1997;15:2403–13

Gemcitabine registration study in advanced pancreatic cancer

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

Gemcitabinen=63

5-FUn=63 p value

Clinical benefit response† (%) 24 5 0.002

Median survival (months) 5.7 4.4 0.002

Time to progression (months) 2.1 0.9 0.001

6-month survival (%) 46 31

1-year survival (%) 18 2

Partial response (%) 5.4 0

Stable disease (%) 39.3 19

†Composite of measurements of pain (analgesic consumption and pain intensity),Karnofsky performance status, and weight

Survival

Phase III combination chemotherapy trials have been negative

Gemcitabine vs gemcitabine + 5-FU Berlin J et al. J Clin Oncol 2002;20:3270–5

Gemcitabine vs gemcitabine + irinotecan Rocha Lima CM et al. J Clin Oncol 2004;22:3776–83

Gemcitabine vs gemcitabine + oxaliplatin Louvet C et al. J Clin Oncol 2005

Gemcitabine vs gemcitabine + pemetrexedOettle H et al. Ann Oncol. 2005;16:1639–45

Gemcitabine vs gemcitabine + exatecanO’Reilly EM et al. Proc ASCO 2004;22:14S (Abs. 4006)

Phase III trials of targeted agents also negative

Ras-farnesyltransferase inhibitors

Gemcitabine vs gemcitabine + tipifarnibVan Cutsem E et al. J Clin Oncol 2004;22:1430–8

Matrix metalloproteinase inhibitors

Gemcitabine vs gemcitabine + marimastatBramhall SR et al. Br J Cancer 2002;87:161–7

Gemcitabine vs BAY 12–9566Moore MJ et al. J Clin Oncol 2003;21:3296–302

Gastrin vaccine

Gemcitabine vs gemcitabine + G17DT– Shapiro J, et al. J Clin Oncol 2005;23(Suppl. 16

Pt I):310 (Abs. 4012)

Rationale for targeting HER1/EGFR in pancreatic cancer

HER1/EGFR overexpression is common1,2

Elevated HER1/EGFR and EGF is 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;32:1184–89

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;29:31–7HER1/EGFR = human epidermal growth factor receptor

Rationale for Tarceva (erlotinib) in pancreatic cancer

In a preclinical study, Tarceva significantly inhibited cell growth and proliferation in pancreatic cancer cell lines in vitro1

Tarceva has been shown to enhance gemcitabine-induced apoptosis in pancreatic tumour cells2

1Durkin A, et al. Am J Surg 2003;186:431–6; 2Ng SS, et al. Mol Cancer Ther 2002;1:777–83

NCIC CTG PA.3

Double-blind, placebo-controlled, randomised phase III trial comparing gemcitabine +/- Tarceva

First-line treatment for locally advanced or metastatic adenocarcinoma of the pancreas

International study conducted independently by the NCIC CTG (2001-2003)

*1:1 randomisationECOG = Eastern Cooperative Oncology GroupPS = performance status

PA.3: study schema

Stratified by:CentreECOG PS (0/1 vs 2)Stage of disease(locally advanced vsdistant metastases)(n=569)

RANDOM I SE

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

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

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

placebo 100/150mg/day p.o.(n=284)

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

*

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

HER1/EGFR-positive status not required

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1 (Abs. 1)

PA.3: endpoints Primary

– overall survival Secondary

– progression-free survival (PFS)– quality of life (QoL) (Canada, USA, other selected

countries)– response rate (RR)– duration of response – toxicity– correlate expression of tissue HER1/EGFR levels

with outcomes

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1 (Abs. 1)

PA.3: statistical considerations

Based on an estimate of a 33% increase in median survival from 6.6 to 8.8 months– 80% power (two-sided 5% significance)– 381 events required– 450 patients with a follow-up of 18 months

(after protocol amendment)

Primary analysis– stratified log-rank test

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1 (Abs. 1)

Tarceva(n=285)

Placebo(n=284)

Median age (years) 63 64Female/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

USA/Canada/RoW (%) 38/20/42 36/21/43

PA.3: patient characteristics

569 patients randomised

– 521 patients at 100mg or placebo

– 48 patients at 150mg or placebo

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1 (Abs. 1)

19% reduction in risk of death

PA.3: overall survival (100mg cohort)

19.423.81-year survival (%)

6.0 6.4Median survival (months)

