ESMO 2021: Phase 3 CLEAR Trial in Advanced Renal Cell Carcinoma: Outcomes in Subgroups and Toxicity Update

( The European Society of Medical Oncology (ESMO) 2021 virtual annual meeting’s non-prostate cancer session included a presentation by Dr. Toni Choueiri discussing outcomes of subgroup analyses and a toxicity update among patients in the phase 3 CLEAR trial for advanced renal cell carcinoma (RCC). In the CLEAR trial, lenvatinib + pembrolizumab demonstrated significant improvement in PFS (24 months versus 9 months; HR 0.39, 95% CI 0.32-0.49), OS (not reached in either arm; HR 0.66, 95% CI 0.49-0.88), and ORR (71% versus 36%; OR 4.35, 95% CI 3.16-5.97) versus sunitinib for patients with advanced RCC. The analysis reported at the 2021 ESMO virtual congress explored efficacy outcomes in patients with or without adverse pathologic features (ie. sarcomatoid histology, bone metastases, liver metastases, and no prior nephrectomy) in the lenvatinib + pembrolizumab versus sunitinib arms. Additionally, the number of patients who received high-dose corticosteroids to manage immune-related adverse events is reported.

 Patients were randomized (1:1:1) to receive 1 of 3 treatments including lenvatinib 20 mg PO QD + pembrolizumab 200 mg IV Q3W, lenvatinib 18 mg + everolimus 5 mg orally once daily, or sunitinib 50 mg PO QD (4 weeks on/2 weeks off). The study design for CLEAR is as follows:




Patients with or without adverse prognostic features (ie, sarcomatoid histology, bone and/or liver metastasis, and no prior nephrectomy) were considered. Median PFS and OS were calculated using the Kaplan-Meier method, and HR and 95% CI comparing PFS (assessed by the independent review committee) and OS were estimated by a stratified Cox model. Additionally, odds ratios were used to compare ORRs by the independent review committee. The number of patients requiring corticosteroids (>= 40 mg prednisone daily equivalent) to manage immune-related adverse events for any duration were also tracked during the study.

 There were 1,069 patients randomly assigned to treatment in CLEAR, including 355 to receive lenvatinib + pembrolizumab and 357 to receive sunitinib. PFS was consistently and clearly improved with lenvatinib + pembrolizumab versus sunitinib for patients in all subgroups:




Additionally, the HR for OS favored lenvatinib + pembrolizumab versus sunitinib across subgroups:




The ORR was greater with lenvatinib + pembrolizumab versus sunitinib for subgroups with sarcomatoid histology (61% vs 24%; OR 8.9, 95% CI 2.1-37.8), bone metastasis (65% vs 23%; OR 6.9, 95% CI 3.5-13.7), liver metastasis (67% vs 34%; OR 4.0, 95% CI 1.8-8.8) and no prior nephrectomy (63% vs 23%; OR 6.3, 95% CI 3.1-12.6). There were 52 (14.8%) patients in the lenvatinib + pembrolizumab group that received high-dose corticosteroids (≥40 mg prednisone daily or equivalent) for any duration to manage immune-related adverse events. The most frequent events included pneumonitis (3.7%), hypothyroidism (2.8%), adrenal insufficiency (1.7%), and rash (1.7%).


Dr. Choueiri concluded his presentation of key subgroup analyses from the CLEAR trial and updated toxicity results with the following take-home messages:

  • In patients with advanced RCC, lenvatinib + pembrolizumab demonstrated efficacy benefits over sunitinib in patients with/without adverse prognostic features, including sarcomatoid histology, bone and/or liver metastasis, and no prior nephrectomy
  • These findings are similar to the efficacy outcomes observed in the intention-to-treat population
  • Only 15% of patients needed high-dose corticosteroids for immune-related adverse events
  • These results support lenvatinib + pembrolizumab combination treatment as a new first-line option for patients with advanced RCC


Presented by: Toni K. Choueiri, MD, Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.