The use of sunitinib in renal cell carcinoma: where are we now?

Abstract

Sunitinib malate (Sutent™) is an inhibitor of multiple protein tyrosine kinases that shows antitumor and antiangiogenic activities. In a randomized Phase III trial of treatment-naive patients with metastatic renal cell carcinoma (mRCC), patients treated with sunitinib showed a significant improvement in progression-free survival compared with those treated with IFN-α. Sunitinib also exhibited antitumor activity in unselected RCC patients, including those with who were refractory to treatment, had non-clear cell histology brain metastases, or an Eastern Cooperative Oncology Group performance status >1. Typical side effects of sunitinib malate are fatigue, asthenia, diarrhea, skin rash, stomatitis, hand–foot skin syndrome, hypothyroidism and hematological abnormalities. Hypertension, other toxicities may serve as biomarkers for improved clinical outcomes in sunitinib treatment. Currently, sunitinib remains the gold standard of care in the treatment of mRCC.

Keywords::

• biomarker
• clear cell cancer
• renal cell cancer
• SU11248
• sunitinib
• tyrosine kinase
• VEGF

Acknowledgements

C Szczylik and AM Czarnecka have been supported with National Science Centre projects 2011/01/B/NZ5/02822 and the Foundation for Polish Science TEAM project TEAM/2010-6/8. AM Czarnecka was supported with National Science Centre UMO-2012/05/D/NZ5/01844 and Foundation for Polish Science SKILLS-Mentoring programme.

Financial & competing interests disclosure

C Szczylik1 received consulting fees and lecture fees from Pfizer, Bayer HealthCare, Astellas, GlaxoSmithKline, and Novartis. AM Czarnecka received lecture fees from Pfizer, GlaxoSmithKline, Novartis, Merck, Vipharm and Roche. B Rini has been a consultant and received research founding for Pfizer, Amgen and GlaxoSmithKline.

No writing assistance was utilized in the production of this manuscript.

Key issues

• In a randomized Phase III trial of metastatic clear cell RCC patients, the progression-free survival of those treated with sunitinib malate was significantly improved compared with those treated with IFN-α.

• Sunitinib malate was effective when used as a second-line treatment after cytokine therapy, and it may also be effective after treatment with the tyrosine kinase inhibitor sorafenib.

• The clinical activity of sunitinib malate has been demonstrated in other metastatic renal cell carcinoma patient populations, including patients with nonclear cell histology, brain metastases and an Eastern Cooperative Oncology Group performance status >1.

• Sunitinib malate should be used as first-line therapy rather than mTOR inhibitors, which should not be used as first-line treatment.

• Although some trials are ongoing, sunitinib malate is currently not recommended as adjuvant or neoadjuvant treatment.

• Sunitinib malate rechallenge may be considered as this showed potential benefits in increasing progression-free survival.

• Administering sunitinib malate in alternative schedules (including 2/1) may mitigate adverse events while achieving outcomes comparable to those of the traditional 4/2 schedule.

• Toxicities should be managed to maintain the clinical benefit of the drug and avoid significant decreases of dose intensity.

• Some AEs may identify patients with inherent pharmacokinetic and pharmacodynamic characteristics that predispose to clinical benefit, with hypertension and hypothyroidism associated with improved clinical outcomes (progression-free survival/overall survival).

• Although there are many potential biomarkers under investigation, their clinical applications in the prognostic or predictive assessment of metastatic renal cell carcinoma patients treated with sunitinib malate have not yet been validated.