Immunomodulatory effects in a phase II study of lenalidomide combined with cetuximab in refractory KRAS-mutant metastatic colorectal cancer patients

Abstract

This study assessed the immunomodulatory effects in previously treated KRAS-mutant metastatic colorectal cancer patients participating in a phase II multicenter, open-label clinical trial receiving lenalidomide alone or lenalidomide plus cetuximab. The main findings show the T cell immunostimulatory properties of lenalidomide as the drug induced a decrease in the percentage CD45RA(+) naïve T cells 3-fold while increasing the percentage HLA-DR(+) activated T helper cells and percentage total CD45RO(+) CD8(+) memory T cytotoxic cells, 2.6- and 2.1-fold respectively (p<0.0001). In addition, lenalidomide decreased the percentage of circulating CD19(+) B cells 2.6-fold (p<0.0001). Lenalidomide increased a modest, yet significant, 1.4-fold change in the percentage of circulating natural killer cells. Our findings indicate that lenalidomide significantly activates T cells, suggestive of an immunotherapeutic role for this drug in settings of maintenance therapy and tumor immunity. Furthermore, reported for the first time is the effect of lenalidomide in combination with cetuximab on T cell function, including increases in circulating naïve and central memory T cells. In summary, lenalidomide and cetuximab have significant effects on circulating immune cells in patients with colorectal carcinoma.

Trial registration: ClinicalTrials.gov NCT01032291.

Figure 1. Study design and enrollment in patient groups.

Study was terminated before the expansion part of phase IIb. *One patient was randomized to the lenalidomide monotherapy group but discontinued before taking any study drug and was therefore excluded from the analyses. AE, adverse event; ITT, intention to treat; PD, progressive disease.

Figure 2. Significant changes in number in four immune cell subsets.

Significant (p ≤ 0.0001) changes in percentage and absolute number in four immune cell subsets from cycle 1 day 1 (C1D1) to cycle 2 day 1 (C2D1) or cycle 3 day 1 (C3D1) in all subjects. The upper edge of the box denotes the 75th percentile whereas the lower edge denotes the 25th percentile. The line inside each box is the median. The lines extend to the maximum and minimum values excluding outliers. The gray lines denote individual subject data. Abs, absolute.