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![Page 1: Clinical benefits with Tarceva combination therapy in pancreatic cancer Malcolm J. Moore Princess Margaret Hospital, University of Toronto.](https://reader031.fdocuments.in/reader031/viewer/2022032607/56649ed25503460f94be188c/html5/thumbnails/1.jpg)
Clinical benefits with Tarceva combination therapy in
pancreatic cancer
Malcolm J. MoorePrincess Margaret Hospital,
University of Toronto
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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
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Trends in the incidence of pancreatic cancer*
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Hong Kong
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Mumbai, India
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Sweden
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Kuwait
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Singapore Chinese
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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
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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
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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
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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)
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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)
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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
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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
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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)
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*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
*
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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)
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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)
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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)
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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)
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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
al p
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
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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
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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)
Su
rviv
al p
rob
abili
ty
1.00
0.75
0.50
0.25
00 6 12 18 24
Survival time (months)
Su
rviv
al p
rob
abili
ty
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
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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)
Su
rviv
al p
rob
abili
ty
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
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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)
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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
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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)
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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)
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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
0
Su
rviv
al p
rob
abili
ty
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
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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
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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
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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