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Sunitinib benefits some patients with non-clear cell renal cell carcinoma
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CHICAGO — Sunitinib improved radiographic PFS compared with everolimus among certain subgroups of patients with metastatic non–clear cell renal cell carcinoma, according to findings from a phase 2 trial presented at the ASCO Annual Meeting.
However, patients assigned sunitinib (Sutent, Pfizer) also demonstrated greater rates of grade 3 or worse toxicities, results showed.
This study marks the first time researchers identified an mTOR-sensitive subgroup of patients with non–clear cell renal cell carcinoma compared with VEGF inhibition in the front-line setting.
Andrew J. Armstrong
Andrew J. Armstrong, MD, ScM, an associate professor of medicine and surgery in the division of medicine-oncology at the Duke University School of Medicine, and colleagues conducted the ASPEN trial — an international, randomized trial — to compare sunitinib with everolimus (Afinitor, Novartis) in 108 patients (median age 63 years; 75% men) with metastatic non–clear cell renal cell carcinoma who had papillary (66%), chromophobe (15%) or unclassified (19%) histology and no prior systemic therapy. Most patients and intermediate-risk disease (59%), 27% had good-risk disease and 15% had poor-risk disease.
Radiographic PFS — measured using RECIST 1.1 criteria — served as the primary endpoint.
Researchers expected 90 PFS events to occur, resulting in an 83% power to detect a 38% decrease in the HR for progression or death.
Researchers stratified patients by their histology and risk group and randomly assigned them to the everolimus arm (n = 57) or sunitinib arm (n = 51). The treatment arms were balanced at baseline.
After 87 PFS events, 53 deaths and two patients still on treatment, sunitinib met the primary endpoint by improving PFS.
Patients in the sunitinib arm achieved a median PFS of 8.3 months (80% CI, 5.8-11.1), whereas the median PFS in the everolimus arm was 5.6 months (80% CI, 5.5-6; HR = 1.41; 80% CI, 1.03-1.92).
Sunitinib specifically improved PFS compared with everolimus in patients considered good risk (14 months vs. 5.7 months; HR = 3.07; 80% CI, 1.51-6.28) or intermediate risk (6.5 months vs. 4.9 months; HR = 1.38; 80% CI, 0.96-2). Researchers also observed improved PFS with sunitinib vs. everolimus in patients with papillary (8.1 months vs. 5.5 months; HR = 1.52; 80% CI, 1.05-2.2) or unclassified histology (11.5 months vs. 5.6 months; HR = 2.55; 80% CI, 1.01-6.45).
However, everolimus improved PFS compared with sunitinib in poor-risk patients (6.1 months vs. 4 months; HR = 0.21; 80% CI, 0.06-0.69) and patients with chromophobe histology (11.4 months vs. 5.5 months; HR = 0.71; 80% CI, 0.31-1.65).
Sunitinib improved median OS compared with everolimus (31.5 months vs. 13.2 months); however, the improvement did not reach statistical significance (HR = 1.17; 95% CI, 0.65-2.14).
Although no unexpected safety signals emerged from the treatment, sunitinib did result in more grade 3 or worse treatment-related adverse events than everolimus (65% vs. 47%).
“Patients with metastatic non–clear cell renal cell carcinoma treated with sunitinib had a statistically significantly prolonged PFS duration compared with patients treated with everolimus,” Armstrong said during his presentation. “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.
“Future trials in this heterogeneous collection of diseases should consider these factors when designing prospective studies. Both agents resulted in short PFS times and low response rates illustrating the unmet need still in this population for better drugs to improve PFS and OS.” – by Anthony SanFilippo
Reference: Armstrong AJ, et al. Abstract 4507. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: Armstrong reports honoraria, research funding and travel expenses from; consultant/advisory and speakers bureau roles with Astellas, Bayer, Bristol-Myers Squibb, Dendreon, ImClone Systems, Janssen Biotech, Janssen Oncology, KangLaiTe, Medivation, Novartis, Pfizer and Sanofi. See the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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David Michael Nanus, MD
That was an excellent study. It was one of the largest and first really good phase 3 studies of patients with non–clear cell renal cell carcinoma, and it’s a big step forward. There were a lot of reports on sunitinib and everolimus in different non–clear cell histolologies such as papillary and chromophobe. This study showed sunitinib was a little bit better in the front-line setting.
The reason that mTOR inhibitors were initially felt to be better for non–clear cell renal cell cancers was based on a study looking at non–clear cell histologies. There wasn’t a really good review of all the histologies, but the investigators thought the mTOR inhibitor was still better, but apparently it’s not that way. I’m not surprised because those of us who take care of patients frequently will start with a vascular endothelial growth factor (VEGF) kinase inhibitor and then go to an mTOR inhibitor. There’s no real rush to start with an mTOR inhibitor because temsirolimus (Torisel, Pfizer) is the only mTOR inhibitor approved in the first line and that requires a patient to come in every week. I have patients who are on a VEGF kinase inhibitor for years. Then, in the second line, you can use everolimus because it’s approved there. So, there’s a little practicality with how you sequence your drugs in non–clear cell histology. This study does suggest that in the chromophobe subtype there’s a hint of an mTOR inhibitor being better in the first line, but with other studies, there’s some debate about that. This study could skew some people in that direction depending on the pace of the disease. Still, you can try it for a couple months because chromophobe tends to be slow-growing. So you may try an oral agent before going to temsirolimus.
I congratulate the investigators. They did a lot of tissue analyses, so there will be more information coming. They got tissue samples from more than 100 patients, and that’s amazing. Overall, I think it was an excellent study and really interesting. It won’t change how we practice, but it validates what we’re doing, and that’s a good thing.
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