A phase III trial of sunitinib has met its primary endpoint of disease-free survival for adjuvant treatment of high-risk renal cell carcinoma after nephrectomy.
The research was presented at the ESMO 2016 Congress.
“The recurrence rate of kidney cancer after nephrectomy, where part or all of a kidney is removed, is up to 50% in some subgroups of patients,” said lead author Professor Alain Ravaud, head of medical oncology, University Hospital of Bordeaux, France. “This distinguishes it from other tumours such as breast cancer where in general there is a low chance of the cancer coming back.” “We have good drugs to control disease in patients with metastatic kidney cancer but there are no standard adjuvant treatments,” he added.
This phase III trial tested the ability of adjuvant treatment with sunitinib, a receptor tyrosine kinase inhibitor, to improve disease-free survival in a type of kidney cancer called clear cell renal carcinoma. The study included 615 post-nephrectomy patients at high risk of their cancer recurring. Patients were randomised to placebo or sunitinib for one year. Sunitinib was administered at 50 mg per day in a four weeks on / two weeks off schedule, and one dose reduction to 37.5 mg per day was allowed. Patients with suspected metastases in an independent central review were excluded from the study.
The primary endpoint was disease-free survival. It was assessed by an independent central review committee of radiologists who examined CT scans and ruled whether an event had occurred or not. Events could be recurrence in the remaining kidney or in local lymph nodes, metastases, or a second malignancy. In cases of disagreement between the independent central review and the study investigators a decision was reached by obtaining a biopsy or surgery sample of the tumour – if it contained cancer this was ruled as a recurrence.
The primary endpoint of the trial was met with a significantly longer disease-free survival of 6.8 years with sunitinib compared to 5.6 years with placebo (hazard ratio 0.761, p=0.03). Adverse events of grade 3 or higher were more frequent with sunitinib (62.1%) compared to placebo (21.1%). There were no deaths due to treatment toxicity.
Ravaud said: “Sunitinib is a potential new option for adjuvant therapy in renal cell carcinoma, given the increase in disease-free survival and the manageable safety profile. The results of this trial could change practice because there is currently no standard treatment in this setting.”
He concluded: “We hope sunitinib will be approved by regulators for adjuvant therapy in renal cell carcinoma. Clinicians should then use the drug according to the trial. In other words, in patients with predominant clear cell renal cell carcinoma without metastases and at high risk of recurrence, at a starting dose of 50 mg and a minimum dose of 37.5 mg per day and with the same dosing schedule. This is particularly important since sunitinib was not beneficial in another trial using a different methodology.”
Commenting on the results, Professor Thomas Powles, professor of urology cancer, Barts Cancer Institute, London, UK, said: “This positive trial should be taken in the context of a previous larger adjuvant study (ASSURE) with a very similar design. ASSURE showed no difference in disease-free survival or overall survival. This generates a lot of uncertainty. I suspect a meta-analysis of progression-free survival would be negative and at this point it would be premature to change practice. Both studies show that adjuvant sunitinib is assocated with toxicity.”
He continued: “Disease-free survival is a useful surrogate endpoint, but the results from different studies have been contradictory. It does not necessarily translate to overall survival, which is the gold standard. Preliminary results in this setting do not point towards 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 towards benefit.”
Powles concluded: “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. A positive survival signal, or meta-analysis for disease-free survival, would be needed. Other studies in this area are awaited.”
Each year, approximately 300,000 persons worldwide are diagnosed with renal-cell carcinoma, resulting in 129,000 deaths. The prognosis for patients with renal-cell carcinoma is dependent on the stage of disease and other risk factors. The 5-year survival rate is 53% for locoregional (stage III) disease and 8% for metastatic disease. Overall, locoregional disease is diagnosed in 16% of patients with renal-cell carcinoma, and up to 40% of these patients have a relapse with metastasis after nephrectomy.5,6 The relapse risk can be assessed with the use of two validated models, the University of California Los Angeles Integrated Staging System (UISS)7,8 and the stage, size, grade, and necrosis (SSIGN) score.9 Although the prognosis for patients with metastatic renal-cell carcinoma has improved in the past decade, no curative treatment is currently available. Several adjuvant strategies, including cytokine therapy, radiotherapy, and hormone therapy, have been explored to decrease the rate of relapse, but none were successful.6 The proven efficacy of antiangiogenic therapies, including the vascular endothelial growth factor (VEGF) pathway inhibitors sunitinib10 and sorafenib,11 in patients with metastatic renal-cell carcinoma12 supports the evaluation of these drugs as adjuvant therapy.6 In a previous phase 3 trial (ASSURE) involving patients with locally advanced renal-cell carcinoma, investigators did not find any treatment advantage for adjuvant therapy with sunitinib or sorafenib over placebo.13 In Sunitinib as Adjuvant Treatment for Patients at High Risk of Recurrence of Renal Cell Carcinoma Following Nephrectomy (S-TRAC), we examined the efficacy and safety of sunitinib versus placebo in preventing relapse in patients with resected locoregional renal-cell carcinoma at high risk for disease recurrence.
Alain Ravaud, Robert J Motzer, Hardev S Pandha, Daniel J George, Allan J Pantuck, Anup Patel, Yen-Hwa Chang, Bernard Escudier, Frede Donskov, Ahmed Magheli, Giacomo Carteni, Brigitte Laguerre, Piotr Tomczak, Jan Breza, Paola Gerletti, Mariajose Lechuga, Xun Lin, Jean-Francois Martini, Krishnan Ramaswamy, Michelle Casey, Michael Staehler, Jean-Jacques Patard