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Pembrolizumab/lenvatinib survival benefit sustained across RCC risk subgroups


A subgroup analysis of the phase 3 CLEAR trial presented at the 2021 ASCO Annual Meeting showed that the overall survival (OS) benefit with frontline pembrolizumab (Keytruda) plus lenvatinib (Lenvima) observed in the overall population was sustained across risk-defined subgroups.1

Risk group stratification was performed using International Metastatic RCC Database Consortium (IMDC) criteria. Beyond OS, benefits in progression-free survival (PFS) and overall response rate (ORR) were also observed for the pembrolizumab/lenvatinib arm across the risk-defined subgroups.

“Overall, our results indicated that lenvatinib plus pembrolizumab has improved efficacy parameters and outcome parameters compared to sunitinib in all subgroups of patients,” Viktor Grünwald, MD, of the University Hospital Essen in Essen, Germany, explained in his presentation of the data.

Of the 1069 patients enrolled in the multicenter, open-label, randomized phase 3 CLEAR study, 335 were assigned to the lenvatinib plus pembrolizumab arm and 357 were assigned to the sunitinib arm. Median patients age in the lenvatinib plus pembrolizumab and sunitinib arms was 64 years (range, 34-88) and 61 years (range, 29-82), respectively.

By IMDC risk groups, the lenvatinib plus pembrolizumab population had 31.0% with favorable-risk disease, 59.2% intermediate, and 9.3% poor risk. Patients in the sunitinib group had 34.7% with favorable risk, 53.8% intermediate, and 10.4% poor risk.

Focusing on PFS, patients in the IMDC–intermediate/poor risk subgroup treated with lenvatinib plus pembrolizumab had a median PFS of 22.1 months compared with 5.9 months for patients treated with sunitinib (HR, 0.36; 95% CI, 0.28-0.47). In the IMDC–favorable risk subgroup, the median PFS was 28.1 months compared with 12.9 months, respectively (HR, 0.41; 95% CI, 0.48-0.62).

The OS data also favored lenvatinib plus pembrolizumab in both the IMDC–intermediate/poor risk (HR, 0.58; 95% CI, 0.42-0.80) and IMDC–favorable risk subgroups (HR, 1.15; 95% CI, 0.55-2.40), although evaluating OS was considered inadequate due to too few events.

A 72.4% ORR was observed in the lenvatinib plus pembrolizumab arm compared with 28.8% ORR in the sunitinib arm when evaluating the IMDC–intermediate/poor risk subgroup (odds ratio, 6.60; 95% CI, 4.39-9.90). For the IMDC–favorable risk subgroup, the ORRs were 68.2% and 50.8%, respectively (odds ratio, 2.00; 95% CI, 1.17-3.42).

The investigative team also analyzed efficacy data via target kidney lesions, with median PFS favored in the lenvatinib plus pembrolizumab arm (22.1 months) over the sunitinib arm (7.5 months) for patients with target lesions (HR, 0.40; 95% CI, 0.25-0.65). For patients without target kidney lesions, corresponding medians were 25.8 months and 9.4 months, respectively (HR, 0.38; 95% CI, 0.30-0.49).

The ORRs were consistently favored in the lenvatinib plus pembrolizumab arms regardless of target kidney lesion status. Specifically, the ORR was 71.8% compared with 27% with target kidney lesions (odds ratio, 10.55; 95% CI, 4.54-24.52) and 70.8% versus 38.5% without target kidney lesions (odds ratio, 3.78; 95% CI, 2.66-5.37).

In the intent-to-treat population of patients in the lenvatinib plus pembrolizumab arm, complete responses were maintained in 79.3% of patients at 24 months and 74.3% of patients at 36 months.

More, in the 6-month landmark analysis, confirmed response or a reduction in target lesions of more than 75% were observed in 12.4% of patients in the lenvatinib plus pembrolizumab arm compared with 4.5% of patients in the sunitinib arm.

“All patients with complete response to lenvatinib plus pembrolizumab at 6 months were alive at 2 years; similar survival rates were observed for patients who had more than a 75% reduction in target lesions,” wrote the investigators in their poster of the data.

“Notably, patients with complete response or near complete response derived tremendous benefit from this type of combination,” continued Grünwald in his presentation.

The CLEAR study randomized patients 1:1:1 to receive oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks, lenvatinib 18 mg plus oral everolimus (Afinitor) 5 mg once daily, or oral sunitinib 50 mg once daily for 4 weeks on and 2 weeks off.

The study’s primary end point was PFS, with focal secondary end points of OS and ORR. Safety was also evaluated.

These results suggest that lenvatinib plus pembrolizumab could be considered as a potential new treatment option in the first-line setting for patients with advanced RCC.

Click to watch Urology Times video with Dr. Grünwald discussing these results


1. Grünwald V, Powles T, Kopyltsov E, et al. Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): Depth of response and efficacy for selected subgroups in the lenvatinib (LEN) + pembrolizumab (PEMBRO) and sunitinib (SUN) treatment arms. J Clin Oncol 39, 2021 (suppl 15; abstr 4560). 10.1200/JCO.2021.39.15_suppl.4560.

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