Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma.
We previously reported results of a randomised, open label, phase 2 trial of lenvatinib, everolimus, and lenvatinib plus everolimus in patients with metastatic renal cell carcinoma who had progressed after one previous VEGF targeted therapy. Our study met the primary endpoint by showing improved progressionfree survival with lenvatinib plus everolimus and lenvatinib alone versus everolimus alone, using investigator assessed objective responses. On the basis of agreements reached with regulatory agencies, an ad hoc, retrospective, blinded, independent radiological review (IRR) was completed to assess whether the effi cacy results based on investigator assessments were supported by those of the IRR. We obtained CT and MRI scans of participants in the study, completed once every 8 weeks from random assignment until disease progression or start of another cancer treatment. IRR was done by radiologists (Parexel Inc, Billerica, MA, USA) masked to treatment using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) The primary endpoint of this study was progression free survival assessed by IRR, in the intention to treat population, with two primary comparisons: lenvatinib plus everolimus versus everolimus alone, and lenvatinib alone versus everolimus alone. Progressionfree survival was analysed by the identical methodology as that reported in the primary assessment; hazard ratios (HR) were derived from stratified Cox regression models, and Mantel Haenszel stratified log rank tests (stratifi cation factors were haemoglobin [men, =130 g/L serve as a proxy for total dose and overall levels of cell death. In human patients, this is commonly achieved with conventionally fractionated radiation. These important diff erences notwithstanding, results from animal models have suggested that low dose per fraction radiation might be more effective at recruiting T cells to a tumour microenvironment than at high doses. Ultimately, examination of existing preclinical dose comparisons do not provide a clear answer. Studies combining radiation and vaccination noted no differences between 8 Gy delivered in either a single fraction and 2 Gy delivered in more than four fractions. As mentioned by Sharabi and colleagues in their Review, Dewan and colleagues' study using a combination of radiation and CTLA 4 blockade showed synergy with three 8 Gy fractions, but not with one 20 Gy treatment. Conversely, other models showed use of one high dose per fraction treatment to be better than low dose regimens. In systematic studies of patients treated with radiation and ipilimumab, systemic responses tended to improve most after low fractional doses of radiation. Additionally, in 2015, Golden and colleagues reported a promising 28% abscopal response in patients treated with fractionated radiation at a dose of 3*5 Gy per fraction (ten fractions in total) in combination with systemic granulocytemacrophage colony stimulating factor. By contrast, a clinical trial that combined ipilimumab with one hypofractionated radiation dose of 8 Gy did not achieve its primary endpoint of overall survival. Similarly, a second study that combined ipilimumab with two or three 8 Gy fractions in 22 patients with melanoma did not result in a significantly different systemic response than might be expected from use of only ipilimumab. Sharabi and colleagues rightfully point out the uncertainty about which radiation dose per fraction might be best to use in conjunction with immunotherapy. The answer will likely depend on tumour histology, the immunotherapeutic strategy used, and many other factors. However, at least in human patients, we would caution presupposing a dose per fraction effect that is not yet established.
The Lancet. Oncology