Cabozantinib as subsequent therapy to an immune checkpoint-based therapy in renal cell carcinoma, phase 2 interventional study (AT ASIA, KCSG GU21-02).

547 Background: Immune checkpoint inhibitors (ICIs) have significantly advanced the treatment of advanced renal cell carcinoma (aRCC). However, many patients develop disease progression, underscoring the need for effective second-line therapies. The optimal sequencing after ICI-based treatment remains under investigation. This phase II study evaluates the efficacy and safety of cabozantinib in patients with aRCC who progressed on first-line ICI combination therapies. Methods: This multicenter, prospective, phase II trial enrolled patients with advanced RCC who had progressed after receiving either nivolumab plus ipilimumab (Cohort 1) or a PD-1/PD-L1 inhibitor in combination with a VEGFR-TKI (e.g., pembrolizumab plus axitinib or pembrolizumab plus lenvatinib; Cohort 2). Non-clear cell histology was allowed in Cohort 2. Eligible patients were treated with cabozantinib at standard dosing. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: From September 2021 to August 2024, 88 patients (Cohort 1, n=49; Cohort 2, n=39) were enrolled across 13 institutions. The baseline International Metastatic RCC Database Consortium (IMDC) risk categories were as follows: favorable (15.9%), intermediate (71.6%), and poor (12.5%). Prior nephrectomy was reported in 42.0% of patients, and non-clear cell histology accounted for 20.5% of Cohort 2. After a median follow-up of 18.3 months (95% CI, 11.3–25.3), the ORR was 47.7%. Partial responses were observed in 51.0% (95% CI, 40.1–61.5) of patients in Cohort 1 (ICI-ICI) and 43.6% (95% CI, 30.5–56.8) in Cohort 2 (ICI-VEGFR-TKI). Stable disease was achieved in 43.2% of patients overall. The median PFS was 7.9 months, with a PFS of 9.2 months (95% CI, 6.6–11.8) in Cohort 1 and 7.1 months (95% CI, 6.7–7.6) in Cohort 2. No significant difference in OS was observed between the cohorts, with a 12-month OS rate of 65.2%. Safety analysis revealed no novel adverse events beyond the known cabozantinib toxicity profile, with grade 3/4 hypertension, hand-foot syndrome, and fatigue being the most commonly reported events. Conclusions: Cabozantinib demonstrated substantial efficacy as a second-line treatment for advanced RCC following progression on ICI-based therapies, with a tolerable safety profile. These findings reinforce cabozantinib as an important treatment option for patients progressing after ICI regimens. Clinical trial information: NCT04714697 .