Alternative Dosing Schedules to Manage Adverse Events in Patients with Metastatic Renal-Cell Carcinoma Receiving Sunitinib

Nonadherence is not a new issue, particularly in the treatment of chronic diseases. Oncology healthcare providers usually assume that patients with cancer will adhere to treatment recommendations because of the gravity of the diagnosis; however, that is not exactly true. Reports in the literature show a treatment adherence rate as low as 20%.

Adherence to prescribed cancer therapy is imperative. Nonadherence can reduce treatment response and result in drug resistance, disease progression, and death. Factors that play a role in nonadherence to oral oncology therapy include socioeconomic background, healthcare system, treatment regimen, and adverse events (AEs).

Nurses and nurse practitioners can improve patient adherence through prompt identification of AEs and effective intervention. AEs can be managed by lifestyle changes, concomitant treatments to alleviate symptoms, and dose adjustments (ie, dose reductions and holding doses).

Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor (TKI) approved for the treatment of metastatic renal-cell carcinoma (mRCC). Since its approval in January 2006, sunitinib has become the standard of care for mRCC. To date, more than 94,000 patients with mRCC have been treated with this oral TKI in the United States, and thousands more globally. The FDA-approved schedule for sunitinib in mRCC is 50 mg orally once daily for 4 weeks, followed by a 2-week break in treatment. This schedule of 4 weeks on, 2 weeks off, totaling a 6-week cycle, is known as the “4/2 dosing schedule.”

Toxicity and grade ≥3 treatment-related AEs have been common in phase 3 trials, with approximately 20% of patients discontinuing treatment as a result of AEs. Despite the 4/2 dosing schedule, patient tolerability, including the development of serious AEs, may necessitate dose reduction or treatment discontinuation. Recently, clinicians interested in identifying alternative dosing schedules to improve the tolerability of sunitinib have made public their prospective and retrospective findings. Most research studies included a 2/1 dosing schedule, in which patients received therapy for 2 weeks, followed by a 1-week break, still totaling 4 weeks of treatment and 2 weeks of rest for a 6-week cycle.

A literature review identified 12 studies conducted between 2009 and 2016 on the 2/1 dosing schedule for sunitinib. A meta-analysis of 10 prospective clinical studies of sunitinib treatment in patients with mRCC and gastrointestinal stromal tumor was undertaken to enable the development of pharmacokinetic (PK) and pharmacodynamic (PD) models with the 4/2 dosing schedule and 2/1 dosing schedule. The PK/PD models predicted comparable efficacy between the 2/1 dosing schedule and 4/2 dosing schedule. The models also predicted that sunitinib-related thrombocytopenia would be less severe with the 2/1 dosing schedule compared with the 4/2 dosing schedule.

RESTORE, a prospective clinical trial, was designed to investigate the impact of sunitinib treatment in mRCC using the 2/1 dosing schedule compared with the 4/2 dosing schedule. Patients receiving treatment on the 2/1 dosing schedule experienced reductions in both overall and grade ≥3 AEs compared with patients treated on the 4/2 dosing schedule. Study results showed that efficacy was not compromised on the 2/1 dosing schedule compared with the 4/2 dosing schedule.

Available data from prospective and retrospective studies show that modifying sunitinib treatment from the 4/2 dosing schedule to a 2/1 dosing schedule is associated with improved tolerability and maintenance of efficacy in patients with mRCC. It is important to note that these studies did not evaluate initiating sunitinib on a 2/1 dosing schedule. These studies were specific to switching from a 4/2 dosing schedule to a 2/1 dosing schedule as a means of managing AEs and preventing temporary treatment discontinuation.

Understanding research findings that support alternative dosing schedules for sunitinib and effectively implementing them in clinical practice is critical to improving patient adherence, AEs experienced, and treatment outcomes in patients with mRCC. Ongoing studies will provide further guidance for optimizing dosing schedules for patients with mRCC who cannot tolerate the 4/2 dosing schedule.

Ryan RC, et al. ONS Abstract IS-20.

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