by ecancer reporter Clare Sansom

Renal cell carcinoma (RCC) is the most common type of kidney cancer, responsible for over 90% of adult cases.

Early stage primary renal cell carcinoma can often be cured with surgery, but the metastatic disease is intractable and the 5-year survival rate for stage 4 kidney cancer, which has spread beyond the kidney and local lymph nodes, is only about 5%.

However, the number of drugs that have been shown to have some efficacy in, and have been licensed for this tumour type is increasing.

The current ‘gold standard’ therapy for metastatic RCC is sequential treatment with single drugs that target the VEGF (vascular endothelial growth factor) and mTOR (mechanistic target of rapamycin) signalling pathways.

Sunitinib and pazopanib – tyrosine kinase inhibitors that target the VEGF pathway – are most commonly used as first-line treatment, and patients who progress are moved on to either another VEGF inhibitor, axitinib, or the mTOR inhibitor everolimus.

Lenvatinib is a multi-targeted kinase inhibitor that is active in the VEGF pathway and that is under investigation in several cancer types.

A combination of this drug with everolimus has been shown to be more potent in a mouse model of renal cell carcinoma than either agent on its own.

This drug combination has also been shown to have some efficacy and an acceptable safety profile in a Phase I trial in patients with the metastatic disease.

A large, international team of clinicians and researchers led by Robert J. Motzer of Memorial Sloan-Kettering Cancer Center, New York, USA have now conducted a Phase II trial of the combination in comparison with each drug as a monotherapy.

This randomised, open-label trial involved a total of 153 RCC patients from 37 centres in five countries, randomised in a 1:1:1 ratio to receive single-agent lenvatinib, single-agent evorulimus or both agents together.

All patients were diagnosed with the clear-cell type of renal cell carcinoma and had progressive disease after one treatment with a VEGF-directed therapy other than lenvatinib.

Patient demographics and disease characteristics were broadly similar between the three arms of the trial.

The study treatment continued and patients were followed until disease progression, unacceptable adverse effects or withdrawal of patient consent.

The primary endpoint was progression-free survival; secondary endpoints included safety and tolerability, objective response and overall survival.

The median progression-free survival at the time of data cutoff was 14.6 months in the lenvatinib plus evorulimus arm, 7.4 months in patients receiving lenvatinib alone and 5.5 months in those receiving evorulimus alone.

The difference in progression-free survival between the combination therapy and evorulimus arms reached statistical significance (hazard ratio 0.61, 95% confidence interval 0.38-0.98, p = 0.048).

However, the difference between the combination therapy and lenvatinib arms was not significant (hazard ratio 0.66, 95% CI 0.39-1.10, p=0.12).

Differences in overall survival did not reach statistical significance at the time of the original data cutoff, but an updated analysis found a significant difference in overall survival between the patients in the combination therapy arm (25.5 months) and those receiving evorulimus alone (15.5 months).

Treatment-associated adverse effects were common but manageable in all arms, with the fewest in those patients who received evorulimus only.

The most commonly reported moderate or severe adverse effects were diarrhoea in the combination therapy arm; proteinuria in the lenvatinib arm; and anaemia in the evorulimus arm.

The results of this Phase II trial therefore show that a combination of lenvatinib with evorulimus can provide significant benefit as a second-line treatment in metastatic RCC, and the study authors suggest that further trials of lenvatinib as a single and combination agent are warranted in this tumour type.

Reference

Motzer, Hutson, Glen et al (2015). Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncology, published online ahead of print 15 October 2015.