Download ASCO_2009_files/Tang Erlotinib PC ASCO 2009

Phase II trial of erlotinib in
advanced pancreatic cancer
P.A. Tang 1,4, S. Gill 2, H. J. Au 3, E. X. Chen 1, D. Hedley 1,
M. Leroux 1, L. Wang 1, M. J. Moore 1
Princess Margaret Hospital, Toronto, Canada1; BC Cancer
Agency, Vancouver, Canada 2; Cross Cancer Institute,
Edmonton, Canada 3, Tom Baker Cancer Centre, Calgary,
Canada 4
Disclosures: Drs Tang and Moore received research
funding from OSI Pharmaceuticals
Background
• The epidermal growth factor receptor (EGFR) is commonly
over-expressed in pancreatic cancer and over-expression
is associated with a poor prognosis 1-3
• Erlotinib, an oral EGFR tyrosine kinase inhibitor, has
antitumor activity in pancreatic cancer in preclinical
models4, and clinically in combination with gemcitabine 5
• Based on preclinical animal models, erlotinib
concentrations of 500 ng/mL have been estimated to
provide sufficient EGFR inhibition to lead to antiproliferative activity 6. OSI-420 is the major metabolite of
Yamanka et al. Anticancer Res 13:565-9, 1993
erlotinib.
1
2
Ueda et al. Pancreas 29:e1-8, 2004
Tobita et al. Int J Mol Med 11:305-9, 2003
4 Ng et al. Mol Cancer Ther 1:777-83, 2002
5 Moore et al. J Clin Oncol. 1960-6 , 2007
6 Hidalgo et al. J Clin Oncol 3267-79, 2001
3
Background
• Clinical benefit from erlotinib correlates with
a dose-dependent skin rash 1
• The purpose of this phase II trial was to
determine the efficacy of erlotinib dosed to
achieve rash in pts with advanced
pancreatic cancer (PC) who had progressed
on or were unable to tolerate gemcitabine
based chemotherapy
1
Wacker et al. Clin Cancer Res 3913, 2007
Key eligibility criteria
• Locally advanced or metastatic PC
• Progressed on or unable to tolerate
gemcitabine
• Measurable disease (RECIST)
• Adequate hematological, renal, hepatic
function
• No prior treatment with EGFR inhibitors
permitted
Archival Tissue
EGFR IHC, Kras mutation
Schema
Continue Erlotinib
150 mg/d
Rash
Cycle 1, Days 1-14
Erlotinib 150 mg/d
No Rash
Trough Erlotinib PK All patients
Baseline, Cycle 1 D 15, Cycle 2 D 1
Intrapatient dose
Escalation to rash
Increase erlotinib by
50 mg/2wks until
Rash, max 300mg/d
Trough Erlotinib PK
Dose escalation pts only
Cycle 2, d 22
Statistical Considerations
• Two stage phase II trial, responses evaluated using
RECIST
• Primary endpoint: prolonged disease control = PR + SD >
8 wks
• α = 0.05; β = 0.10
• Stage I: If > 3/18 evaluable pts respond or have prolonged
SD (> 8 wks), proceed to stage II
• Stage II: accrue an additional 17 pts. If > 7/35 pts respond
or have prolonged SD, erlotinib considered active.
Results
• Between November 2006 and December
2008, 51 pts were enrolled from 5 Canadian
centres
• Pts received a median of 2 cycles, range (115).
• 3 pts never took study drug
• 48 pts evaluable for toxicity, TTP, and OS.
• 38 pts evaluable for response
Patient Characteristics
Characteristics
Median Age (Range)
Number of pts (n=51)
62 (37-79)
Female:Male
26:25
ECOG 0:1:2
5:42:4
Locally advanced:Metastatic
Prior gemcitabine
None: adjuvant : with RT: palliative
Dose escalation
Erlotinib 200mg:250mg:300mg
6:45
2:16:5:33
10
7:1:2
Pharmacokinetics
Trough concentrations of erlotinib and OSI-420
Erlotinib dose
Erlotinib concentration OSI-420 concentration
No escalation (n=24)
1244.0 + 877.4 ng/mL 1
174.0 + 184.0 ng/mL
Dose escalation (n=8)
873.4 + 281.4 ng/mL 2
88.8 + 48.3 ng/mL
0.08
0.04
P value
1
6 pts had an erlotinib concentration below 500 ng/mL
2 1 pt had an erlotinib concentration below 500 ng/mL
There was wide inter-patient variability with respect to erlotinib and OSI-420
trough concentrations.
Trough concentrations of erlotinib
No escalation
Dose escalation
Line denotes 500 ng/mL
Trough concentrations of OSI-420
No escalation
Dose escalation
Results
Best response to erlotinib (n=38)
Response
Number of
pts
Percent
(95% CI)
Partial response
0
0
Stable disease
Prolnoged stable disease (> 8 wks)
13
10
34 (19-49)
26 (12-40)
Progressive disease
25
66
13 pts were inevaluable
Dose escalation 10 pts: 2 inevaluable, 3 PD, 5 SD (3 prolonged SD range 12-31 wks)
Median TTP was 1.61 mo (95% CI: 1.58-2.11)
Medial OS was 4.08 mo (95% CI: 3.16-6.68)
Kaplain meier curve of time to progression
Kaplain meier curve of overall survival
Treatment related adverse events (CTC AE v 3.0)
Adverse Event
All Grades
Grade 3/4
# pts
%
# pts
%
Rash
40
83.3
2
4.2
Diarrhea
21
43.8
3
6.3
AST increased
11
22.9
1
2.1
Fatigue
10
20.8
1
2.1
Nausea
8
16.7
0
0
Anorexia
8
16.7
0
0
Dry skin
7
14.6
0
0
Pruritis
7
14.6
0
0
Treatment related adverse events continued
Adverse Event
All Grades
Grade 3/4
# pts
%
# pts
%
ALP increased
7
14.6
1
2.1
Hypoalbuminemia
7
14.6
2
4.2
Vomiting
7
14.6
0
0
Anemia
6
12.5
1
2.1
Lymphopenia
6
12.5
1
2.1
Mucositis
5
10.4
0
0
Hypocalcemia
5
10.4
0
0
Grade 3+ Treatment related AEs in 1 pt each: Bilirubin increased, cecum perforation,
lower GI bleed, renal failure, hypokalemia
Correlation between rash and
stable disease
• The presence of grade 2+ rash was
associated with stable disease (p = 0.018)
Conclusions
• Erlotinib is associated with prolonged stable
disease in a subset of patients with
advanced refractory pancreatic cancer
• Grade 2 + rash was associated with disease
control
• Dose escalation in the absence of toxicity is
feasible and safe
• Wide inter-patient variability was observed
in erlotinib trough levels
Acknowledgements
• Trial was supported by OSI Pharmaceuticals
Inc.
• This protocol was developed at the FECSAACR-ASCO Methods in Clinical Cancer
Research