52: CABOSUN II: A Phase 2, Open-Label, Multi-Center Randomized Study of Cabozantinib (CABO) vs. Sunitinib (SUN) for Non-Clear Cell Renal Cell Carcinoma (NCCRCC)

Background: NCCRCC are diverse, rare diseases with limited data to guide treatment. CABO is highly effective
in clear cell RCC, but it is unknown whether it is superior to SUN for metastatic NCCRCC.

Methods: In this phase II study (NCT03541902), patients (pts) were randomized 1:1 to CABO 60mg daily or SUN 50mg daily (4 weeks on, 2 weeks off). SUN dose modification was allowed for toxicity. Sixty pts with metastatic NCCRCC were planned to detect CABO as better than SUN (1-sided). Stratification was by papillary RCC (PRCC) vs. non-PRCC (NPRCC), IMDC risk group, and prior TKI. The primary outcome was progression-free survival (PFS) [RECIST v1.1] compared between arms (log-rank test). Secondary outcomes were objective response rate (ORR), overall survival (OS), and adverse event (AE) rates (2-sided).

Results: 32 pts were randomized to CABO (N=15) or SUN (N=17) between 9/2018 and 6/2021. The trial stopped early
due to a change in standard therapy for PRCC. Median ages were 57 and 61 years for CABO and SUN. Pts were primarily white (84%), male (72%), and with good/intermediate risk (88%). NPRCC were chromophobe (N=6; 5 received SUN), unclassified (N=5), and MiT family translocation (N=3; all received
CABO). With median follow-up 33.3 months, median PFS for CABO vs. SUN was 8.2 vs. 13.8
months (p=0.96). There were no statistically significant differences in ORR or OS between arms. AEs were in
line with previous studies.

Conclusions: CABO was not superior to SUN in this study. Despite stratification by PRCC/NPRCC, differences in NPRCC subtypes between arms may have impacted the results. Most pts with chromophobe histology (often indolent)
received SUN while all pts with MiT family translocation (relatively aggressive) received CABO. Permitted SUN
dose modifications may have influenced outcomes. While CABO was superior to SUN
for PRCC in the PAPMET study, optimal treatments for rare, NPRCC remain a pressing need.