Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma.
Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. Median progression-free survival durations were 3.8 and 1.9 months, respectively, for patients treated with temsirolimus or IFN, and median overall survivals were 10.9 and 7.3 months, respectively. Exploratory analyses indicate that temsirolimus benefits those patients with metastatic RCC and multiple adverse prognostic factors regardless of tumor histology or nephrectomy status. Most adverse events that occur in patients receiving temsirolimus can be managed medically (eg, hyperglycemia, hyperlipidemia) or addressed by supportive measures (eg, stomatitis, rash). Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.
Hudes
Gary R
GR
Genitourinary Malignancies Program, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, USA. gary.hudes@fccc.edu
Berkenblit
Anna
A
Feingold
Jay
J
Atkins
Michael B
MB
Rini
Brian I
BI
Dutcher
Janice
J
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002986:Clinical Trials as Topic / Q000379:methods* / Q000639:trends; D018450:Disease Progression; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008954:Models, Biological; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus