Temsirolimus for advanced renal cell carcinoma

Abstract

Renal cell carcinomas (RCCs) represent one of the ten leading cancer entities with an increasing incidence especially in the western world. Unfortunately, about 25% of the patients develop metastatic RCC (mRCC) associated with a most unfavorable prognosis. In the recent years, various new agents targeting VEGF or VEGF receptor (VEGFR) or the mTOR pathway have been approved for the treatment of mRCC with significant prolongation of progression-free survival and, in part, of overall survival (OS). Targeting the mTOR kinase is an interesting option for mRCC. Temsirolimus, one of the available mTOR inhibitors, has been approved as a single agent in poor-risk mRCC patients based on the pivotal Phase III trial showing a significant superiority in OS versus IFN-α or temsirolimus + IFN-α, which has been verified by a pivotal Phase III trial. The benefit has been shown for clear cell carcinoma and papillary RCC as well. For poor prognosis patients, temsirolimus improves median survival by 3.6 months. In second-line treatment compared with sorafenib following first-line treatment with sunitinib temsirolimus showed a relative progression-free survival benefit for patients with nonclear cell RCC with temsirolimus. The median OS for the temsirolimus group was 12.27 and 16.64 months for the sorafenib group. In 2007, the US FDA granted approval for temsirolimus for the treatment of advanced RCC.

A Randomized Phase IIa Trial with Temsirolimus versus Sunitinib in Advanced Non-Clear Cell Renal Cell Carcinoma: An Intergroup Study of the CESAR Central European Society for Anticancer Drug Research-EWIV and the Interdisciplinary Working Group on Renal Cell Cancer (IAGN) of the German Cancer Society

“…Regarding different risk subgroups, ASPEN especially indicated a benefit for VEGF-TKI therapy in patients with good or intermediate risk according to MSKCC criteria (PFS 14 vs. 5.7 months in good risk and 6.5 vs. 4.9 months in intermediate risk patients) compared to everolimus. However high-risk patients according to MSKCC criteria showed a better PFS with everolimus (4.0 vs. 6.1 months, HR 0.3) [9]. Taken together, the three studies support a superiority of SUN to mTOR inhibitors as everolimus or TEM in nccRCC.…”

“…Since nccRCC are excluded from most kidney cancer studies, their optimal treatment is yet not defined. Reports on mTOR inhibitors in RCC have proven a benefit for TEM compared to interferon-α (IFN) [9, 13]. The subgroup analysis of the ARCC study showed a comparable mOS for ccRCC and nccRCC patients receiving TEM, whereas nccRCC patients with IFN had a significantly shorter mOS and a lower ORR than nccRCC patients [13].…”

Welche Chancen bietet die Immunonkologie für ein indikationsübergreifendes Langzeitüberleben?

“…Zu einer deutlichen Verbesserung der Prognose (verlängertes progressionsfreies Überleben) kam es allerdings erst mit der Etablierung von anti-angiogenetisch wirksamen Tyrosinkinase- sowie mTOR-Inhibitoren im Therapiealgorithmus des metastasierten RCC [38,39,40]. Stratifiziert nach den Risiken für eine günstige, mittlere bzw.…”

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“…3 However, due to dose-limiting side effects, the effective concentration of TEM in target tissues is not high enough, and systemic administration has considerable toxic and side effects, thereby affecting the prognosis of RCC. 4 As a result, safer and more effective targeted therapies continue to be demanded in clinical treatment to increase the effective drug concentration in specific target tissues, thereby improving the treatment efficacy and reducing side effects. The targeted drug delivery system (TDDS) is a possible approach to solve this problem.…”