STUDY DESIGN

Bone metastases occur in approximately one-third of patients with advanced renal cell carcinoma (aRCC) and are associated with poor prognosis. This is partly due to RCC-driven immune dysregulation and the release of factors such as fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) that promote osteoclast activation and bone resorption.¹ Dysregulation of the FGF or FGF receptor (FGFR) axis further contributes to bone metastases development.¹ Lenvatinib is an oral tyrosine kinase inhibitor (TKI) that targets several growth factor receptors, including VEGFR1-3, FGFR1-4, PDGFRα, CD117 (KIT), and the RET proto-oncogene.¹ When combined with pembrolizumab, it has shown significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to sunitinib in first-line advanced RCC, with benefits sustained after 4 years of follow-up.¹ The captioned analysis presents additional outcomes in patients with and without bone metastases after approximately 4 years of follow-up.¹

The CLEAR trial is a global, phase 3, randomized study involving 1,069 patients with treatment-naïve advanced clear cell RCC.¹ Eligible patients had measurable disease, adequate organ function, and a Karnofsky performance status (KPS) ≥70.¹ Patients were stratified by geographic region and Memorial Sloan Kettering Cancer Center (MSKCC) risk groups before being randomized in a 1:1:1 ratio to receive oral lenvatinib 20mg once daily (QD) + intravenous (IV) pembrolizumab 200mg every 3 weeks, lenvatinib + everolimus, or sunitinib 50mg QD on a 4-weeks-on/2-weeks-off schedule.¹ Tumor responses were assessed via independent imaging review and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score changes were evaluated 6 months after treatment initiation.¹ Baseline characteristics were generally balanced across treatment arms for patients both with and without bone metastases.¹ Notably, few patients with bone metastases had received prior bone-targeted therapies, which were more commonly used in the sunitinib arm than in the lenvatinib + pembrolizumab arm.¹

The primary endpoint of the trial was independent review committee (IRC)-assessed PFS.¹ Key secondary endpoints included OS, ORR, health-related quality of life (HRQoL), and safety.¹ Key exploratory endpoints were duration of response (DoR) and biomarkers analyses.¹

FINDINGS

 

“OS, PFS, ORR, DoR and IMDC risk improvement continue to support lenvatinib + pembrolizumab as a standard-of-care treatment for patients with aRCC, regardless of the baseline bone metastases status.”

Professor Camillo Porta
University of Bari Aldo Moro & Policlinico Consorziale,
Bari, Italy