Estimands Framework: Getting Specific About In-Treatment Events

Identifying estimands can harmonize clinical trial findings and facilitate more detailed meta-analytic summaries of, or comparisons between, studies. The study authors analyzed data from the placebo-controlled phase 3 S-TRAC (615 participants) and PROTECT trials (1538 participants; ClinicalTrials.gov Identifier: NCT01235962) to assess the effects of different estimands on adjuvant therapy outcomes among patients with RCC.4 The analysis was funded by Pfizer.

Specifically, they evaluated 4 estimands using data from the 2 studies:

1. Did treatment improve DFS if no patient received a new therapy?


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2. Did treatment improve DFS and delay time to new therapy?

3. Did treatment improve DFS value whether or not the patient received a new therapy?

4. Did the drug improve recurrence-free survival if no patient received a new therapy?

While the estimand framework allowed assessments of these more specific questions than traditional trial outcomes, that specificity came at the cost of lost statistical power, at least in this retrospective setting. (Although treatment effects were similar for the assessed estimands and each trial’s specified primary outcomes, the studies had not been statistically powered to answer estimand-based questions and therefore, some associations failed to reach statistical significance, the authors noted.)

But the authors hope the consistency between these 2 clinical trial data sets will encourage incorporation of estimands in future studies’ designs.

“The new framework clarifies that different analyses address different questions,” the authors reported. “The choice of the primary estimand impacts study design and may have regulatory implications. In RCC, considerations as to whether all second primary malignancies or non–disease-related deaths should be considered disease-free survival events are required to further specify study objectives and to determine the events needed for the final analysis.”

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Adjuvant sunitinib involves significant but manageable toxicities for patients with high-risk RCC, Dr George acknowledged. The most common toxicities were hand-foot syndrome, fatigue, and hypertension, which were “generally reversible.” Toxicity resulted in a dose reduction for only one S-TRAC patient.

“That is probably the biggest difference between S-TRAC and all the other adjuvant studies that were done,” Dr George said. “In fact, if you look at some of the adjuvant trials that were done where they started at full dose and didn’t dose-reduce, those patients saw similar benefits to what we saw in the entire population of S-TRAC. It really suggests that if you have a patient who is healthy, is motivated, is young, and you believe can tolerate sunitinib, those patients very well may benefit.”

“Whether the patient chooses to do adjuvant sunitinib or not, they ought to be given an opportunity to have an informed discussion,” Dr George said.

With additional genomic and estimand-informed studies and analyses, those informed conversations might become much more tailored to individual patients.

References

1. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. New England Journal of Medicine. 2016;375:2246-2254.

2. George DJ, Martini JF, Staehler M, et al. Phase III Trial of Adjuvant Sunitinib in Patients with High-Risk Renal Cell Carcinoma: Exploratory Pharmacogenomic Analysis. Clinical Cancer Research. 2019; 25(4):1165-1173. doi: 10.1158/1078-0432.CCR-18-1724

3. Rini B, Escudier B, Martini JF, et al. Validation of the 16-gene recurrence score in patients with locoregional, high-risk renal cell carcinoma from  a phase III trial of adjuvant sunitinib. Clinical Cancer Research. 2018;24(18):4407-4415.

4. George DJ. Impact of estimand selection on adjuvant treatment outcomes in renal cell carcinoma (RCC). Presented at the 2019 ESMO Congress; September 27-October1, 2019; Barcelona, Spain. Poster abstract 980P.