Lloyd, R

4043 Background: Systemic treatment options for progressive metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express the epidermal growth factor receptor (EGFR). Gefitinib, a small-molecule inhibitor of the EGFR tyrosine kinase, has been shown to inhibit the growth of NET cell lines. Methods: Eligibility criteria included: radiographic progression by RECIST criteria, ECOG PS ≤ 2, ≤ 1 prior chemotherapy, and good organ function. Prior interferon and prior or concurrent octreotide (if disease progression documented on stable dose) were allowed. Pts received gefitinib 250 mg po daily. We evaluated 6 month (mos) progression-free survival (PFS) in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. 6 mos PFS rates of 30% (CT) and 10% (ICC) were considered promising. Results: 96 pts were enrolled: (57 CT, 39 ICC). For pts evaluable for the primary endpoint, 23 of 38 (61%) CT pts and 9 of 29 (31%) pts with ICC were progression-free at 6 mos. 1 PR and one minor response (MR = 20–29% decrease in sum of target lesion diameters) were observed in 40 CT pts; 2 PR and 1 MR in 31 ICC pts. In addition, 32% (12/38) of CT and 14% (4/29) of ICC pts had stable disease on study for a duration that exceeded by at least 4 months the time to progression documented prior to study entry. Grade 3–4 toxicity was infrequent with fatigue (6%), diarrhea (5%) and rash (3%) most common. Evaluation of markers of the EGFR pathway on tumor tissue will be presented. Conclusions: Gefitinib is well-tolerated and results in prolonged disease stabilization in pts with prior documented objective progression of CT and ICC, with rare objective responses. Supported by NOI CM17104. No significant financial relationships to disclose.

4504 Background: Treatment options for metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor receptor-β (PDGFR-β). Sorafenib, a small-molecule inhibitor of the VEGFR-2 and PDGFR-β tyrosine kinase domains, is a rational targeted therapy to evaluate in NET. Methods: Eligibility criteria included: ECOG PS = 2, = 1 prior chemotherapy, good organ function and signed informed consent. Prior interferon and prior or concurrent octreotide at a stable dose were allowed. Pts unable to take oral medications, with uncontrolled hypertension or with symptomatic coronary artery disease were excluded. Pts received sorafenib 400 mg po BID. Primary endpoint was response by RECIST in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. Results: 93 pts were enrolled: (50 CT, 43 ICC). For pts evaluable for the primary endpoint, 4 of 41 (10%) CT pts and 4 of 41 (10%) ICC pts had a PR. There were 3 minor responses (MR = 20–29% decrease in sum of target lesion diameters) in CT pts and 9 MRs in ICC pts for PR+MR rate of 17% for CT pts and 32% for ICC pts. For pts evaluable, 6-month progression-free survival was observed in 8/20 CT and 14/23 ICC pts. Grade 3–4 toxicity occurred in 43% of pts, with skin (20%), GI (7%) and fatigue (9%) most common. Translational studies from tumor tissue will be presented. Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade = 3 toxicity. Supported by NOI CM6225. No significant financial relationships to disclose.

Background. Hepatitis C virus (HCV) nondetectability in the liver may predict a sustained viral response (SVR) in patients with an end of treatment response. HCV RNA can be detected in liver tissue by in situ hybridization (ISH).Aim. To determine if HCV nondetectability in liver allografts by ISH can predict SVR in patients who cleared virus serologically on treatment.Methods. Twenty five patients with undetectable serum HCV on Interferon/Ribavirin therapy for HCV recurrence post liver transplant (LT) were studied. All had biopsies at 4 months post LT (baseline) and follow up with HCV ISH analysis performed.Results. 10 were ISH positive (group 1); 15 were ISH negative (group 2). Groups 1 and 2 had similar patient, donor, and viral characteristics at LT, as well as treatment duration at the time of the ISH assayed liver biopsy (13±16versus10±4monthsP= .24). However, group 1 had longer total treatment duration (24±10versus14±5months,P= .001). Eight (80%) group 1 and 9 (60%) group 2 patients achieved SVR. Mean grade and stage (modified Ishak score) were similar at 4 months, however, group 1 had higher grade (3±1.7versus1.6±1.3,P= .039) and stage (1.4±1.4versus0.5±0.6,P= .084) on the ISH assayed biopsy, after similar post LT intervals (23±10versus24±12months,P= .91).Conclusion. Allograft HCV ISH nondetectability does not predict SVR in treatment responsive HCV recurrence, but is associated with less severe histologic disease.