4555 Background: A subset of patients (pts) with metastatic renal cell carcinoma (mRCC) receiving contemporary first line (1L) immune checkpoint inhibitor (ICI) combinations are considered to be primary refractory. The optimal sequence therapy for this patient population is not well established. Herein, we report practice patterns and clinical outcomes of second line (2L) therapy in pts with primary refractory mRCC. Methods: Data from pts with primary refractory mRCC to 1L ICI and who received 2L therapy were collected through the IMDC. Patients with primary refractory RCC were defined as patients who experienced progressive disease (PD) as best response per RECIST 1.1 criteria. Overall survival (OS) and time to treatment failure (TTF) were calculated from initiation of 2L therapy; their distributions were estimated by the Kaplan Meier methodology. Results: In total, 494 pts had primary progression on 1L ICI, of which 356 (72%) went on to receive subsequent 2L therapy. The most common regimens in the 2L setting included: cabozantinib (n = 137; 38%); sunitinib (n = 115; 32%), and pazopanib (n = 37; 10%). 22% of patients had IMDC poor risk at initiation of 2L. Median follow-up from 2L initiation was 18.8 months. Median OS was 14.5 months, and the median TTF was 5.4 months for the whole cohort. The median OS was 14.4 months (95% CI 11 – 21.4) for cabozantinib, 10.7 months (95% CI 7 -16.6) for sunitinib, and 15.3 months (95% CI 9 – 46) for pazopanib. The median TTF was 4.5 months (95% CI 3.7 -5.6) for cabozantinib, 3.1 months (95% CI 2.8 – 4.4) for sunitinib, and 2.8 months (95% CI 1.7 – 3.6) for pazopanib. The ORR was 20% for pts receiving cabozantinib, 10% for pts receiving sunitinib, and 16% for patients receiving pazopanib. For pts treated with 2L cabozantinib, 84 (61%) had prior dual ICI and 53 (39%) had prior ICI + VEGF. By contrast, for patients treated with sunitinib or pazopanib, the majority (96% and 95%, respectively) had prior dual ICI as 1L. Conclusions: To our knowledge, this is the first initiative to report practice patterns and outcomes of subsequent 2L therapies in patients with primary refractory mRCC to contemporary 1L ICI combinations. Cabozantinib was the most frequently used regimen in this patient population and demonstrated favorable clinical outcomes compared to sunitinib or pazopanib. Biomarker evaluation is needed to explore the mechanism of primary resistance and novel therapeutic strategies for this group. Outcomes of patients with primary refractory mRCC receiving 2L therapies. Treatment Arm N Median OS, months (95% CI) Median TTF, months (95% CI) ORR, % 2L Cabozantinib (1L dual ICI) 84 15 (11 – 26.2) 4.2 (3.4 – 6.6) 20 2L Cabozantinib (1L ICI + VEGF) 53 13.5 (9.8 – NR) 4.8 (3.6 – 5.9) 20 2L Sunitinib 115 10.7 (7 – 16.6) 3.1 (2.8 - 4.4) 10 2L Pazopanib 37 15.3 (9 – 46) 2.8 (1.7 – 3.6) 16