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Adjuvant sunitinib extends DFS in high-risk renal cell carcinoma
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COPENHAGEN, Denmark — Adjuvant treatment with sunitinib significantly prolonged DFS compared with placebo among patients with locoregional clear-cell renal cell carcinoma at high risk for tumor recurrence after nephrectomy, according to randomized phase 3 study results presented at the European Society for Medical Oncology Congress.
Sunitinib (Sutent, Pfizer) also exhibited a safety profile consistent with the broad treatment experience for the drug in metastatic renal cell carcinoma, according to researcher Alain Ravaud, MD, PhD, head of medical oncology at University Hospital of Bordeaux in France.
“These results represent a major step forward in the clinical management of clear-cell renal cell carcinoma,” Ravaud said during a press conference.
Sunitinib — which targets multiple receptor tyrosine kinases, including platelet-derived growth factor and vascular endothelial growth factor receptors — is approved by FDA for the first-line treatment of advanced kidney cancer.
However, no standard adjuvant treatment exists, and recurrence rates after nephrectomy reach 50% in some patient subgroups.
Ravaud and colleagues conducted a double blind trial to assess the safety and efficacy of sunitinib in 615 patients with locoregional renal cell carcinoma at high risk for recurrence after nephrectomy.
Researchers assigned patients to 50 mg sunitinib daily (n = 309) or placebo (n = 306).
Treatment groups were balanced with regard to median age (sunitinib, 57 years; placebo, 58 years), sex and UCLA Integrated Staging System group. The majority of patients in each group had baseline ECOG performance status of 0 (73.8% vs. 71.9%) or 1 (25.6% vs. 27.5%).
Treatment followed a 4-weeks-on, 2-weeks-off schedule for 1 year. Patients remained on treatment until disease recurrence, unacceptable toxicity or withdrawal of consent.
DFS assessed by blinded independent central review served as the primary endpoint. Investigator-assessed DFS, OS and safety served as secondary endpoints.
Patients assigned sunitinib achieved significantly longer DFS (6.8 years vs. 5.6 years; HR = 0.76; 0.59-0.98). Sunitinib-treated patients were more likely to remain disease free at 3 years (64.9% vs. 59.5%) and 5 years (59.3% vs. 51.3%).
OS data had not matured by the time of analysis.
A higher percentage of sunitinib-treated patients experienced grade 3 or higher adverse events (62.1% vs. 21.1%).
Incidence of serious adverse events was comparable between treatment groups (21.9% vs. 17.1%). The most common serious events in sunitinib-treated patients were hypertension (2.6%), thrombocytopenia (2.3%), pulmonary embolism (1.6%) and pyrexia (1.6%).
More patients assigned sunitinib required adverse event–related dose reductions (34.3% vs. 2%), dose interruptions (46.4% vs. 13.2%) or treatment discontinuation (28.1% vs. 5.6%).
No patients died due to treatment-related toxicity.
The results should be viewed in context of the randomized, placebo-controlled, phase 3 ASSURE trial, according to Thomas Powles, MBBS, MD, MRCP, clinical professor of genitourinary oncology at Barts Cancer Institute in London.
That trial showed neither sunitinib or sorafenib (Nexavar, Bayer) improved DFS or OS in patients with locally advanced kidney cancer.
“Disease-free survival is a useful surrogate endpoint, but the results from different studies have been contradictory,” Powles said in a press release. “It does not necessarily translate to overall survival, which is the gold standard. Preliminary results in this setting do not point toward a survival benefit. There are a number of other trials ongoing in this area, and I would like to see one of these being positive to tip the balance toward benefit.
“Without a consistently positive disease-free survival signal, it would be premature for me to recommend sunitinib as adjuvant therapy for my patients, particularly when one considers the toxicity,” Powles added. “A positive survival signal, or meta-analysis for disease-free survival, would be needed. Other studies in this area are awaited.” – by Mark Leiser
For more information: Ravaud A, et al. Abstract LBA11_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclos ure: Ravaud reports grant support, personal fees or nonfinancial support from Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Robert Uzzo, MD, FACS
Management of kidney cancer is rapidly evolving. In high-risk locally advanced, nonmetastatic kidney cancer, the standard of care is surgical excision with subsequent observation. It is accepted that there will be a 30% to 70% risk for recurrence depending on the pathologic findings of radiographic surveillance. Additionally, between 20% and 30% of these patients will die of any cause within 5 years.
Two recent adjuvant studies have been reported in this disease. The first trial — known as the ASSURE trial — compared sunitinib (Sutent, Pfizer) to sorafenib (Nexavar, Bayer) to placebo. This trial found no difference in DFS or OS between the three groups. The current study — simultaneously published in The New England Journal of Medicine and presented at the European Society for Medical Oncology Congress — randomly assigned patients to sunitinib or placebo.
The current study found a DFS benefit for patients assigned sunitinib. The trial enrolled 615 patients, smaller than the ASSURE trial’s population of 1,294 patients. Although both trials treated patients for 1 year, patients in the current study tended to have higher-risk disease — 100% of patients had T3 or T4 disease, with or without node positivity. The ASSURE trial included some lower-risk patients.
The current findings are surprising, with approximately 59% of patients assigned sunitinib disease free at 5 years, compared with 51% assigned placebo (P = 0.03). The prior ASSURE trial did not have any significant difference in DFS. There are several potential causes for this. The difference in patient population offers one theory, but it is important to note that an OS benefit has not been shown for sunitinib yet. Sunitinib may delay identifiable progression, but we don’t yet know if it will affect the actual length of survival.
It is also possible that because this trial occurred in the wake of ASSURE, clinicians may be more comfortable managing adverse toxicities in this patient population. The other aspect relates to delaying the manifestation of occult disease. By taking the drug, a patient may be delaying the progression of micrometastatic disease while receiving therapy. But ultimately, when a patient comes off the drug, it might not result in an actual OS benefit. The protection occurs while the patient is on the drug. These drugs are not known to be curative, even in patients with metastatic disease, so the question is whether patients on the drug are just suppressing further growth. We have to wait for the data to mature for a conclusive answer, but it seems that patients don’t actually live longer if they take the drug. They just have fewer metastatic events.
Providers should discuss the potential benefit of the drugs with their patients, and whether it is worth enduring the toxicity. The surveillance imaging will likely be negative for longer, but is it worth it if no survival benefit is shown? I think that is where this debate is ultimately heading.
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