Relationships between clinical stage, pathological stage, and disease-free (DFS) survival in renal cell carcinoma as used to inform future neoadjuvant study design: ECOG-ACRIN EA8143 PROSPER analysis.

4540 Background: Estimating risk of renal cell cancer (RCC) relapse based only on pre-surgical data is key to future neoadjuvant trial design. The EA PROSPER phase 3 study accrued pts with clinical stage ≥T2 or T any N+ RCC of any histology for nephrectomy. Pts were randomized to presurgical nivolumab (nivo) followed by primary tumor resection and 9 cycles of adjuvant nivo, or surgery alone followed by observation. We used PROSPER data to assess how baseline data informs risk. We reviewed cT to pT stage transitions, associated cT stages with outcome, and asked if size in addition to cT stage increases predictive accuracy. Methods: Pts with clear cell (cc) RCC were included. cT to pT concordance was assessed by TNM 8 th edition. DFS analysis (time from surgery to recurrence, second primary, or any cause death) was performed; pts with no event were censored at date of last assessment. DFS analysis compared cT groups (cT1/cT2 vs cT3/cT4) in the overall eligible study population and within each study arm. A subset DFS analysis by tumor size among cT2a (> 7-8cm vs >8-10cm) and cT3a (< 7cm vs 7-8cm vs > 8cm) was explored. Cox proportional hazards models were used, and log-rank test was reported to represent global p-value of each model. Wald test p-value was reported for individual group comparison (in assessing more than two groups). Two-sided p-values are reported, all p-values were considered significant at 0.05. Results: Of 819 pts randomized, 732 ccRCC pts (382 surgery only, 350 nivo + surgery) had data available. DFS was significantly different between cT1/cT2 vs. cT3/cT4 group, favoring cT1/cT2 among all pts (HR [cT1/cT2 as reference]=1.56, two-sided log-rank p < 0.001) and in each of the treatment arms separately (nivo + surgery arm HR=1.48, two-sided log-rank=0.04 ; surgery only arm HR=1.63, two-sided log-rank p=0.007). About half of cT1/T2 pts were upstaged to pT3/4, whereas <10% of cT3a were downstaged to pT1b. Higher grade cT1/T2 were more likely to upstage (p-value < 0.001).119 pts with cT2a and 233 pts with cT3a had tumor size data available. There was no significant DFS difference between tumor size groups in the cT2a subset. In cT3a patients, DFS analysis by tumor size showed a trend of increasing risk for 7-8cm and > 8cm groups when compared to < 7cm group, with a statistically significant difference comparing > 8cm vs < 7cm (HR=3.33, two-sided Wald p < 0.001) signifying worse outcome for pts if tumor size > 8cm. Conclusions: In ccRCC pts, baseline cT assessment is associated with DFS outcome. High grade cT1/2 pts risk pathological upstaging to pT3. cT3+ identifies high risk pts, with <10% being downstaged. Pts with cT3a > 8cm have a worse prognosis than patients with < 7cm tumors. These findings should be accounted for in eligibility criteria and risk assessment models for neoadjuvant trials, and explored in other international datasets.