Graham Cohen

PURPOSE: Vandetanib is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The antitumor activity of vandetanib monotherapy or vandetanib with paclitaxel and carboplatin (VPC) was compared with paclitaxel and carboplatin (PC) in previously untreated patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: All NSCLC histologies and previously treated CNS metastases were permitted in this partially blinded, placebo-controlled, randomized phase II study. Patients were randomly assigned 2:1:1 to receive vandetanib, VPC, or PC. Progression-free survival (PFS) was the primary end point, and the study was powered to detect a reduced risk of progression with VPC versus PC (hazard ratio = 0.70; one-sided P < .2) and to demonstrate noninferiority for vandetanib versus PC. Overall survival was a secondary assessment. RESULTS: The risk of progression was reduced for patients receiving VPC (n = 56) versus PC (n = 52; hazard ratio = 0.76, one-sided P = .098); median PFS was 24 weeks (VPC) and 23 weeks (PC). The vandetanib monotherapy arm (n = 73) was discontinued after a planned interim PFS analysis met the criterion for discontinuation (hazard ratio > 1.33 v PC). Overall survival was not significantly different between patients receiving VPC or PC. Rash, diarrhea, and hypertension were common adverse events; no pulmonary or CNS hemorrhage events required intervention. CONCLUSION: VPC could be safely administered to patients with NSCLC, including those with squamous cell histology and treated brain metastases. Compared with the PC control arm, patients receiving VPC had longer PFS, meeting the prespecified study end point, whereas those receiving vandetanib monotherapy had shorter PFS.

Carcinoma of unknown primary (CUP) site accounts for approximately 6.5% of all cancers. Optimal therapy for patients with CUP has not yet been delineated. The current study was undertaken to evaluate response, time to treatment failure and survival in patients with CUP treated with a combination regimen comprising mitomycin C, epirubicin and cisplatin (MEP) versus mitomycin C alone (MITOC). Eighty-four patients with CUP were randomised to receive either the combination (MEP) or MITOC. Both treatment arms were well matched for age, gender, performance status, dominant site and number of disease sites. Eighty of the above patients were evaluable. Twenty patients (50%) treated with MEP responded to treatment compared with 7 (17%) who received MITOC. Grade III-IV hemopoietic toxicity was documented in 2 patients treated with MEP and no patients treated with MITOC. A single patient treated with MEP developed grade I peripheral neuropathy. Median time to treatment failure was 4.5 months for patients receiving MEP as opposed to 2 months for those receiving MITOC (p = 0.05). Median survival was 9.4 months in patients treated with MEP compared to 5.4 months in those receiving MITOC (p = 0.05). This study indicates that the addition of cisplatin and epirubicin to MITOC results in a significant improvement in the response rate, time to treatment failure and survival in patients with adenocarcinoma of unknown primary site.