Alternate sunitinib dosing shows benefit in intermediate- or poor-risk mRCC

Treatment with sunitinib 50 mg daily in an alternating 2 weeks on/1 week off (2/1) schedule does not reduce grade 3 toxicity in metastatic renal cell carcinoma (mRCC) vs the standard schedule. However, the approach was significantly linked with an absence of grade 4 toxicity, low patient discontinuation rates, and strong clinical efficacy, according to a new study published in the Journal of Clinical Oncology.

Sunitinib, an oral inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 and platelet-derived growth factor receptor, is currently administered in a 4 weeks on/2 weeks off (4/2) schedule. In 2006, the FDA approved sunitinib for the treatment of mRCC, after the drug increased median progression free survival (PFS) during phase 3 clinical trials.

“In real-world practice, maintenance of dose intensity of sunitinib can be challenging because of treatment-related adverse effects, including fatigue, hand-foot syndrome (HFS), and diarrhea,” wrote the authors, led by Eric Jonasch, MD, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston. “The current study tested the hypothesis that administration of sunitinib on a 2/1 schedule would decrease toxicity for patients relative to historical control data.”

In this single-arm, multicenter, phase 2 study, the researchers treated 59 patients with mRCC using a 2/1 schedule between August 2014 and March 2016, with dosing adjusted if toxicity developed. In total, 77% of these patients were characterized as intermediate or poor risk according to the Memorial Sloan Kettering Cancer Center criteria. The median age was 65.5 years, 62% of the patients were men, and the patients demonstrated a median of two affected sites, with lung metastases most common (65%).

The primary endpoint for this study was the incidence of grade 3 fatigue, diarrhea, and HFS; the team hypothesized these treatment-related effects would occur in <15% of patients vs the historical rate of 20% to 25%. Secondary endpoints included quality of life (QOL) measures that the team determined using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, which they administered at baseline, 12, 24, and 36 weeks of treatment.

Dr. Jonasch and colleagues found that the primary endpoint was not reached during a median follow-up period of 17 months. Overall, 25% of patients exhibited grade 3 fatigue, diarrhea, or HFS; 37% of patients needed a dose reduction; and 10% of patients stopped treatment due to toxicity. Median PFS was 13.7 months (95% CI, 10.9-16.3 months), with median overall survival not reached.

Finally, FACT-G scores dropped between 0% and 10% by week 12, with patients who continued longer in treatment experiencing lower reductions in these QOL measures.

“Thirty-three patients (56%) responded (95% CI: 42.4% to 68.8%); one (2%) with a complete response and 32 (54%) with a partial response,” the researchers wrote. “Seven patients (12%) had progressive disease as their best response.”

Although the primary endpoint was not met and dose reduction rates were higher than in the phase 3 Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma (COMPARZ) study, the researchers noted that no grade 4 toxicities occurred, and discontinuation rates were substantially lower than in the COMPARZ study.

One limitation of this study is the academic center setting. Bias could exist in outcomes when compared with practices where clinicians have less experience with respective treatment and pathology. In addition, there was no randomization in the study and the power was low.

“Sunitinib administered to a predominantly intermediate- and poor-risk frontline RCC population results in low treatment discontinuation rates, a maintained QOL, and robust efficacy,” concluded the researchers. “These nonrandomized data also support the use of alternate sunitinib scheduling as a means to maintain patient QOL and to extend duration of treatment.”

To read more about this study, click here.