Efficacy outcomes by patterns of progression in patients with advanced renal cell carcinoma from the phase 3 CLEAR trial.

4527 Background: In CLEAR, lenvatinib + pembrolizumab (L+P) significantly improved efficacy vs sunitinib (S) in treatment-naïve patients with advanced renal cell carcinoma (Motzer 2021, Motzer 2024). We summarize efficacy by patterns of progressive disease (PD) for the L+P arm and report survival per a modified PD classification system (based on patients receiving immunotherapy; data cutoff 31 July 2022). Methods: Treatment‐naïve patients (n=1069) who had clear‐cell advanced renal cell carcinoma were randomized (1:1:1) to receive: L 20 mg PO daily + P 200 mg IV Q3W; or L + everolimus; or S 50 mg PO daily (4 wks on/2 wks off). Methods for post-progression survival/OS analyses were previously reported (Grünwald 2025). A modified system of classifying PD (Saal 2025) is used in new analyses of the L+P arm reported here: low risk (progression of existing lesions); intermediate risk (new lesions without progression of existing lesions); high risk (progression of existing lesions + new lesions). The number of patients with PD was determined by independent imaging review at the data cutoff date. Results: At the time of PD, the median tumor burden of target lesions was lower with L+P (−48.1%) vs S (−17.4%). Patients in the L+P arm with larger % decreases in sums of target lesion diameters at PD had longer median post-progression survival (≤-61% n=59, 35.6 mos 95% CI 28.4−39.2; >-61%-≤-34% n=58, 24.4 mos 95% CI 15.5−34.5; >-34% n=59, 20.2 mos 95% CI 16.4−26.9) and OS (Grünwald 2024, 2025). In the L+P arm, most patients had low/intermediate risk PD (Table). Patients with low (HR 0.39; 95% CI 0.22-0.70) or intermediate risk (HR 0.47; 95% CI 0.27-0.81) PD had improved OS vs patients with high risk PD. Patients with low/intermediate risk PD stayed on 1 st subsequent anticancer medication longer than patients with high risk PD (Table). Conclusions: In the L+P arm, PD was mainly characterized by progression of existing lesions or formation of new lesions without progression of existing lesions (low/intermediate risk PD); these patients had improved OS (vs high risk PD) suggesting prognostic/predictive value of patterns of PD. Patients with low/intermediate risk PD stayed on 1 st subsequent anticancer medication longer than patients with high risk PD, implying that 2L therapy can be used effectively upon progression with L+P. These results, together with lower tumor burden seen at PD in the L+P arm (Grünwald 2024), indicate that L+P has robust tumor control, supporting its use as a standard 1L therapy in advanced renal cell carcinoma. Clinical trial information: NCT02811861 . Low risk PD(n=69) Intermediate risk PD(n=91) High risk PD(n=30) Patients with any subsequent systemic anticancer medication during survival follow-up, n (%) 49 (71.0) 58 (63.7) 15 (50.0) Time to discontinuation of 1 st anticancer medication during survival follow-up, median (Q1, Q3) (months) 14.4 (5.6, not estimable) 7.3 (3.1, 20.3) 4.3 (1.5, 13.7) Included data is from the L+P arm.