Adjuvant therapy with the vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) sunitinib after nephrectomy was associated with increased mortality among older women with renal cell carcinoma (RCC), according to a post-hoc subgroup analysis of data from the ASSURE (E2805) clinical trial, presented (abstract 575) at the 2018 Genitourinary Cancers Symposium, held February 8–10 in San Francisco.
“Any post-hoc exploratory analysis requires confirmatory studies,” cautioned lead study author Ronac Mamtani, MD, of the University of Pennsylvania in Philadelphia. “These findings, if validated, highlight the importance of considering sex and age on VEGF-TKI treatment outcomes, future study designs, and RCC tumor biology.”
The benefit of adjuvant VEGF TKIs for RCC has been a matter of debate. The ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable RCC) trial found no overall or disease-free survival (DFS) benefit for patients undergoing adjuvant sunitinib or sorafenib—but the STRAC study found a DFS benefit for sunitinib, Dr. Mamtani said.
VEGF pharmacokinetics are known to differ by sex. Older patients and women are at higher risk of toxicity from both sunitinib and sorafenib.
“Given the uncertain risk–benefit ratio, identifying subgroups expected to derive benefit or harm from therapy could lead to a more precise approach to therapy,” Dr. Mamtani said. “Because of known sex-differences in the pharmacokinetics and tissue distribution of VEGF-TKIs, we assessed the interaction of age and sex on treatment outcomes among patients in the phase III ASSURE trial.”
The study authors’ post-hoc analysis included data from 1,943 patients with ≥ pT1b resected grade 3–4 and/or node-positive RCC.
Disease recurrence risk among women older than the median trial population age of 56 years and who received adjuvant sunitinib was significantly increased compared to those receiving placebo (hazard radio [HR] for DFS, 1.53; 95% CI, 1.03–2.28)—as was the risk of mortality (HR for overall survival, 2.38; 95% CI, 1.39–4.07; P = .017). The DFS finding was “only marginally” statistically significant, Mamtani noted.
There were not similarly increased risks of mortality for younger women or men of any age treated with sunitinib, nor for male or female patients of any age who were treated with sorafenib.
Older patients were “slightly more likely” to develop toxicity with sunitinib regardless of sex, Dr. Mamtani said.
If the reported increase in sunitinib risk for older women is confirmed, potential explanations might include sex differences in sunitinib metabolism related to estrogen. Statistical analyses were not adjusted for multiple tests of correlation, and the post-hoc study design precluded determining mechanisms that may underlie the reported association, acknowledged Dr. Mamtani.
Dr. Mamtani disclosed an advisory or consulting role with Takeda.