Combination VEGF, mTOR Inhibition Promising In Metastatic RCC

Metastatic renal cell carcinoma patients could benefit from treatment with lenvatinib, which blocks multiple enzymes of the vascular endothelial growth factor receptor family, together with everolimus

medwireNews: Addition of lenvatinib, a multitarget tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3, to everolimus significantly improves progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC).

Lenvatinib alone also significantly extended PFS relative to the mammalian target of rapamycin (mTOR) blocker, but the researchers comment that the “size of the benefit and the relatively long duration of objective response suggest that efficacy was most robust with the combination regimen.”

Median PFS was 14.6 months for the 51 patients randomly allocated to receive lenvatinib 18 mg/day plus everolimus 5 mg/day and 7.4 months for the 52 patients given lenvatinib alone at a dose of 24 mg/day, with no significant difference between the groups. However, these times were significantly longer than the median PFS of 5.5 months for the 50 participants given single-agent everolimus 10 mg/day, with hazard ratios (HRs) of 0.40 and 0.61, respectively.

The objective response rate was also significantly higher in the lenvatinib plus everolimus and the lenvatinib alone treatment arms than in the everolimus arm, at a respective 43% and 27% versus 6%. And the duration of response was a median of 13.0, 7.5 and 8.5 months, respectively.

Overall survival (OS) did not differ significantly between the groups at the primary analysis, undertaken after a median follow-up of between 16.5 and 18.5 months.

But an updated analysis carried out after a median follow-up of 24.2, 22.3 and 25.0 months in the combination therapy, lenvatinib monotherapy and everolimus monotherapy groups, respectively, showed a significant increase in OS for patients given lenvatinib plus everolimus compared with those given everolimus alone, at 25.5 versus 15.4 months (HR=0.51).

By contrast, lenvatinib alone did not prolong OS either compared with single-agent everolimus or dual therapy.

Adverse events of grade 3 or 4 occurred in 71% of patients in the lenvatinib plus everolimus group, 79% of those in the lenvatinib alone group and 50% of everolimus-treated participants. Diarrhoea (20%) was the most common grade 3 or 4 toxicity in the combination arm, while proteinuria (19%) and anaemia (12%) were most frequent in the lenvatinib monotherapy and everolimus monotherapy arms, respectively.

Two of the six deaths during the study – one each in the lenvatinib dual and monotherapy groups – were attributed to the study treatment.

“The safety profile of lenvatinib plus everolimus is, therefore, a consideration for further development of the combination regimen, which will need diligent monitoring and optimisation of management strategies for diarrhoea and other common adverse events and careful assessment of the risk–benefit ratio”, write Robert Motzer, from Memorial Sloan-Kettering Cancer Center in New York, USA, and colleagues in The Lancet Oncology.

Nonetheless, they conclude that lenvatinib warrants further study in this patient population.

In a related comment, Sebastiano Buti and Melissa Bersanelli, from the University Hospital of Parma in Italy, laud the study authors for reviving a hypothesis thus far rejected by several negative studies of synergistically using VEGFR tyrosine kinase inhibitors and mTOR blockers in this setting.

The “unusually high proportion” of poor-risk patients in the study suggests “the reproducibility of similar results in real-life populations”, they write. “These findings reinforce the potential effect of this trial on future clinical practice.”

However, the commentators note that the two deaths in the lenvatinib groups “are alarming and certainly not negligible”, and together with the adverse event profiles, “suggest that careful reflections are needed about appropriate dose reductions and management of toxic effects”.


Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; Advance online publication 15 October. doi:

Buti S, Bersanelli M. Combination therapy in kidney cancer: the next revolution?Lancet Oncol 2015; Advance online publication 15 October. doi:

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