Long-term efficacy and patient experience with neoadjuvant cabozantinib for locally advanced renal cell carcinoma.

511 Background: Our phase 2 trial (NCT04022343) established that neoadjuvant cabozantinib provided clinical benefit in high-risk clear cell renal cell carcinoma (ccRCC) without complicating subsequent nephrectomy and was associated with increased intratumoral CD8+ T-cell infiltration. Here, we report updated long-term survival and analyze its impact on sarcopenia, frailty, and quality of life (QoL). Methods: Seventeen patients with clinical stage ≥T3 ccRCC received cabozantinib (60 mg daily) for 12 weeks, after which they underwent nephrectomy. Overall (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Skeletal muscle index (SMI) was calculated from segmented muscle area at the L3 vertebra level on MRI scans using Slice-O-Matic software. Frailty was scored as a sum of 5 metrics (shrinking, weakness, exhaustion, low activity, slow walking speed). QoL was assessed with the FKSI-19. Changes from baseline were analyzed using the Friedman and Wilcoxon signed-rank tests. Results: At a median follow-up of 57.7 months, the 5-year OS rate was 81.4% and the 5-year DFS rate was 65.7%. There was no significant change in SMI, indicating no treatment-induced muscle loss. While underpowered, sarcopenic patients had a trend toward less favorable tumor response (22% partial response vs 43% in non-sarcopenic; p=0.63). Frailty scores remained low, indicating a non-frail status, with no clinically significant change during treatment (mean 1.18 to 2.06 on a 25-point scale). Mean QoL scores declined from baseline to week 6 (60.0 vs 48.7; p=0.0004), consistent with the therapy's early side-effect profile, but did not decline at week 12. This decline was not associated with survival outcomes. Conclusions: Long-term follow-up demonstrates encouraging survival for high-risk ccRCC patients received neoadjuvant cabozantinib. The regimen is well-tolerated; patients proceeded to surgery without developing frailty or losing vital muscle mass. QoL stabilized after an initial decrease, suggesting patient adaptation to side effects rather than cumulative toxicity, which supports further investigation of this strategy. Clinical trial information: NCT04022343 . Mean FKSI-19 QoL scores (0=worst, 76=best). Timepoint Mean (±SD) Baseline 60.0 (±10.5) Week 6 48.7 (±10.6) Post- Cabozantinib 48.5 (±9.9)