Sunitinib (2 weeks on/1 week off schedule) in metastatic renal cell cancer patients. Progression free and overall survival

Abstract

Background: The recommended schedule of sunitinib (SU) for metastatic renal cell cancer (mRCC) pts is 50 mg/day p.o. for 4 weeks and 2 weeks rest. The half-life of SU and its active metabolite is very slow: 40-60 and 80-110 hours, respectively. Given on several consecutive days the accumulation is 3-4-fold and 7-10-fold, respectively. The steady state concentration is achieved on days 7-10 and 10-14. 50 mg daily is enough to achieve the target concentration of ≥ 50 ng/mL. During the 14 days rest the concentration will decrease to the starting level. The correlation between the SU AUC and the time to progression is well known. Methods: Based on the above in case of short term adverse events (AEs) we have applied the 2 weeks on/1 week off schedule instead of dose reduction. Results: Altogether 130 mRCC pts (median age: 61 yrs, M/F: 91/39) were enrolled in the study. 121 (93%) pts were nephrectomized, 95% (123pts) had RCC histology. 67 (30%); 49 (38%) and 42 (32%) pts belongs to the good, intermediate and poor MSKCC prognostic groups, respectively. SU was the first-line treatment in 75 cases (58%), 34 (26%) had IFN and 21 (16%) patients had IL-2 treatment before. Patients received altogether 1617 cycles of SU (median 8, range: 1-68); 344 (range1-56) cycles were given according to 4/2, and 1273 (1-18) according to 2/1 schedule, respectively. Upon progression on SU the following therapies were given: sorafenib (n = 10), axitinib (7), pazopanib (1), cabozantinib (1), everolimus (16). The median progression-free survival (mPFS) was: 13.5 (95%CI 12-16.5) mos and the median overall survival (mOS) was 30 (24-36) mos. If the 2/1 schedule was given in more than 2/3 of the total cycles (n = 83) the mPFS was 18 (13.5-28.5) mos and mOS was 38 (30-44) mos compared to those who had 2/1 schedule in less than 2/3 of the total cycles (n = 47) with mPFS 6 (4.5-9; P = .0002) mos and mOS 11 (7-21); P = .0001) mos. Short-term AEs were as follows: fatigue 41%; anorexia 25%; mucositis 35%, diarrhea 37%; hand-foot syndrome 35%; hypertension: 30%. Although the AEs were quite frequent they lasted shorter and dose reduction had to be performed only in 12% (n = 16) during the 2/1 schedule. Conclusions: Changing the SU 4/2 to 2/1 schedule instead of reducing the dose, was safe and resulted in a longer median progression-free and overall survival.