Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action

Abstract

Few types of cancer have had their treatment evolve as rapidly as metastatic renal cell carcinoma (mRCC). Since 2005, six new targeted therapies with proven efficacy have been approved for the treatment of mRCC. The downside is that our knowledge about the mechanisms of action of these therapies and the intrinsic and extrinsic mechanism of resistance has not evolved equally fast, and many questions remain unanswered. The only approved agent to date in the European Union for patients who progress on sunitinib or sorafenib is everolimus. The results of the phase III trial comparing axitinib vs. sorafenib after failure on sunitinib, bevacizumab, temsirolimus, or cytokines have recently been published, and axitinib has recently been licensed by the Food and Drugs Administration. Other phase III trials that are being conducted include a comparison between everolimus plus bevacizumab and everolimus after failure on tyrosine kinase inhibitors, and between temsirolimus and sorafenib after failure on sunitinib. In this article, we will review the available evidence from clinical studies on sequential therapy for mRCC, including those that are still in progress. In addition, information on the mechanism of resistance or tolerance to first-line therapy, recommendations of the main practice guidelines for second-line treatment, potential therapies for third or successive treatment lines, and the major reasons why patients who progress may benefit from a change of mechanism of action will also be discussed.

Changing Mechanisms of Action as a Strategy for Sequential Targeted Therapy of Metastatic Renal-Cell Carcinoma

“…Research of the mechanisms of resistance is very important in planning the development of new targeted agents [3,23,24]. Most of information about drug resistance in mRCC known today is from the preclinical studies or studies on patients with different types of cancer, where targeted therapies are being in clinical practice for longer time (e.g.…”

“…breast cancer). This is partially due to the rapid approval of targeted agents in mRCC which surpassed understanding of the mechanisms of response and resistance [3].…”

“…Responses to second line cytokine therapy were modest. Fewer than 4% of patients had partial response and < 12% had stable disease [2,3].…”

“…Better treatment results in the first line therapy are allied to the better outcome of the patients on subsequent lines of treatment. Prognosis of patients improved and mRCC is becoming more a chronic type of disease, rather than a rapidly progressing and fatal one [3].…”

“…Patients on targeted therapies progress some time during their treatment and mRCC is considered an incurable disease [4]. In trying to overcome this, the mechanism of action and especially mechanisms of resistance to targeted therapies, need to be studied and explained even more in detail [3][4][5][6][7].…”