Sunitinib vs. everolimus: PFS, toxicity differ in study

Durham, NC-In a head-to-head comparison, sunitinib (Sutent) prolonged radiographic progression-free survival (PFS) compared with everolimus (Afinitor), but with greater toxicity, in patients with specific subtypes of metastatic renal cell carcinoma (RCC) and non-clear cell histology, said Andrew J. Armstrong, MD, MSc.

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Dr. Armstrong“Sunitinib resulted in improved PFS both in good- and intermediate-risk patients and papillary and unclassified histologies, whereas everolimus resulted in improved PFS in both poor-risk and chromophobe subtypes. Sunitinib and everolimus resulted in different rates of expected toxicities, with slightly more severe toxicities with sunitinib but more drug discontinuations due to toxicity from everolimus,” said Dr. Armstrong, co-director of the Genitourinary Oncology Research Program, Duke Cancer Institute, Durham, NC.

Non-clear cell RCC is a genetically and histologically diverse collection of heterogeneous diseases that account for about 25% of kidney cancers, most commonly comprised of papillary types 1 and 2, chromophobe, and a group of diseases called unclassified carcinomas, each with varying prognoses.

Published evidence from single-arm trials, uncontrolled case series, and expanded access studies supports a front-line standard of care systemic therapy. Evidence from individual studies supports an anti-vascular endothelial growth factor (VEGF) or anti-mTOR approach to non-clear cell RCC, “but the data are limited by heterogeneity across different risk groups and lines of therapy,” so conclusive evidence is therefore not strong, Dr. Armstrong said.

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He presented the study at the 2015 American Society of Clinical Oncology annual meeting in Chicago. Results were subsequently published in Lancet Oncology (2016; 17:378-88).

Next: About the study

Known as ASPEN, the study is an investigator-initiated international phase II clinical trial of patients with RCC of non-clear cell pathology who had measurable disease per RECIST v1.1 and no prior systemic therapies.

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In it, 108 patients were randomized to sunitinib, 50 mg orally on days 1 to 28 of a 6-week cycle, or everolimus, 10 mg orally once daily on days 1 to 42 of a 6-week cycle.

Sixty-five percent of patients randomized had type 2 papillary disease. Chromophobe histology was present in 20% of patients randomized to sunitinib and 11% randomized to everolimus. There was sarcomatoid differentiation in 10% of the sunitinib arm and 27% of the everolimus arm. About one-fourth of patients were in Memorial Sloan Kettering Cancer Center (MSKCC) risk group 0 and about 60% were MSKCC risk 1-2.

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The median duration of treatment was 5.1 months in the sunitinib group and 4.1 months in the everolimus group, with only 6% to 7% remaining on study drug at the end of 12 months of treatment. Fourteen percent in the sunitnib arm and 23% in the everolimus arm stopped therapy due to toxicity.

Next: rPFS favors sunitinib

Radiographic PFS favors sunitinib

The median follow-up was 15 months in the sunitinib arm and 12 months in the everolimus arm. Radiographic PFS favored sunitinib, with a median rPFS of 8.3 months, compared with 5.6 months in the everolimus arm, for a hazard ratio of 1.14 (p=.15, which met the prespecified boundary of p<.20).

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By histologic subtype, median PFS was longer in the sunitinib arm compared with the everolimus arm in patients with papillary subtype (8.1 months vs. 5.5 months, respectively) and in those with unclassified disease (11.5 months vs. 5.6 months, respectively), but was superior with everolimus in the patients with the chromophobe subtype at 11.4 months versus 5.5 months in the sunitinib arm.

Overall survival was a secondary endpoint, and again favored sunitinib over everolimus (median,  32 vs. 13 months), but based on a small number of events, the difference was not statistically significant (p=.60).

Eighteen percent in the sunitinib arm and 9% in the everolimus arm had complete response (CR) or partial response (PR) by RECIST v1.1. Clinical benefit response (CR + PR + stable disease) was observed in 22% of the sunitinib group versus 11% of the everolimus group. “However, sunitinib actually led to an average of 10.7% [tumor] growth while everolimus was more of a cytostatic agent [2.1% growth], where most patients were within the stable disease criterion by RECIST,” Dr. Armstrong said.

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The median duration of response was longer with sunitinib compared with everolimus (5.5 vs. 3.3 months, respectively).

Next: No unexpected adverse events

No unexpected adverse events

There were no unexpected adverse events in the study. Sunitinib was associated with more nausea, diarrhea, decreased appetite, hypertension, hand foot syndrome, vomiting, venous thromboembolism, and hypothyroidism. Everolimus resulted in higher rates of stomatitis, rash, peripheral edema, and pneumonitis.

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Almost one-fourth (23.5%) in the sunitinib arm had grade-3 hypertension and 9.8% had grade-3 diarrhea. Everolimus recipients had an 8.8% rate of grade-3 stomatitis, 8.8% rate of pneumonitis, and a 7% rate of grade-3 fatigue.

Rates of thrombocytopenia and neutropenia were greater with sunitinib, including eight instances of grade-3 thrombocytopenia with sunitinib (vs. two with everolimus), while hypertriglyceridemia, hyperlipidemia, and hyperglycemia were more common with everolimus.

“Future trials in this heterogeneous collection of diseases should consider these factors in designing prospective studies,” said Dr. Armstrong. “Both agents resulted in short PFS times and low response rates illustrating the unmet need still in this population for better drugs that may prolong PFS and OS.”

Dr. Armstrong is a consultant/adviser for Novartis and his institution has received research funding from Novartis and Pfizer. Several of his co-authors have financial or other disclosures with Novartis, Pfizer, and other pharmaceutical companies.

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