Phase II trial of continuous once‐daily dosing of sunitinib as first‐line treatment in patients with metastatic renal cell carcinoma

Abstract

BACKGROUND: Sunitinib at 50 mg/day on the 4-weeks-on-2-weeks-off schedule is the current approved regimen for advanced/metastatic renal cell carcinoma (mRCC). Escudier et al reported that continuous, once-daily dosing with sunitinib 37.5 mg had a manageable safety profile and significant antitumor activity as second-line mRCC therapy. In this prospective, multicenter, phase II study, we evaluated the activity of continuous once-daily dosing with sunitinib 37.5 mg as first-line mRCC treatment. METHODS: One hundred nineteen treatment-naive patients with measurable mRCC received sunitinib. The primary endpoint was objective response; secondary endpoints included progressionfree survival (PFS), safety, pharmacokinetic measurements, exploration of response biomarkers, and patient reported outcomes (PRO). RESULTS: Objective response rate (ORR) was 35.3%; median response duration was 10.4 months; 36% of patients had stable disease 12 weeks. Median PFS at 1 year was 9 months, and 1-year survival probability was 67.8%. The most common any-grade treatment-related adverse events (AEs) were diarrhea (50%) and hand-foot syndrome (43%); the most common grade 3-4 treatment-related AEs were hand-foot syndrome (13%), neutropenia (11%), and diarrhea (9%). Steady-state pharmacokinetics were reached within 3 weeks, with no disproportionate accumulation of sunitinib or its active metabolite throughout the study. No significant correlations between trough drug, active metabolite, or soluble protein levels and clinical response were observed. PRO was largely maintained, although fatigue appeared to worsen after treatment started, with improvement over time. CONCLUSIONS: Continuous once-daily dosing with sunitinib 37.5 mg was active with a manageable safety profile as first-line mRCC therapy, making this a feasible alternative dosing regimen. Cancer 2012;118:1252-

Alternate sunitinib schedules in patients with metastatic renal cell carcinoma

“…The most commonly reported treatment-related AEs were diarrhea (50%) and HFS (43%). The most commonly reported grade 3-4 treatment-related AEs were HFS (13%), neutropenia (11%) and diarrhea (9%) [14]. A recent randomized phase II study comparing a 37.5-mg CDD regimen to the 4/2 schedule (EFFECT trial) demonstrated no differences in drug tolerance or patient-reported symptoms, but showed a trend toward superiority of the 4/2 schedule over CDD in time to tumor progression (9.9 months for 4/2 schedule versus 7.1 months for CDD, HR 0.77, 95% CI 0.57-1.04, P = 0.09).…”

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

“…In the subgroup of patients who received one TKI, median PFS in everolimus group was 5.4 months, and in group who received two TKI-s 4 months. This was statistically significant longer than in placebo groups, where PFS was 1.9 and 1.8 months respectively [8,20,[36][37][38].…”

“…Di Lorenzo and colleagues indirectly compared survival benefit in patients on everolimus or sorafenib in the second line. Median overall survival was 81.5 weeks for patients receiving everolimus and 32.0 weeks for sorafenib [37].…”

“…Sunitinib is approved in intermittent schedule of 4 weeks on drug and 2 weeks off drug. Continuous low-dose therapy has been shown to be a feasible treatment option in first and second line of treatment [37,38]. Comparison between the two scheduling is currently not very well determined, but clinical and toxicological differences may in future be important issue in treatment individualization.…”

Practical Insights and Challenges in the Rational Use of Targeted Agents in Metastatic Clear Cell Renal Carcinoma

“…Continuous dosing of sunitinib (37.5 mg orally daily) demonstrated antitumor activity with a manageable safety profile in first and second-line mRCC appearing to be an alternative dosing strategy (Escudier, Roigas, et al, 2009), (Barrios et al, 2011). Phase II EFFECT trial compared the two dosing strategies; sunitinib 50 mg taken daily on 4/2 schedule versus 37.5 mg taken daily continuously in treatment naive mRCC (R. Motzer et al, 2011 A randomized phase II discontinuation trial in 225 patients who were either treatment naïve or progressed on prior cytokine or bevacizumab containing regimen showed durability and tolerability of the agent at a dose of 800 mg once daily with an overall response rate of 35% and median duration of response of 52 weeks .…”