Phase IIA Trial Testing Erlotinib as an Intervention Against Intraductal Pancreatic Mucinous Neoplasms

Intraductal Papillary Mucinous Neoplasms (IPMNs) are a distinct type of precursor lesion that causes ~5% of pancreatic adenocarcinoma[1, 2]. Four year survival rates of 40-75% are reported [3-7]. There is currently no chemotherapy specifically approved for treating IPMNs. The number of IPMN cases has significantly increased over the last decade[8].

Erlotinib (Tarceva©) is an orally active Epidermal Growth Factor Receptor (EGFR) inhibitor. Combined Erlotinib/gemcitabine therapy improves overall survival and progression-free survival vs. gemcitabine alone in pancreatic adenocarcinoma patients[9]. However, whether Erlotinib and its active metabolite achieve therapeutic levels in pancreatic tissue has never been evaluated. Pre-clinical work shows that epidermal growth factor receptor (EGFR) is important in IPMN tumorigenesis [10, 11]. To test whether EGFR inhibition is efficacious in the treatment of IPMNs, we performed a Phase IIA observational single-arm study of Erlotinib 100 mg/day in patients with IPMNs (ClinicalTrials.gov Identifier NCT00482625). The primary hypothesis was that Erlotinib decreases tumor protein levels of MUC5AC, a biomarker of activated EGFR, which is highly expressed in IPMNs[12, 13] (Supplemental Figure 1). Secondary outcomes included safety in IPMN patients and pharmacokinetics in pancreatic tissue. The latter would be consistent with the proposed mechanism of action that Erlotinib acts intrinsically on the IPMN cells, rather than through an indirect mechanism such as activation of immune surveillance. Inclusion/exclusion criteria for patient selection are in Supplemental Table 1. Participants were required to have pre- treatment IPMN EUS-FNA core biopsy tissue for comparison with post-treatment tissue. All patients underwent endoscopic ultrasound using a GF-UC160P curvilinear array echoendoscope with Prosound Alpha 10 ultrasound processor. FNA of solid lesions used a 22g EchoTip needle and 10ml of negative suction. IPMN cell blocks were fixed, embedded in paraffin and processed in the same manner as post-surgical specimens. Participants received 100mg Erlotinib for 21-42 days before their scheduled surgical IPMN resection. After partial pancreas resection, pre- and post-treatment IPMN MUC5AC protein levels were compared. Resected pancreatic tissue was also used to quantify pharmacokinetics of Erlotinib and OSI-420, its major active metabolite, which had not previously been performed. Six participants were enrolled, 5 were treated with Erlotinib 100mg for 21-42 days and 4 completed the trial and had pre and post-treatment tissue for analysis. One participant, a 54yo Caucasian male who presented with abdominal pain and had an IPMN 3cm low density mass in head of pancreas (Supplemental Figure 2) had a complete clinical response, as assessed by pre-treatment CT scan and post-resection pathological analysis of the resected pancreas. No mass lesion consistent with residual IPMN was present at resection, however residual carcinoma-in-situ was identified in the resected specimen. As a result, there was insufficient post-treatment tissue for evaluation of post-treatment MUC5AC protein levels. Importantly, the patient remains in complete remission 2.5 years after erlotinib neoadjuvant therapy and surgery. Three patients had usable tissue samples for pre- and post-Erlotinib treatment analysis of MUC5AC. Immunohistochemistry for MUC5AC showed a reduced number of positive IPMN cells and staining intensity in 2 of 3 patient matched tissue comparisons (Figure 1). For the third, pre-treatment biopsy tissue was insufficient for analysis and not scored.

Figure 1.

H+E and MUC5AC Immunohistochemistry on pre and post-Erlotinib pancreatic specimens. IPMN tissue is indicated by the arrow. DUO, normal duodenal epithelium in section.

Pharmacokinetics of pancreatic Erlotinib were performed in 4 participants (Supplemental Table 2) Concentrations were determined in matched plasma and pancreatic tissue by HPLC-MS/MS as previously described[14]. Erlotinib (OSI-774) and its major active metabolite (OSI-420) were detected in pre-op plasma and post-resection pancreas. These data are consistent with a direct mechanism EGFR inhibition by Erlotinib in pancreatic adenocarcinoma and IPMN, rather than indirect mechanisms. The highest plasma and pancreatic tissue concentrations (plasma 754ng/dl and pancreatic tissue 360ng/ml) were in the participant with the complete clinical response. The pancreatic tissue Erlotinib concentration was more than 4 times vs. the lowest concentration. The concentration of major active metabolite OSI-420 almost double that of the lowest concentration sample.

No patient terminated the trial early and no unanticipated Grade 3-4 adverse events were reported. In particular, no significant issues with Grade 3-4 rash were noted. One patient had a Grade 1 acneiform rash. Two patients Grade 1 dry skin, two had Grade 1 decreased appetite, one had Grade 1 headache, one had Grade 2 diarrhea, one had Grade 1 insomnia. Overall, 100mg Erlotinib was well tolerated by patients and no unanticipated drug related adverse events seen. The one participant with Grade 2 rash also had the highest pancreatic tissue Erlotinib and OSI-420 levels and the complete clinical response.

This study was limited by the number of evaluable trial participants and does not allow definitive conclusions as to the primary hypothesis that 100mg Erlotinib reduces IPMN MUC5AC protein levels. Our results show that of 4 participants who completed the protocol, 3 had evaluable tissue. Of these 3 participants with evaluable tissue, two of three had reduced MUC5AC levels, consistent with a reduction of activated EGFR in IPMN. One of three evaluable participants had a complete clinical response with only microscopic disease detectable after Erlotinib. This participant also developed Grade 2 rash and had the highest serum and pancreatic concentrations of Erlotinib and its active metabolite OSI-420.

There is currently no approved medical therapy to treat IPMN. Because of this, there is great variance in the standard of care for IPMNs. Some US centers approach any pancreatic mass (including adenocarcinomas, IPMNs, neuroendocrine tumors, mucinous cystic neoplasms and other tumor types) as potentially harboring malignancy and resect the entire pancreas without pre-diagnostic biopsy. At the other end, based on the same literature, other centers perform watchful waiting only. Overall, our data are consistent with potential efficacy of Erlotinib in the treatment of IPMNs and revealed no unforseen safety issues in IPMN patients. These data support further investigation of Erlotinib and other EGFR inhibitors for the treatment of IPMNs in larger, multi-center trials.