Final database lock results of the phase 2 cohort of lenvatinib + pembrolizumab for progressive disease after a PD-1/PD-L1-containing therapy in metastatic clear cell renal cell carcinoma

BACKGROUND: Lenvatinib + pembrolizumab is approved for the first-line treatment of advanced renal cell carcinoma (RCC). In the CLEAR trial, the combination showed statistically significant/clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs sunitinib (Motzer R et al. NEJM. 2021). As immune checkpoint inhibitors (ICIs) have become standards of care as first-line treatment of RCC, an unmet need exists for patients who have disease progression after treatment with ICIs. A phase 1b/2 trial of lenvatinib + pembrolizumab was performed in multiple tumor types enrolling patients who had or had not received prior therapy; the primary analysis of the RCC cohort has been reported previously (Lee C-H et al. Lancet Oncol. 2021). Here, we report the final results of this RCC cohort with an additional 24 months of follow-up. METHODS: Eligible patients ≥18 years old with measurable disease were treated with lenvatinib 20 mg daily + pembrolizumab 200 mg once every 3 weeks. The primary endpoint (ORR at week 24 [ORRwk24] per immune-related [ir] RECIST by the investigators) has been previously reported (Lee C-H et al. Lancet Oncol. 2021). Secondary endpoints included ORR, duration of response (DOR), PFS (each by the investigators), OS and safety. In the analyses reported herein, efficacy data were grouped by prior therapy patients had received, including ICI-pretreated, treatment-naïve, and previously treated but ICI-naïve. Tumors were assessed by the investigators per irRECIST and RECIST v1.1 (modified to allow assessment of ≤10 target lesions [≤5 per organ]). RESULTS: 145 Patients were enrolled, of whom 105 were ICI-pretreated, 23 were treatment-naïve, and 17 were previously treated ICI-naïve. By the final database lock date (August 24, 2022), the median duration of follow-up for OS was 37.7 months (95% CI 35.2–42.7). Efficacy analyses included 104 ICI-pretreated patients and 22 treatment-naïve patients; 1 patient in either group was excluded as they were negative for clear cell disease. Per irRECIST by investigator assessment, ORR was 62.5% for ICI-pretreated patients (median DOR: 14.1 months), 77.3% for treatment-naïve patients (median DOR: 24.2 months), and 52.9% for previously treated ICI-naïve patients (median DOR: 9.0 months) (Table). Notably, 18-month PFS rates were 38.0% for ICI-pretreated patients, 70.5% for treatment-naïve patients, and 36.1% for previously treated ICI-naïve patients (Table). The median OS was 32.1 months for ICI-pretreated patients, 55.8 months for treatment-naïve patients, and 30.3 months for previously treated ICI-naïve patients; 24-month OS rates were >50% in all groups. Additional efficacy data are included in the Table. For those who had their dose of lenvatinib reduced (per recommended algorithms for standard adverse event [AE] management) the median time to first dose reduction was 2.10 months (range 0.1–16.6) for ICI-pretreated patients (n=75), 6.47 months (range 0.3–33.1) for treatment-naïve patients (n=18), and 2.89 months (range 1.0–12.5) for previously treated ICI-naïve patients (n=10). Overall, treatment-related (TR) AEs were reported in 99.3% of all 145 patients; grade ≥3 TRAEs were reported in 66.2%. The most common TRAE was diarrhea (n=88). Treatment-emergent, clinically significant (CS) AEs and AEs of special interest for pembrolizumab (AEOSIs) were reported in 95.2% and 55.9% of patients, respectively. Hypertension was the most common grade ≥3 CSAE (n=37), severe skin reactions were the most common grade ≥3 AEOSI (n=6). The median time to first onset of CSAEs was 0.64 months; the median time to first onset of AEOSIs was 2.07 months. [Image: see text] CONCLUSIONS: Lenvatinib + pembrolizumab demonstrated promising and durable antitumor activity with a manageable safety profile in patients with metastatic RCC, including in those who were ICI-pretreated. To our knowledge, this represents the largest cohort of ICI-pretreated patients with RCC prospectively treated in a clinical trial. CDMRP DOD Funding: no