Abstract
BackgroundNo biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus.MethodsOf 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3−5, CBS-low: 0–2; 2-factor-CBS high: 1–2, CBS-low: 0).ResultsPFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus).ConclusionsThe 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required.Clinical trial registrationThe clinical trial registration number is NCT01136733.
Highlights
No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC)
Patients Of the 153 patients included in the intent-to-treat population, 96.1% had serum samples taken for the biomarker analysis
We constructed composite biomarker scores (CBSs) models according to levels of circulating biomarkers in the blood serum of patients with metastatic RCC from Study 205 at baseline
Summary
No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). Several molecularly targeted agents (VEGF receptor and mTOR inhibitors) are approved to treat metastatic renal cell carcinoma (RCC).[1,2,3,4,5,6,7] treatment of RCC remains challenging as most patients develop resistance to systemic therapy.[8] Such difficulties have led to the development of combination therapies (i.e., tyrosine kinase inhibitors with immune checkpoint inhibitors or mTOR inhibitors).[9] Lenvatinib—an oral multityrosine kinase inhibitor of VEGF receptors 1–3, fibroblast growth factor (FGF) receptors 1–4, platelet-derived growth factor receptor α, RET, and KIT8,10–12—in combination with everolimus has demonstrated efficacy in preclinical models of RCC.[13] In a randomised, 3-arm, Phase 2 study (Study 205) in metastatic RCC, patients assigned to lenvatinib-pluseverolimus combination therapy had significantly improved progression-free survival (PFS) compared with patients who were assigned to everolimus monotherapy (median PFS 14.6 vs 5.5 months; HR 0.40; 95% confidence interval [CI]: 0.24–0.68; P < 0.001).[3] As a result, lenvatinib-plus-everolimus was approved by the US Food and Drug Administration for the treatment of patients with advanced RCC following 1 prior anti-angiogenic therapy.[14,15]
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