Placebo + gemcitabine

Tarceva + gemcitabine

*HR=0.81 (0.68–0.97), p=0.028

23% increase in survival

1.00

0.75

0.50

0.25

0

Su

rviv

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rob

abili

ty

0 6 12 18 24

Survival time (months)

Tarceva (n=261)

Placebo (n=260)

*Hazard ratio (HR) adjusted for PS and extent of disease at baseline

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

PA.3: hazard ratios for survival by pretreatment characteristics (100mg cohort)

0 0.50 1.00 1.50 2.00 2.50

Factors n HR 95% CI

HR

Tarceva: 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

HER1/EGFR positiveHER1/EGFR negativeHER1/EGFR 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

*Stratified by PS and extent of disease**Only chemotherapy given concurrently with radiationtreatment as a radiosensitiser was allowedCI = confidence interval

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

PA.3: survival by HER1/EGFR status (100mg cohort)

HER1/EGFR positive (n=70)HER1/EGFR negative (n=66)

1.00

0.75

0.50

0.25

00 6 12 18 24

Survival time (months)

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abili

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1.00

0.75

0.50

0.25

00 6 12 18 24

Survival time (months)

Su

rviv

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abili

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Tarceva (n=34)

Placebo (n=32)

HR=0.75

95% CI: 0.46–1.23 (p=NS)

Tarceva (n=41)

Placebo (n=29)

HR=0.82

95% CI: 0.50–1.32 (p=NS)

NS = not significantMoore M, et al. J Clin Oncol 2005;23(Suppl.16 Pt I):1s (Abs. 1)

Genentech: Tarceva® full prescribing information

PA.3: progression-free survival (100mg cohort)

*HR adjusted for PS and extent of disease at baseline

30% increase in PFS

1.00

0.75

0.50

0.25

00 6 12 18 24

Survival time (months)

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abili

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Tarceva + gemcitabine median = 3.8 months (n=261)

Placebo + gemcitabine median = 3.5 months (n=260)

*HR=0.76 (0.64–0.92), p=0.006

Moore M, et al. J Clin Oncol 2005;23(Suppl.16 Pt I):1s (Abs. 1)

Genentech: Tarceva® full prescribing information

PA.3: tumour response (100mg cohort)Patients (%)

Tarceva/gemcitabine(n=244)

Placebo/gemcitabine(n=241)

Complete response (CR) 0.4 0.8

Partial response (PR) 8.2 7.1

CR + PR 8.6 7.9

Stable disease (SD) 50.4 41.5

CR + PR + SD 59.0 49.4

Progressive disease 22.5 26.1

Not evaluable/missing 18.4 24.5

Median duration (weeks) ofCR + PR (95% CI) 23.9 (16.3–31.9) 23.3 (16.1–32.4)

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1 (Abs. 1)

PA.3: QoL

Measures

Impact of adding Tarceva to gemcitabine on patient’s self-reported QoL

Changes from baseline in global QoL; function and symptom domains; and single items – EORTC QLQ-C30 questionnaire

Outcomes

No detrimental effects on global QoL compared with gemcitabine alone

No significant differences between treatments for QoL domains, except for diarrhoea, higher score for Tarceva plus gemcitabine

Tarceva/gemcitabine(n=259)

Placebo/gemcitabine(n=256)

Any (%) Grade 3/4 (%) Any (%) Grade 3/4 (%)

Rash 69 5 30 1

Diarrhoea 48 5–6 36 2

Infection* 39 16 30 11

Stomatitis 22 <1 12 0

Fatigue 73 16 70 15 *Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class

PA.3: selected adverse events (100mg cohort)

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1 (Abs. 1)

PA.3: serious adverse eventsTarceva/

gemcitabine(%) (n=282)

Placebo/gemcitabine(%) (n=280)

Infections (all) Pneumonia Sepsis Infection NOS

16 4 4 2

13 3 3 5

ILD-like* events 2.5 (n=7) 0.4 (n=1)

Nervous system Cerebral ischaemia

5 2

<1 0

Renal insufficiency 1 0

*Pneumonitis, lung infiltration, and acute respiratory distress syndromeNOS = not otherwise specified; ILD = interstitial lung disease

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1 (Abs. 1)

PA.3: overall survival according to grade of rash

Moore M, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):1s (Abs. 1)

HR (rash)=0.71, p<0.0001

Grade 0Grade 1Grade 2

1.0

0.8

0.6

0.4

0.2

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0 5 10 15 20Time (months)

