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Pembrolizumab plus lenvatinib boosts PFS2 in advanced renal cell carcinoma

Kidney Cancer

Kidney Cancer

A prespecified analysis from the phase 3 CLEAR trial showed that the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) extended the time to progression on next line of therapy (PFS2) compared with sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC).1

Results presented at the 2022 ASCO Annual Meeting showed that he median PFS2 was not reached (95% CI, not estimable [NE]-NE) for the 355 patients in lenvatinib plus pembrolizumab cohort compared with 28.7 months (95% CI, 23.0-NE) among the 357 patients in the sunitinib cohort. The risk of second progression was reduced by 50% (HR, 0.50; 95% CI, 0.39-0.65).

At the 24-month mark, PFS2 rate was 72.7% (95% CI, 67.3%-77.4%) and 54.2% (95% CI, 48.4%-59.6%) in the investigative combination therapy and sunitinib arms, respectively. At 36 months, PFS2 rate was 61.9% (95% CI, 53.7%-69.0%) and 42.9% (95% CI, 32.8%-52.5%) in the lenvatinib/pembrolizumab arm and sunitinib arm, respectively.

“These findings remained consistent after accounting for subsequent therapies, as evidenced by PFS2 and adjusted overall survival,” the authors wrote in a poster of the data. “These results further support the use of lenvatinib plus pembrolizumab as a standard-of-care first-line treatments for patients with [advanced] RCC.”

The overall CLEAR trial comprised 1069 patients with advanced RCC who were then randomized in a 1:1:1 fashion to receive lenvatinib 20 mg oral QD plus pembrolizumab 200 mg IV Q3W (n = 355), lenvatinib 18 mg oral QD plus everolimus 5 mg oral QD (n = 357), or sunitinib 50 mg oral QD for 4 weeks on and 2 weeks off (n = 357).

Previously reported data from the primary analysis showed that the median PFS with lenvatinib plus pembrolizumab was 23.9 months (95% CI, 20.8-27.7) compared to 9.2 months (95% CI, 6-11) with single-agent sunitinib, translating to a (HR, 0.39; 95% CI, 0.32-0.49; < .001). The median OS in either arm was not yet reached at the time of the analysis, but the data indicated the end point was significantly longer in the lenvatinib and pembrolizumab arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

The PFS2 analysis presented at ASCO included a total of 117 patients in the lenvatinib plus pembrolizumab cohort and 206 patients in the sunitinib cohort who had gone on to receive another therapy. Median time to next-line therapy was 12.2 months (range, 1.45-37.36) and 6.4 months (range, 0.39-28.52) in the lenvatinib/pembrolizumab and sunitinib groups, respectively.

The most common next-line of therapy was anti-VEGF treatment, mainly cabozantinib (Cabometyx) which was received by 33.0% of patients in the lenvatinib/pembrolizumab cohort and 57.7% in the sunitinib group. Other therapies included checkpoint inhibition (30.4% and 33.6%, respectively), MTOR inhibition (8.2% and 43.1%), CTLA-4 inhibition (1.7% and 5%), and other (1.7% and 5%).

A PFS2 benefit was also seen with lenvatinib plus pembrolizumab over sunitinib in patients with favorable-risk disease (HR, 0.47; 95% CI, 0.26-0.87), intermediate-risk disease (HR, 0.53; 95% CI, 0.39-0.71), and poor-risk disease (HR, 0.42; 95% CI, 0.20-0.88) defined by Memorial Sloan Cancer Center risk criteria.

Similarly, when defined by International Metastatic Renal Cell Carcinoma Database Consortium risk groups, median PFS2 was not reached for the favorable, intermediate, or poor-risk groups for those on lenvatinib plus pembrolizumab, and was 34.7 months (95% CI, 28.7-NE), 23.0 months (95% CI, 17.7-NE), and 10.2 months (95% CI, 4.2-12.2), in the sunitinib groups, respectively.

Median duration of first subsequent treatment was 5.2 months (range, 0.10-31.23) for the lenvatinib plus pembrolizumab cohort and 6.8 months (range, 0.03-30.72) in the sunitinib cohort.

To be eligible for the trial, patients had to have a histologically or cytologically confirmed diagnosis of RCC with clear-cell components and documented evidence of advanced disease. Patients could not have undergone prior systemic therapy have one or more measurable lesion per RECIST 1.1 criteria and a Karnofsky performance score of 70 or higher.


1. Voss MH, Powels T, McGregor BA, et al. Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study. J Clin Oncol. 2022;40(suppl 16):4514. doi:10.1200/JCO.2022.40.16_suppl.4514

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