Background: LEN 18 mg + EVE 5 mg is approved for advanced RCC following anti-angiogenic therapy. Study 218 was a phase II study evaluating LEN 14 mg vs LEN 18 mg, both in combination with EVE 5 mg, for the treatment of clear cell RCC following treatment with a VEGF-targeted therapy. We have previously reported that the LEN 14 mg arm did not demonstrate noninferiority vs the LEN 18 mg arm for objective response rate (ORR) as of wk 24 by investigator assessment, the primary endpoint of the study. In this exploratory analysis of Study 218 data, we evaluated the efficacy of LEN 14 mg vs LEN 18 mg, both in combination with EVE 5 mg, per IIR assessment and by prior ICI status per investigator assessment. Methods: Pts with measurable clear cell RCC (1 prior VEGF-targeted therapy; prior PD-1/PD-L1 therapy permitted) were randomly assigned 1:1 to LEN 14 mg or 18 mg (starting dose) + EVE 5 mg daily. 115 pts in the LEN 14 mg arm were titrated to LEN 18 mg at cycle 2 as they did not experience intolerable grade 2 or any grade ≥3 TEAEs requiring dose reduction within cycle 1. We analyzed ORR and PFS by IIR per RECIST v1.1; additionally, efficacy endpoints (ORR, PFS, and OS) were analyzed by investigator assessment per RECIST v1.1 by prior ICI status. Results: 311 pts (LEN 14 mg arm, n=156; LEN 18 mg arm, n=155) were included in the efficacy analysis and 341 pts (LEN 14 mg arm, n=173; LEN 18 mg arm, n=168) were included in the summary safety analysis. ORR by IIR (LEN 14 mg arm: 39.7%, 95% CI 32.1–47.4; LEN 18 mg arm: 38.7%, 95% CI 31.0–46.4) was similar between treatment arms. PFS by IIR was numerically longer in the LEN 18 mg arm (median 12.9 mos, 95% CI 9.2–17.1) vs the LEN 14 mg arm (median 11.0 mos, 95% CI 9.3–12.9). OS was numerically longer in the LEN 18 mg arm (median not evaluable [NE], 95% CI 23.8–NE) vs the LEN 14 mg arm (median 27.0 mos, 95% CI 18.3-NE) (previously reported). In 82 pts with prior ICI, for the LEN 14 mg (n=43) vs 18 mg (n=39) arms (95% CI): ORR was 30.2% (17.2–46.1) vs 51.3% (34.8–67.6) by investigator assessment, respectively; median PFS was 12.0 mos (8.9–16.7) vs 12.9 mos (8.4–NE) by investigator assessment, respectively; and median OS was 17.1 mos (10.6–NE) vs 18.0 mos (13.1–NE), respectively. Endpoints were generally numerically improved in the LEN 18 mg arm in pts without prior ICI (data will be presented). As previously reported, the safety profile was similar in both treatment arms: 71.7% of pts in the LEN 14 mg arm and 76.8% of pts in the LEN 18 mg arm had grade 3/4 TEAEs. Conclusions: ORR was similar between treatment arms and PFS was numerically longer in the LEN 18 mg arm per IIR. Efficacy outcomes were generally numerically improved for the LEN 18 mg arm compared with the LEN 14 mg arm, regardless of prior ICI. As previously reported, safety was similar in both treatment arms. These results further support starting pts with RCC at the higher 18 mg dose of LEN + EVE 5 mg. Clinical trial information: NCT03173560.