COPENHAGEN — Patients with renal cancer who are at a high risk for recurrence after nephrectomy may benefit from adjuvant treatment with the tyrosine kinase inhibitor sunitinib (Sutent, Pfizer Inc). The drug has just been shown to improve disease-free survival by over a year compared with placebo in a phase 3 trial.
The finding comes from the Sunitinib as Adjuvant Therapy for Patients at High Risk of Recurrence of Renal Cell Carcinoma Following Nephrectomy (S-TRAC) trial and was presented here at the European Society for Medical Oncology (ESMO) Congress 2016 and simultaneously published in The New England Journal of Medicine.
"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," lead author Alain Ravaud, MD, PhD, head of medical oncology at the University Hospital of Bordeaux, France, commented in a statement.
However, two outside experts said the results as they stand now are not yet practice changing (see below). Speaking at a press briefing, Dr Ravaud also gave a nuanced comment. On the basis of the new results, he said, "If you ask me, does this become to be the standard, the answer is 'no.'" Instead, he feels that sunitinib is "an option to be discussed with patients," with the potential gains to be balanced against the risk for adverse events and their impact on quality of life.
While Dr Ravaud hopes that sunitinib will be approved as an adjuvant therapy in renal cell carcinoma (RCC), he also acknowledged recently published data from the ASSURE trial, which, as reported by Medscape Medical News, showed that neither sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals) nor sunitinib prolonged disease-free survival (DFS) in patients with resected, locally advanced RCC.
In view of that negative trial, he said, "Clinicians should then use the drug according to [our] trial…with the same dosing schedule. This is particularly important since sunitinib was not beneficial in another trial using a different methodology."
An expert not involved in either study, Thomas Powles, MD, PhD, clinical professor of genitourinary oncology at Barts Cancer Institute, London, United Kingdom, said that the discrepancy between the current S-TRAC results and those of ASSURE "generates a lot of uncertainty," adding that DFS "does not necessarily translate to overall survival, which is the gold standard."
Noting that several other trials in this field are ongoing, he continued: "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 associated with toxicity."
The S-TRAC study randomly assigned 615 treatment-naive patients with locoregional RCC to sunitinib 50 mg/day or placebo in a 4 weeks on, 2 weeks off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. One dose reduction to 37.5 mg/day was allowed. The results were analyzed by investigators and under blinded central review.
The two patients were well balanced in terms of their baseline characteristics. During a median follow-up of 5.4 years, the median number of treatment cycles was 9, and the relative dose intensity was 88.4%. The starting dose was maintained by 54.2% of sunitinib recipients.
At analysis, fewer patients receiving sunitinib had experienced a DFS event than those in the placebo group, at 36.6% vs 47.1%. On blinded central review, DFS was significantly longer with sunitinib, at a mean of 6.8 years vs 5.6 for placebo and a hazard ratio of 0.76 (P = .03).
The proportion of patients who were disease-free at 3 years was 64.9% with sunitinib vs 59.5% with placebo. At 5 years, the corresponding proportions were 59.3% and 51.3%, respectively.
Notably, the difference in DFS between the sunitinib and placebo groups was not significant on investigator review, at 6.5 years and 4.5 years, respectively, for a hazard ratio of 0.81 (P = .08).
This split between central and investigator review was maintained when the researchers restricted the analysis to a subgroup of patients at higher risk than the overall population, at hazard ratios for DFS with sunitinib vs placebo of 0.74 (P = .04) on central review and 0.76 (P = .06) on investigator review.
Grade 3 or 4 adverse events were more common in the sunitinib group than the placebo group, at 62.1% vs 21.1%. This was reflected in a higher proportion of treatment discontinuations due to adverse events with sunitinib than with placebo (28.1% vs 5.6%).
However, the proportions of patients experiencing a serious adverse events were similar in the two groups, at 21.9% vs 17.1%, and no deaths were attributed to treatment toxicity.
At a press conference, Dr Ravaud pointed out that the DFS curves for sunitinib and placebo diverged "very early." Moreover, the gap was maintained throughout follow-up, resulting in a survival gain of over 1 year overall and over 2 years in high-risk patients. "It's clear that's the first time there is a gain with a drug in the adjuvant setting," he noted.
Data Not Practice-Changing Yet
Discussing the study after its presentation, Axel Bex, MD, PhD, from the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, said differences between ASSURE and the current study may explain the discrepancy in DFS. These include the number of patients, the risk group selection, the inclusion of non–clear-cell RCC in ASSURE, the dosage differences, and the use of central review in the current study.
He reminded the audience that the ideal adjuvant therapy "eradicates occult disease, and by doing this it should eventually pick up a survival benefit, and this survival benefit, together with it being a good, tolerable drug, should improve quality of life."
Looking at the results with sunitinib, Dr Bex said that a survival difference is not yet seen with the drug, partly because it is too early to analyze overall survival, but also potentially because of the biology of the disease and the law of diminishing returns with drug exposure.
He also pointed to the three-fold increased rate of grade 3/4 adverse events with sunitinib vs placebo and the high rate of discontinuation. Alongside that, the survival curves indicate that "there are many patients who are exposed to sunitinib who many develop recurrence."
Dr Bex therefore questioned whether it was worth treating patients for a year to delay mostly asymptomatic recurrences discovered on imaging by a median of 1.2 years.
When Dr Bex and his colleagues first heard about the current results, he organized a poll of European Association of Urology guideline panel members to ask them what results would be needed from the study to convince them to change their practice.
Most respondents said that to change their practice they would need to see a significant improvement in DFS, at a hazard ratio of at least 0.66 to 0.75 and, crucially, a significant overall survival difference, at a hazard ratio of at least 0.75.
A similar poll of 22 patient representatives from the International Kidney Cancer Coalition who had nonmetastatic disease and had previously undergone surgery indicated that they would consider taking a drug like sunitinib in the absence of an overall survival benefit if it yielded a DFS of at least 2 years.
However, more than 30% of patients said they would not consider taking the drug at all if it did not come with an overall survival benefit.
Summarizing, Dr Bex said that the current evidence in support of sunitinib in the adjuvant setting is "weak" and that mature overall survival data from the currently available study, alongside further results from ongoing investigations, are needed before clinical practice should be changed.
The study was funded by Pfizer Inc. Dr Ravaud disclosed that he was a member of advisory boards in RCC for Pfizer, Novartis, GlaxoSmithKline, Roche, and Bristol-Myers Squibb; received institutional support grants from Pfizer and Novartis; and received housing and transportation for meetings and speeches by Pfizer, Novartis, and Bristol-Myers Squibb. Other authors disclosed several relevant financial relationships, including receipt of funding from Pfizer.
European Society for Medical Oncology (ESMO) Congress 2016. Abstract LBA11_PR. Presented October 10, 2016.
N Engl J Med. Published online October 10, 2016. Abstract
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Cite this: Sunitinib Shows Promise as Adjuvant Therapy in RCC - Medscape - Oct 13, 2016.