Moshe Ornstein, MD
Balancing the clinical benefit with the toxicity of chronic therapy continues to be a major challenge for patients being treated with sunitinib for metastatic renal cell carcinoma (mRCC). The findings from the phase II study of intermittent sunitinib (Sutent) in patients with previously untreated mRCC demonstrate that periodic extended sunitinib treatment breaks are feasible and the clinical efficacy does not seem to be compromised.
“What this study implies is that patients who have stable disease while on sunitinib (in our study 4 cycles of therapy), can be given at least a short break from treatment. As such, patients who are experiencing difficult side effects or just want to be off therapy for a few weeks for improved quality of life, should be considered for therapy breaks,” lead study author Moshe Ornstein, MD, Cleveland Clinic Foundation, said in an interview with OncLive
Thirty-seven patients were enrolled into this study, 70% being male with a median age of 63 years, and 92% having a good performance status.
Sunitinib was dosed at 50 mg once per day for the first 28 days of a 42-day cycle (4/2 schedule) with a treatment of 4 cycles with the absence of unacceptable toxicity or RECIST-defined progressive disease (PD). Patients with ≥ 10% reduction in tumor burden could hold the treatment and repeat imaging every 2 weeks, which would continue until there was an increase in tumor burden by ≥10% compared with scans immediately before the break in sunitinib treatment. Sunitinib was then administered at the patient’s previous dose for 2 cycles.
Patients who did not achieve less than 10% reduction at the end of any cycle continued with their current sunitinib dosage and schedule.
The primary endpoint of this study was to determine the feasibility of an intermittent sunitinib dosing schedule, with the secondary endpoint being objective response rate (ORR), progressive-free survival (PFS) and overall survival (OS) measured from the start of treatment.
Of the 37 enrolled patients, 17 could not go to the intermittent phase. Of these 17 patients, 13 patients had PD, 1 developed grade 3 nephrotic syndrome possibly related to sunitinib, and 3 patients withdrew consent. Twenty of the 37 patients were eligible to go to the intermittent phase at the end of 4 cycles and all 20 entered.
Of the 20 patients who entered the intermittent phase, 16 restarted therapy after initial break, 3 had not yet reached the required tumor growth to restart therapy, and one withdrew consent to seek a treatment facility closer to home. Among the 16 patients who had restarted therapy, 12 had sufficient tumor regression to allow at least 1 other break from therapy, but 3 developed PD before any subsequent treatment breaks, and 1 stopped therapy due to adverse events (AEs).
Among the patients who entered the intermittent phase, there was a total of 83 breaks among all patients, with a median of 3. The median treatment break duration was 8.3 weeks (range, 4.7-192.1) and the median period of retreatment with sunitinib was 12.0 weeks (range, 2.0-86.9).
The median follow-up was 21.6 months for all patients, 32.9 months excluding the patients who withdrew early, and 49.1 months for patients still alive (n = 13).
All patients achieved a median of 1.7 cm tumor reduction during the first 4 cycles, with 17 patients (46%) achieving a RECIST-defined partial response. The median tumor reduction of the 20 patients eligible to enter the intermittent phase was 2.0 cm (45%).
The median PFS for all patients involved in the study was 22.4 months and 37.6 months for those 20 patients who entered the intermittent phase, with a median OS of 34.8 months.
Of the total number of patients enrolled in the study, 25 (68%) patients discontinued treatment at the time of data analysis (June 30, 2016) due to progression, 3 (8%) due to AEs, 4 (11%) withdrew consent, and 1 (3%) died during the study.
For 17 patients, the 50-mg dosage was reduced to 37.5 mg during the first 4 cycles. Nine patients were switched from a 4/2 schedule to a 2/1 due to toxicity levels. The most common AEs of any grade include fatigue (89%), mucositis (86%), and thrombocytopenia (84%). The most common grade 3 AEs consisted of hypertension (38%), neutropenia (24%), and fatigue (22%).
“Based on our clinical practice, we were certainly expecting to see patients tolerate some breaks from sunitinib therapy. What was more interesting, however, was the range of breaks patients were able to experience without having disease progression,” said Ornstein.
Ornstein MC, Wood LS, Elson P, et al. A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients with Metastatic Renal Cell Carcinoma (published online January 23, 2017). J Clin Oncol. doi:10.1200/JCO.2016.71.1184