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Temsirolimus, Interferon Alfa, Or Both For Advanced Renal-Cell Carcinoma

October 02, 2017

UroToday- Temsirolimus is a specific inhibitor of mTOR kinase a key component of intracellular signaling involved in cell proliferation. Via mTOR inhibition the drug hampers the translation of key proteins involved in cell cycle progression (cyclin D1, c-myc) and angiogenesis (HIF 1-alpha, HIF 2-alpha).

In the May 31st issue of the New England Journal of Medicine, Hudes and colleagues for the Global ARCC trial report the results of an international multicenter trial comparing temsirolimus (CCI-779) with or without interferon-alpha to interferon-alpha alone in the treatment of poor-risk metastatic renal cancer.

A total of 626 patients with metastatic renal cancer with poor risk features were randomized and received no previous therapy. Patients were required to fulfill 3 of 6 requirements for poor risk, including LDH > 1.5 x upper limit of normal, low hemoglobin, corrected calcium > 10 mg/dl, time from diagnosis to first treatment < 1 year, performance status 60-70, or multiple sites of metastasis. Accrual was closed in April 2005 after a growth time of 20 months. Two-thirds of patients had undergone cytoreductive nephrectomy.

Patients in the temsirolimus and TEMSR+IFN arms exhibited improved progression-free survival compared with the interferon arm with a median time to progression of 3.7 months versus 1.9 months (p =0.0001). Treatment with temsirolimus alone was associated with a statistically significant improvement in survival (hazard ratio 0.73, 95% CI 0.57 to 0.92, p = 0.0069) which was not seen in the TEMSR+IFN arm. The median survival for patients in the temsirolimus arm was 10.9 months, compared with 8.4 months in the combination arm and 7.3 months in the interferon arm (49% difference).

Grade 3-4 toxicities in the TEMSR arm included asthenia (12%), nausea (4%), dyspnea (9%), with 24% of patients exhibiting hypercholesterolemia (all grades). Toxicity was slightly higher for patients in the TEMSR + IFN arm for asthenia (30%), dyspnea (11%), and hypercholesterolemia (27%, all grades). Only 23% of patients in the TEMSR arm required dose reduction, compared with 40% and 52% in the interferon and TEMSR+IFN arms, respectively.

This well-conducted multicenter study demonstrated that temsirolimus was better tolerated than interferon with a 16% reduction in grade 3-4 adverse events. With these data, it is a matter of time before the FDA approves temsirolimus monotherapy as first line therapy for metastatic renal cancer with high risk features.

Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IGH, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ

N Engl J Med. 356(22):2271-81. May 31, 2007
Reported by UroToday Contributing Editor Ricardo F. Sánchez-Ortiz, MD

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