New Drugs Bring New Questions

September 1, 2007

The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease. In particular, the hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) signal transduction pathway have been exploited. Sunitinib malate (Sutent), sorafenib tosylate (Nexavar), bevacizumab (Avastin)/interferon alfa, and temsirolimus (Torisel) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways. Combinations and sequences of these agents are being evaluated. Other novel multitargeted tyrosine kinase inhibitors (pazopanib and axitinib) and mTOR inhibitors (everolimus) are in clinical development. Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC.

This article is a review of Evolving Role of Novel Targeted Agents in Renal Cell Carcinoma.

In this issue of ONCOLOGY, Hutson and Figlin provide a timely, cogent, and comprehensive review of recent major progress in the therapy of renal cell cancer with targeted agents.

Important Advances

In a little over 2 years, we have witnessed no less than four positive phase III randomized clinical trials of agents that impact pathways implicated in angiogenesis.[1-4] Each of these agents offers differing but overlapping mechanisms of action and variable but generally tolerable side effects. Each of the drugs sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), and bevacizumab (Avastin) have demonstrated a doubling of progression-free survival when compared to or added to what was considered standard therapy in variably but carefully selected populations of patients with renal cell carcinoma. In each of these trials, the side-effect profiles have been satisfactory, resulting in a net qualify-of-life stabilization or improvement.[5]

Importantly, two of these drugs (those for which we have mature data)-sorafenib and temsirolimus-demonstrate an overall survival benefit of around 3.5 months over standard care.[1,3,6] While this important principle has been validated in separate trials, we await follow-up in the studies involving sunitinib and bevacizumab to see if this will be further borne out.[2] In these latter trials, conducted after the availability of sorafenib, we may not see an overall survival advantage simply because patients in the control arm gained access to sorafenib, diluting the ability of the trial to determine a difference between the arms even if one really existed.

Evidence to support the potential for this effect comes from the crossover that occurred in the Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) trial, where 215 of 450 patients in the placebo arm switched to sorafenib after investigators demonstrated an impressive gain in progression-free survival.[6] Patients crossing over to sorafenib had similar responses and response duration to patients starting on the drug, with a resultant vectoral improvement in their survival as demonstrated by Kaplan-Meier analysis. This may be a testament to the effect of these agents as being relatively independent of timing in the progression of renal cell cancer-an important concept for those of us who are keen to test newer strategies in these patients, either before or after the use of this most recent wave of novel agents.

 Work Undone

As we enthusiastically use these new entities in an uncommon cancer that has previously proven a therapeutic miasma and see some success in other cancers such as hepatocellular carcinoma and gastrointestinal stromal tumor (GIST),[7,8] it is very important that we not lose sight of the work undone, questions unanswered.

First, while these drugs may produce significant periods of disease stability or nonprogression in up to 80% of patients, they are not-at least in the current monotherapeutic dosage schema-curative. This has implications for fiscal cost of therapy and adverse drug effects. It also means that there is little room for self-congratulatory navel-gazing and reinforces the need to seize the momentum from recent trials to do even better for renal cancer patients, by continuing to offer them clinical trials.

Second, the optimal dose of these agents has not been determined. A "one-dose-fits-all" strategy does not consider a paradigm of different body mass indices, varying metabolism, and differential end-organ responses related to tumor response and side effects.

Third, the optimal dose sequence for drugs has not been determined. While an excellent clinical and biochemical rationale exists for giving different Memorial Sloan-Kettering Cancer Center risk-level patients individual agents as first-line therapy, there is no consensus on sequences of treatment.[9] Switching from one of the currently available tyrosine kinase inhibitors to the other (eg, sorafenib to sunitinib and vice versa) can produce major clinical and radiologic improvement in patients who experienced disease progression on the first drug. This defies our standard paradigms for cancer treatment with classes of drugs, where development of resistance portends switching to another class and not returning to the failed class.

Soon we may be further "spoiled for choice" with at least another three agents being considered for regulatory approval, providing a further challenge for clinicians in deciding which agent and when, how much, how often, and for how long. Clinical and molecular factors predictive of differential outcome with each drug may eventually help us resolve some of these issues.[10,11]

 Conclusions

Targeted therapies have brought us much, especially in advanced renal cancer, where our scorecard had shown close to naught. We now have "debutante" drugs to challenge our art, but to make more substantive progress, we as oncologists will need to remain true to the science and answer the questions these new entities bring.

References:

1. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007.

2. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115-124, 2007.

3. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271-2281, 2007.

4. Escudier B, Koralewski P, Pluzanska A, et al: A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon-α2a as first-line therapy in metastatic renal cell carcinoma (abstract 3). J Clin Oncol 25(18S):2s, 2007.

5. Bukowski R, Cella D, Gondek K, et al: Effects of sorafenib on symptoms and quality of life: Results from a large randomized placebo-controlled study in renal cancer. Am J Clin Oncol 30:220-227, 2007.

6. Bukowski RM, Eisen T, Szczylik C, et al: Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis (abstract 5023). J Clin Oncol 25(18S):240s, 2007.

7. Abou-Alfa GK, Schwartz L, Ricci S, et al: Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:4293-4300, 2006.

8. Demetri GD, van Oosterom AT, Garrett CR, et al: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 368:1329-1338, 2006.

9. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289-296, 2002.

10. Bui MH, Visapaa H, Seligson D, et al: Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear cell carcinoma. J Urol 171:2461-2466, 2004.

11. Lam JS, Belldegrun AS, Figlin RA: Tissue array-based predictions of pathobiology, prognosis, and response to treatment for renal cell carcinoma therapy. Clin Cancer Res 10:6304S-6309S, 2004.