GENITOURINARY CANCER

Targeting mTOR Produces Positive Results After VEGFr-TKI Therapy in Metastatic Renal Cell Carcinoma
Results from a randomized phase III trial of RAD001 (everolimus), an oral inhibitor of mTOR, an intracellular kinase that regulates cell proliferation and angiogenesis, versus placebo in 410 patients with metastatic renal cell carcinoma (RCC) after progression on VEGFr-TKI therapy (sunitinib, sorafenib, or both) demonstrate a significantly better PFS for patients receiving everolimus compared to those given placebo. The RCC had to have a clear cell component and both arms of the study received best supportive care (BSC) as well. An independent data monitoring committee recommended termination of the trial after interim results demonstrated the primary endpoint (PFS) was superior to placebo (HR=0.30, p<0.0001) with a median PFS of 4.0 months compared to 1.9 months for placebo.

Conclusion: RAD001 (everolimus) established clinical benefit and prolonged PFS with a favorable safety profile in this heavily pretreated patient population. We await the data on median OS.
LBA5026 R.J. Motzer, et al. J Clin Oncol 26: 2008

Tumor Vascular Disrupting Agents: Will They Play a Role in Hormone-Refractory Metastatic Prostate Cancer and Other Solid Tumors?
DMXAA (ASA404) is a novel small molecule tumor vascular disrupting agent (Tumor-VDA) that targets established tumor blood vessels causing apoptosis of tumor endothelial cells. It has synergistic anti-tumor effects in combination with cytotoxics, including taxanes in animal models. A randomized study in NSCLC reported a 5-month survival benefit when DMXAA was added to carboplatin plus paclitaxel. The randomized phase II study presented at ASCO evaluated efficacy and safety of DMXAA in combination with docetaxel in hormone-refractory metastatic prostate cancer (HRMPC). A prior report of this regimen quoted an increase in PSA response rate of 59% vs. 37% for docetaxel alone. This update involves patients with progressive metastatic disease and that have not been previously treated with cytotoxics. Efficacy endpoints include PSA response rate, RR, TTP, and median survival. 38 patients received docetaxel alone (control arm) and 33 patients received DMXAA plus docetaxel (DMXAA arm). 62.5% of patients in the DMXAA arm had at least a 30% reduction in PSA during the first 3 months of treatment compared to 47.4% of patients in the control arm. Response rates were 23.1% in DMXAA arm and 9.1% in the control arm. TTP was 7.3 months in the DMXAA arm and 6.9 months in the control arm.

Conclusion: Addition of the DMXAA to docetaxel was well tolerated and the data reported above support the previous PSA response findings in suggesting improved efficacy with a DMXAA + docetaxel combination compared to docetaxel alone. Further evaluation of DMXAA in HRMPC is warranted.
Abstract #5007 R. Pili, et al. J Clin Oncol 26: 2008