Posthoc analysis yields silver lining for lenvatinib/everolimus OS results in RCC

Audrey Sternberg

A posthoc analysis from the phase 3 CLEAR trial in renal cell carcinoma (RCC) suggests that the failure of lenvatinib (Lenvima) plus everolimus (Afinitor) to improve overall survival (OS) versus sunitinib (Sutent) in the primary analysis was impacted by a difference in subsequent anticancer therapies received in the 2 study arms.1

Data presented during the 2021 ASCO Annual meeting showed that fewer patients in the lenvatinib/everolimus arm were treated with subsequent anticancer treatments compared with the sunitinib arm. After adjusting for receipt of subsequent regimens for RCC, the hazard ratio for OS shifted below 1.0 and support the clinical benefit of therapy with lenvatinib plus everolimus in this population. These results are supported by prior data that show the combination led to a statistically significant benefit to progression-free survival (PFS) versus sunitinib (HR, 0.65; 95% CI, 0.53-0.80; P <.0001).

“These post hoc analyses of patients with advanced RCC who were treated in the first-line setting in CLEAR demonstrated that differences in subsequent anticancer medication affected the comparison of OS for the lenvatinib plus everolimus versus sunitinib arm,” Thomas Hutson, DO, PharmD, of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center in Dallas and professor of medicine at Texas A&M College of Medicine, and colleagues wrote in their poster presentation.

A 2-stage estimation approach was used to adjust for effects of subsequent therapy on OS outcomes for lenvatinib/everolimus versus sunitinib, with a data cutoff of August 28, 2021. Median follow-up duration for each arm was 27 months and 26 months, respectively.

Duration of study treatment was shorted with sunitinib at 7.8 months versus 11.0 months with lenvatinib/everolimus. For those who did go on to receive other medications, duration from randomization to initiation of subsequent therapy was shorter with sunitinib versus the combination, at 6.62 months versus 8.03 months, respectively. For those whose next therapy was a PD-1/PD-L1 inhibitor, the median duration to initiation was 7.64 months with sunitinib and 9.69 months with lenvatinib/everolimus.

In the overall population, the Kaplan-Meier estimate for OS showed comparable efficacy of the 2 regimens (HR, 0.95; 95% CI, 0.51-1.76). However, the investigators noted that more patients in the sunitinib arm (57.7%) had any subsequent therapy versus those treated with lenvatinib/everolimus (46.8%). After adjusting for the confounding effects of subsequent medication, the adjusted hazard ratio for OS was 0.84 (95% CI, 0.64-1.12) in favor of lenvatinib/everolimus. In both models, the median OS for either arm had not yet been reached.

The most commonly used medications in the second-line setting were PD-1/PD-L1 inhibitors (43.1% vs 35.3%), VEGF inhibitors (33.6% vs 28.0%), CTLA-4 inhibitors (5.0% vs 6.2%), and mTOR inhibitors (4.8% vs 0.8%). Looking at patients who received subsequent PD-1/L1 inhibitors alone, the hazard ratio for OS was 0.89 (95% CI, 0.68-1.19).

Despite a higher rate of treatment-emergent adverse effects (TEAEs) resulting in death noted in the experimental arm (n = 355; 12.4%) versus the control (n = 340; 6.8%), the investigators contributed a majority of these to progressive disease (9.6% vs 6.2%). Overall, the toxicity profiles of each regimen were consistent with their known safety profiles.

Patient baseline characteristics of the 2 study arms were well balanced, with a few notable exceptions. Median age was 62 years (range, 32-89) for lenvatinib/everolimus and 61 years (range, 29-82) for sunitinib. More patients in the sunitinib (77.0%) than the lenvatinib/everolimus (72.8%) arm had prior nephrectomy. PD-L1 expression and risk stratification by MSKCC and International Metastatic RCC Database criteria were well balanced.

Treatment of patients on the CLEAR trial remain ongoing across the 3 study arms comparing the combinations of lenvatinib plus either everolimus or pembrolizumab versus control therapy with sunitinib. Results of the lenvatinib/pembrolizumab arm of the trial are being considered by the FDA as supporting evidence for the approval of the combination as frontline therapy of RCC.


1. Huston TE, Choueiri TK, Motzer RJ, et al. Post hoc analysis of the CLEAR study in advanced renal cell carcinoma (RCC): Effect of subsequent therapy on survival outcomes in the lenvatinib (LEN) + everolimus (EVE) versus sunitinib (SUN) treatment arm. J Clin Oncol. 2021;38(suppl 15):4562. doi: 10.1200/JCO.2021.39.15_suppl.4562