Body composition and quality of life (QOL) with lenvatinib + everolimus (len + eve) versus cabozantinib (cabo) in metastatic clear cell renal cell carcinoma (ccRCC) after PD-1 inhibitor progression: Results from the randomized phase II LenCabo trial.

4538 Background: The LenCabo trial (NCT05012371) was the first randomized head-to-head comparison of contemporary second-line or later treatments after progression on PD-1 based immune checkpoint inhibition (ICI). Len + eve significantly improved progression-free survival (PFS). There were numerical, but not statistically significant, differences in treatment discontinuation and ≥ grade 3 adverse events. Although cabo and len share many kinase targets, lenvatinib also blocks FGFR, and its combination with the mTOR inhibitor everolimus may affect body composition through metabolic effects. We sought to investigate how patient QOL and body composition changed after treatment with len + eve and cabo. Methods: LenCabo was a multicenter, phase II trial that randomized pts with metastatic ccRCC to len 18 mg/d plus eve 5 mg/d vs cabo 60 mg/d after 1-2 prior lines of treatment, including a PD-1 ICI. Pre-planned, health-related QOL was measured by FKSI DRS at baseline and after 60 days. Post-hoc, body composition was measured using an AI segmentation tool (Voronoi DAFS) at the L3 vertebra from baseline CT scans and after 4 months. Outcomes were compared using proportional odds models adjusting for baseline values and including nonlinear terms as restricted cubic splines. Pre-specified, body composition models additionally adjusted for prior VEGF-targeted therapy, age, IMDC risk category, and sex. Results: 86 pts received at least 1 dose of assigned len + eve (n=40) or cabo (n=46). 38 pts completed baseline and day 60 FKSI DRS (len + eve = 20, cabo = 18). The QOL comparison by FKSI DRS at day 60 was inconclusive (OR = 0.51 in favor of cabozantinib, 95% CI 0.16-1.64, p=0.26). 67 pts had body composition measured at baseline and 4 months (len + eve = 30, cabo = 37). After 4 months of treatment, len + eve was associated with a significantly lower odds of having a higher body mass index (BMI), skeletal muscle mass (SMMi), and subcutaneous adiposity (SATi, Table). Conclusions: In patients with metastatic ccRCC progressing on PD-1 ICI, len + eve was associated with significantly greater reductions in BMI, skeletal muscle mass, and subcutaneous adiposity compared with cabo at 4 months. The study did not contradict the supposition that the two treatment arms yield the same QOL at day 60. These results suggest that the superior PFS efficacy of len + eve in this setting is accompanied by a more pronounced catabolic effect. Clinical trial information: NCT05012371 . Body composition measures at 4 months by treatment. Adjusted mean of len + eve vs. cabo Odds ratio for higher measure(95% CI) P value BMI 28.5 vs. 29.4 0.36(0.15 – 0.88) 0.03 SMMi 47.5 vs. 49.7 0.30(0.11 – 0.79) 0.01 SATi 65.7 vs. 73.4 0.21(0.08 – 0.55) 0.002 Abbreviations: BMI, body mass index; SMMi, skeletal muscle mass index; SATi, subcutaneous adipose tissue index.