Abstract LB-226: mTOR inhibition by Temsirolimus as second-line treatment for advanced RCC: The Medical optimization of Torisel® (MoTOR) phase II trial by the Italian Kidney Cancer Group (GIR)
Authors: Michele Milella, Alessandra Felici, Giuseppe Di Lorenzo, Michele Aieta, Raffaele Ardito, Corrado Boni, Ermanno Rondini, Enrico Aitini, Eugenio Villa, Giovanni Lo Re, Renato Algeri, Paolo Foa, Domenico Amoroso, Luca Moscetti, Michele Gallucci, Diana Giannarelli, Sabino De Placido, Francesco Cognetti
Journal: Cancer Research (2012)

Abstract Background: The mammalian target of rapamycin (mTOR) kinase is an essential regulator of growth and response to hypoxic and metabolic stress and a well-established therapeutic target in renal cell carcinoma (RCC). The mTOR inhibitor Temsirolimus (CCI-779, Torisel®) is the first-line treatment of choice for RCC patients with poor-risk features. Preclinical and clinical evidence indicates that mTOR inhibitors may be effective in controlling RCC growth, even after resistance to agents targeting the VEGF/VEGFR axis ensues. Thus we designed a multicenter phase II trial to assess the activity and safety of Temsirolimus as II-line treatment for advanced RCC patients (pts). Methodology: This was an open-label, multicenter, phase II trial of Temsirolimus (25 mg/wk i.v.), administered to advanced RCC pts with documented progression after I-line treatment. Primary endpoint was PFS rate at 6 mos. Tumor response was assessed every 8 wks. Considering a 6-mo PFS rate of 20% unacceptable (p0=20%) and a 6-mo PFS rate of 40% (p1=40%) of interest, a minimum targeted accrual of 47 pts in the sunitinib-pretreated group was to be pursued in order to reach 90% power at a significance level of 5%. Pts who underwent any other I-line treatment were allowed on study until the target accrual in the sunitinib-pretreated group was met. Results: From May 2009 to January 2012, 76 pts were enrolled (median age: 67 yrs, range: 36-86; M/F: 58/18; ECOG PS 0/1/2: 51/19/6); I-line therapy included sunitinib (60 pts), bevacizumab (8), sorafenib (3), cytokines (2), or other (3). With 18/57 evaluable patients free from progression at 6 mos in the sunitinib-pretreated group the primary endpoint was met. Median PFS was 4.0 mos (95% CI: 2.7-5.3) and 4.6 mos (95% CI: 2.8-6.5) in the overall (n=71) and sunitinib-pretreated (n=57) populations, respectively; OS in the same groups was 13.7 mos (95% CI: 9.1-18.3) and 14.6 mos (95% CI: 8.9-20.3), respectively. Six out of 71 pts (8%) had PR and 33/71 (46%) had SD as their best response. Toxicity (n=68) was mild with G3 anemia, neutropenia and thrombocytopenia in 2, 1, and 1 pts, respectively; G3 hyperglycemia and G3 hypertriglyceridemia in 2 and 7 pts, respectively; G4 hypercholesterolemia in 2 pts; G3 stomatitis in 5 pts; G3 asthenia in 3 pts; G3-4 pulmonary toxicity in 2 pts; G3 diarrhea in 2 pts; G3 cutaneous rash in 1 pt. Only 1 hypersensitivity reaction occurred during Temsirolimus infusion. Treatment compliance was good, with &amp;lt;10% of weekly administrations omitted and 15/67 (22%) pts requiring dose reductions (to 20 mg/wk and 15 mg/wk in 11 and 4 pts, respectively). Mean number of weekly administrations received was 15. Conclusions. Temsirolimus is an active and well-tolerated II-line treatment for advanced RCC, particularly in sunitinib-pretreated pts, and may constitute a suitable therapeutic option in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-226. doi:1538-7445.AM2012-LB-226