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 anti-proliferative activity 6. OSI-420 is the major metabolite of erlotinib. 1 Yamanka et al. Anticancer Res 13:565-9, 1993 2 Ueda et al. Pancreas 29:e1-8, 2004 3 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

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

Schema Continue Erlotinib 150 mg/d Rash Cycle 1, Days 1-14 Archival Tissue EGFR IHC, Kras mutation Continue Erlotinib 150 mg/d Rash Cycle 1, Days 1-14 Erlotinib 150 mg/d Intrapatient dose Escalation to rash Increase erlotinib by 50 mg/2wks until Rash, max 300mg/d No Rash Trough Erlotinib PK All patients Baseline, Cycle 1 D 15, Cycle 2 D 1 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 (1-15). 3 pts never took study drug 48 pts evaluable for toxicity, TTP, and OS. 38 pts evaluable for response

Patient Characteristics Number of pts (n=51) Median Age (Range) 62 (37-79) Female:Male 26:25 ECOG 0:1:2 5:42:4 Locally advanced:Metastatic 6:45 Prior gemcitabine None: adjuvant : with RT: palliative 2:16:5:33 Dose escalation Erlotinib 200mg:250mg:300mg 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 P value 0.08 0.04 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) Number of pts Percent (95% CI) Partial response 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) All Grades Grade 3/4 # 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 Nausea 8 16.7 Anorexia Dry skin 7 14.6 Pruritis

Treatment related adverse events continued All Grades Grade 3/4 # pts % ALP increased 7 14.6 1 2.1 Hypoalbuminemia 2 4.2 Vomiting Anemia 6 12.5 Lymphopenia Mucositis 5 10.4 Hypocalcemia 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 FECS-AACR-ASCO Methods in Clinical Cancer Research