A retrospective evaluation of treatment patterns following cabozantinib treatment for advanced renal cancer: The CABONEXT study.

451 Background: Cabozantinib with nivolumab is considered as a standard of care in first-line treatment for metastatic renal cell carcinoma (mRCC). Cabozantinib, a TKI targeting anti-VEGFR, MET and AXL, showed efficacy as a monotherapy or combined with checkpoint inhibitors (CPI). However, little is known about subsequent systemic therapy. This study aimed to report clinical outcomes from subsequent lines following a 1 st or 2 nd line cabozantinib-based therapy in mRCC pts. Methods: We performed a multicentric retrospective study in 19 centers in Europe. From February 2024 to September 2025, all included pts received at least one treatment after 1st or 2nd line based on cabozantinib for mRCC. Patients were divided in 2 groups: Group A with patients that received 1st line cabozantinib-nivolumab and Group B for patients treated by CPI-based therapy followed by 2nd line monotherapy cabozantinib. Primary endpoint was time to treatment failure (TTF). Potential prognostic factors for TTF were assessed in Group B. Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results: 88 pts were included, 78% males with a median age of 62 years. 24 pts (27%) received cabozantinib with nivolumab as 1st-line therapy (group A), and 73% in 2nd line pretreated with dual CPI in 30% and CPI with TKI in 43% (group B). In group A, patients received axitinib (71%), 1st generation TKI (25%) and lenvatinib monotherapy (1pt). Median TTF was 7.5 months with an ORR of 25% and a DCR of 66.7%. 12 pts (50%) had a subsequent line, 8 pts were still on treatment and 4 died before starting a new line. In group B, pts receivred axitinib (25%),everolimus monotherapy (27%), lenvatinib-based therapy (25%), CPI (7.8%) including 2 in combination with tivozanib and 1 with belzutifan. Median TTF was 3.0 months with an ORR of 9.3% and a DCR of 39%. 6 pts (9.3%) were still on treatment, 31 pt (48%) had a subsequent line, 26 (41%) died before (Table 1.). Based on multivariable analysis, 2nd generation TKI seemed to be the best option in the Group B compared to other treatment (HR = 3.91, 95%CI 1.81;8.43, p=0.0005). Previous dose reduction of cabozantinib was associated with prolonged TTF (HR = 2.20, p=0.02). Complete data are expected until December 2025. Conclusions: This analysis confirms antitumoral efficacy of 2nd-generation TKI, mostly axitinib and lenvatinib, after 1st or 2nd-line cabozantinib. These benefits remain modest and the need for innovative therapies targeting resistance mechanisms and optimal treatment sequences is still pending. Treatment characteristics following cabozantinib-based therapy in group A and group B. Group A Group B Number of pt 24 64 Axitinib 17 (70.8) 16 (25) Lenvatinib based therapy 1 (4.1) 16 (25) Everolimus alone 0 17 (26.6) CPI 0 3 (4.7) Tivozanib 0 4 (6.3) Other 6 (25) 7 (10.9) Median TTF (months) 7.5 3 ORR 25.0% 9.3% DCR 66.7% 39.1%