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4524 Background: In the primary analysis of the CLEAR trial of patients (pts) with aRCC, L+P significantly improved efficacy vs S (Motzer NEJM 2021). Results were further confirmed at the final prespecified OS analysis (Motzer JCO 2024). Here, we discuss patterns of progression and subsequent therapy in CLEAR. Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomly assigned (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were region and MSKCC prognostic risk group. To explore progression pattern within individual organs, time to progression was defined for each organ independently using lesions within each specific organ only, based on Independent Image Review per RECIST v1.1. Medians and quartiles were estimated with Kaplan-Meier (KM) method; 95% CIs were estimated with a generalized Brookmeyer and Crowley method. Hazard ratio (HR) reported is for L+P vs S based on Cox regression model with treatment as factor; HR was stratified by region and MSKCC prognostic groups. The Efron method was used for correction for ties. Results: The HRs (95% CI) of time to progression for L+P vs S across tumors in different organs were: bone, 0.40 (0.25-0.63); CNS, 0.47 (0.19-1.19); kidney, 0.65 (0.37-1.14); liver, 0.52 (0.32-0.84); lung, 0.48 (0.36-0.62); and lymph nodes, 0.63 (0.46-0.85). At overall disease progression, the median sums of diameters of target lesions were lower with L+P vs S (29.8mm vs 42.8mm; Table). In the L+P arm, 181 pts received subsequent anticancer regimens during survival follow-up (43 received axitinib and 101 received cabozantinib). In the S arm, 246 pts received subsequent anticancer regimens (47 received axitinib and 107 received cabozantinib). The median duration of axitinib as the first anticancer regimen (95% CI) after L+P was 23.7 months (5.3-not estimable NE), and after S was 12.6 months (6.8-NE). The median duration of cabozantinib as the first anticancer regimen (95% CI) after L+P was 13.2 months (8.2-NE), and after S was 7.1 months (4.1-20.0). Conclusions: Pts in the L+P arm trended to show later progression across tumors in different organs. At overall disease progression, the tumor burden of target lesions was lower with L+P vs S; and pts in the L+P arm stayed on 2L axitinib or cabozantinib longer than pts in the S arm. Together, these results continue to support L+P as a standard-of-care 1L therapy in pts with aRCC. Clinical trial information: NCT02811861 . Table: see text
Grünwald et al. (Sat,) studied this question.