Adjuvant TKI Use in High-Risk Clear Cell RCC Not Effective

Initial results of the ASSURE trial showed that adjuvant sunitinib or sorafenib did not improve disease-free survival among patients with renal cell carcinoma (RCC). Recently published updated results of the trial looked at outcomes among a high-risk subset of patients and showed that neither prognostic category of the tumor nor dose intensity of therapy led to a difference in survival in this group of patients.

“High-risk patients might be the ideal population in which to detect activity of adjuvant sunitinib or sorafenib,” wrote Naomi B. Haas, MD, of Abramson Cancer Center at the University of Pennsylvania, and colleagues, in JAMA Oncology. “Consistent with the primary analysis, our analysis of E2805 patients with clear cell RCC and high-risk (pT3 and higher or node-positive) disease showed no statistically significant benefit from these agents vs placebo. In addition, we observed no difference in outcome by dose quartile.”

Initial results of the ASSURE trial were published in March 2016. The trial looked at the use of vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) in patients with primary resected RCC. Patients received 1 year of adjuvant sunitinib, sorafenib, or placebo. Results showed a median disease-free survival of 70.0 months for sunitinib, 73.4 months for sorafenib, and 79.6 months for placebo, showing no benefit for sorafenib or sunitinib in this patient population.

Since these results were published, results of the S-TRAC trial showed improved disease-free survival with sunitinib in patients with clear cell predominant pT3–4 or node-positive disease. Based on this, Haas and colleagues conducted an updated analysis of their study looking only at a high-risk subset of patients.

The 5-year disease-free survival rates for this group were 47.7% for sunitinib, 49.9% for sorafenib, and 50.0% for placebo. The 5-year overall survival rates were 75.2% for sunitinib, 80.2% for sorafenib, and 76.5% for placebo.

The researchers also looked at disease-free survival outcomes for these high-risk patients by agent in quartiles of total dose per 6-week cycle, but they found no difference by treatment arm. In addition, duration of therapy or starting dose had no effect on disease-free survival.

In an editorial that accompanied the results, Bhupinder Mann, MBBS, and James Zwiebel, MD, of the Cancer Therapy Evaluation Program at the National Cancer Institute, highlighted some of the limitations of this study, including that the cohort with clear cell RCC was prespecified, but that the analyses of dosing cohorts and higher stage were post hoc. In addition, the trial was not adequately powered to detect differences in these subsets of patients.

They went on to question one of the existing paradigms of clinical trials as demonstrated by the results of the ASSURE trial.

“Clinical benefit of a treatment demonstrated in patients with metastatic cancer leads to an optimistic and, understandably, logical belief that the same treatment is likely to be active against those apparently quiescent malignant cells that lead to disease recurrences after removal of the primary cancer,” they wrote. “Thus, a simple paradigm has directed the development of adjuvant systemic therapy of solid tumors: administration of the systemic treatment regimen found to be active in the metastatic disease to a subset of patients at high risk of disease recurrence.”

Based on the negative results of this study, they wrote that they would not necessarily abandon the existing paradigm, but that “the biology of established and visible growing metastatic tumors and the biology of apparently quiescent malignant cells in transition urgently need to be understood better and should be studied in parallel.”