Efficacy of re-challenging metastatic renal cell carcinoma with mTOR inhibitors

Dear Editor,

mTOR inhibitors have been approved for treatment of metastatic renal cell carcinoma (MRCC) in first line (temsirolimus), or in second, or further line (everolimus), treatment after progression under VEGFR TKI (Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor) [1]. So far, by using different sequentially targeted agents (antiangiogenics and mTOR inhibitors), it has been possible to offer a clinical benefit for a long period of time. But, at some point, disease progression arises again, requiring a change in targeted drugs, in or pathway inhibition.

It has already been reported that patients with MRCC could be re-challenged with antiangiogenics, thus re-inducing a clinical benefit and even an objective response [2–4]. This may be an additional and useful proposition for treating patients.

We report here, for the first time, the case of a patient who was re-challenged with an mTOR inhibitor, inducing an objective response, after having previously received, and responded to, everolimus, and who had also previously received sunitinib (VEGFR TKI) and TKI258 (an oral multitargeted receptor tyrosine kinase VEGFR/PDGFR/FGFR inhibitor).

This 61-year-old patient had had a nephrectomy in July 2006 for pT3aN1M1, Furhman's grade 3, clear cell renal carcinoma. Due to lung metastases and retro-peritoneal lymph nodes, he was treated with sunitinib for one year but this was stopped due to progression. The patient was included in the RECORD-1 study receiving everolimus [1]. Treatment was followed for 33 months and a prolonged partial response was obtained [5]. At the time of pulmonary progression, he was treated in a TKI 258 study which re-challenged the antiangiogenic pathway [2], in addition to the FGFR pathway inhibition, but he progressed after four months of treatment. At time of progression, there was no standard and, considering both the efficacy seen in this patient with previous use of everolimus, and the reports on re-challenging with antiangiogenics [2–4], we decided to try the most active treatment for this patient again. He received everolimus again at the standard dose of 10 mg/d. It again induced a partial response according to RECIST criteria on lung and subcutaneous metastasis which was still present after five months. He did not experience any ≥ grade 2 toxicity, as was the case with the previous exposure [6].

This case illustrates that patients with MRCC may be sensitive to a particular previously efficient drug after a drug holiday, as has already been shown with VEGFR TKI, and as reported here for mTOR inhibitors. This clinical observation, along with others involving antiangiogenics [2–4], challenges the concept of “resistance” to targeted agents and should be considered as a transient insensitivity. More work in translational research is required to understand it.

Conflict of interest: Alain Ravaud:member of Global, European or French Boards in urological tumors and/or renal tumors for Pfizer, Novartis, Glaxo Smith Kline, Bayer Schering, Roche, Dendreon. Institutional grant support by Novartis and Pfizer. No conflict of interest for other co authors