At the 2019 ESMO Congress in Barcelona, Spain, a team reported findings from an initial “estimand” framework analysis of data from S-TRAC and another placebo-controlled study, PROTECT, suggesting that more specific subgroup analyses can be incorporated into future clinical renal cell carcinoma (RCC) studies that could account for in-treatment events and help physicians understand how they are likely to affect treatment outcomes in the real world.

Even among younger and otherwise healthy patients with locoregional renal cell carcinoma (RCC) who are at high risk of recurrence after nephrectomy, sunitinib’s toxicities are largely reversible without dose reductions and offer modest but meaningful reductions in disease recurrence, according to authors of the randomized, prospective phase 3 S-TRAC study (ClinicalTrials.gov Identifier: NCT00375674).1,2 The study enrolled 615 patients with high-risk RCC — those with T3 disease or node-positive disease — to compare long-term disease recurrence among those who underwent a year of sunitinib therapy vs those who were administered placebo. Adjuvant sunitinib prolonged disease-free survival (DFS) with manageable toxicities.

“We were able to show about a 24% reduction in the risk of disease recurrence associated with that 1 year of treatment with sunitinib,” study coauthor Daniel J. George, MD, Division of Oncology, Duke Cancer Center, in Durham, North Carolina, told Cancer Therapy Advisor. “If you follow this out to 5 years, there is still an 8% absolute benefit of adjuvant sunitinib in this setting.”

However, these overall treatment outcomes in clinical trial settings can obscure important genomic or experiential influences that can vary from patient to patient, particularly in real-world clinic settings. For example, in S-TRAC, the prognostic value of a 16-gene recurrence score assay was confirmed, suggesting the assay can identify which patients are genetically, rather than merely clinicopathologically, at high risk of recurrence, and who are therefore thought to be more likely to benefit from adjuvant treatment.3

Genomic Influences

More recently, to further explore germline genomic influences on adjuvant sunitinib therapy outcomes in RCC, researchers also conducted an exploratory analysis of an insertion/deletion mutation and 10 single-nucleotide polymorphisms (SNPs) for angiogenesis- and hypoxia-related genes and their associations with clinical outcomes in the S-TRAC study, using patient blood samples.2 A total of 286 patients were genotyped; 142 who were administered adjuvant sunitinib and 144 who received placebo. DFS was longer among patients in the sunitinib group who had the VEGFR1 SNP rs9554320 C/C (hazard ratio [HR], 0.44; 95% CI, 0.21–0.91; P =.023), VEGFR2 rs2071559 T/T (HR, 0.46; 95% CI, 0.23–0.90; P =.020), and eNOS rs2070744 T/T (HR 0.53; 95% CI, 0.30–0.94; P =.028), the authors reported.2 

“Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P ≤.05), and A/A versus C/C with sunitinib (P =.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P =.038) and combined (P =.006) groups,” they reported.2  (Importantly, however, P values were not statistically adjusted for multiple comparisons, increasing the risk of false-positive findings.)

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Separately, using an “estimand” framework to better account for variations in patients’ cancer care experiences and events, the study authors explored outcomes from 2 clinical studies of adjuvant therapy for RCC.

Estimands more precisely identify and define treatment effects and events of interest than do traditional outcomes measures in clinical trials, in order to better account for variations in patients’ experiences (so-called “intercurrent events” such as treatment-emergent adverse event discontinuations, second primary malignancies, initiation of new treatment regimens or patient deaths due to causes other than disease or treatment).

“Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma,” the authors concluded, cautioning that independent validation studies are needed to confirm the findings.2