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

PA3: summary

Primary endpoint was met – improvement in overall survival

The benefit with Tarceva plus gemcitabine is both statistically and clinically meaningful– 23% increase in overall survival– 30% increase in PFS

The addition of Tarceva to gemcitabine was generally well tolerated

Tarceva 100mg/day is the recommended dose in combination with gemcitabine in this setting

Tarceva in pancreatic cancer: summary

Unresectable, locally advanced or metastatic pancreatic cancer is a difficult disease with few treatment options

Tarceva builds on the standard of care by increasing survival with manageable additional toxicity

The Tarceva + gemcitabine platform represents a step forward in the treatment of pancreatic cancer

Tarceva is a simple and convenient once-daily oral agent with manageable toxicity

InvestigatorsS. ACKLANDA. ALVAREZH. ANDERSONF. ARENA S. ARIFC. ARVANITAKISR. ASBURYA. ASIKH. AUP. BEALEJ. BECKR. BELTS. BERRY J. BIAGIE . BIONDIG. BJARNASONL. BLASZKOWSKYH. BLEIBERGJ. BLONDALJ. BOYDF. BRASFIELDJ. BRELLJ. BRIDGEWATERM. BROWNA. BUIUCM. BURNELLH. BURRISC. BUTTSP. BYEFFJ. CEBONM. CHACONH. CHALCHALE. CHEND. CHOIP. CHOW

N. COHENB. COLWELLDB. COMPOSF. COXONC. CRIPPSG. DARSYS. DAVIDSONS. DEL PRETEP. DESIMONEJ. DEVITTM. DIDOLKARA. DISTEFANOP. DUBEJ. EGNERM. ESTEVEZD. FENTOND. FERRYA. FIGERA. FIGUEREDOE. FILIPCZYK-CISARZJ. GALLARDOD. GALLARDOV. GANJUR. GANSLR. GAURG. GEILSJ. GIESBRECHTR. GOELD. GOLDSTEINL. GONZALEZG. GONZALEZ-OSETEM. GOODYEARP. GRAZEE. GREENOG. GROSSA. GROTHEYJ. GURTLERK. HAGANJ. HAINSWORTHD. HALLER J. HAMM

J. HECHTW. HEIMT. HERRMANNP. HESKETHH. HOCHSTERR. HOHLD. IRWINW. ISACOFFG. JEFFREYD. JONKERS. JOVTISL. KALMANI. KATOSA. KATZP. KENNEDYI. KERRR. KERRJ. KNOXW. KOOE . KORBENFELDP. KOZUCHM. KRAHNJ. KUGLERD. LAHERUJ. LANGREHRS. LEBELA. LEEB. LESPERANCER. LIM W. LOFTERSC. LOHRISCHR. LUYUNS. MADAJEWICZA. MAKSYMIUKI. MALIKA. MARAVEYASC. MARTINL. MARTINC. MATHIAST. MAUGHAN

L. MAURERM. MCCRYSTALJ. MEHARCHANDB. MELOSKYM. MICELIM. MIDDLETON D MINTZER M. MOOREM. MULLANER. MUNDISA. MURADP. MURAWAR. MYERSI. OLIFFI. OLVERY. ONGD. OSBORNA. OZAS. PALMERIF. PARNISM. PATRANM. PFREUNDSCHUHB. PIERCEJ. POLIKOFFA. POSTERAROT. PRINCED. PROPPERY. RAHIMN. RAJAP. RATHJ. REYES-VIDALP. ROBERTSONJ. RODGERS. RORKES. ROSEWICZK. ROSSM. RUBINJ. RUBINS

H. RUECKLE-LANZJ. RUSSELLD. SALTERA. SCARFES. SEEBERA. SHANIL. SIUJ. SMITHR. SOOS. SPADAFORAB. STEINR. STEISS. STEMMERA. SULLIVANM. TAYLORM. THOMASP. THOMPSONA. TOMIAKD. TRENTC. TUDOR-ELIADEJ. VALLEM. VARELAM. VEEDERD. VILLAJ. VINHOLESD. WALDEJ. WASSERD. WECKSTEINL. WEINERB. WEINERMANR. WHITTOMS. WILLIAMSONI. WIZNITZERR. WOLFFR. WONGJ. ZALCBERGE. ZERVOSS. ZEUZEMH. ZIMBLER