Immunomodulatory Effects in a Phase II Study of Lenalidomide Combined with Cetuximab in Refractory <i>KRAS</i>-Mutant Metastatic Colorectal Cancer Patients

<div><p></p><p>This study assessed the immunomodulatory effects in previously treated <i>KRAS</i>-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.</p><p>Trial Registration</p><p><a href="http://clinicaltrials.gov/show/NCT01032291" target="_blank">ClinicalTrials.gov NCT01032291</a></p></div

Significantly regulated cell populations in all subjects.

<p>Abs, absolute; C1D1, cycle 1 day 1; C2D1, cycle 2 day 1; C3D1, cycle 3 day 1; FC, fold change; NK, natural killer.</p

Study design and enrollment in patient groups.

<p>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.</p

Patient baseline characteristics.

<p>ECOG PS, Eastern Cooperative Oncology Group performance status.</p

Significantly regulated cell populations in the lenalidomide plus cetuximab arm.

*<p>Cell populations that are unique to the lenalidomide plus cetuximab arm only.</p><p>Abs, absolute; C1D1, cycle 1 day 1; C2D1, cycle 2 day 1; C3D1, cycle 3 day 1; FC, fold change; NK, natural killer.</p

Significantly regulated cell populations in the lenalidomide monotherapy arm.

*<p>Cell populations that are unique to the lenalidomide monotherapy arm only.</p><p>Abs, absolute; C1D1, cycle 1 day 1; C2D1, cycle 2 day 1; C3D1, cycle 3 day 1; FC, fold change; NK, natural killer.</p

Baseline characteristics phase IIa and IIb.

a<p><i>KRAS</i> mutations as determined by Genoptix Medical Laboratory.</p>b<p><i>KRAS</i> mutation found in local laboratory.</p><p>Abbreviations: ECOG PS: Eastern Cooperative Oncology Group performance status; n.a.: not applicable.</p

Phase II Open-Label Study to Assess Efficacy and Safety of Lenalidomide in Combination with Cetuximab in <i>KRAS</i>-Mutant Metastatic Colorectal Cancer

<div><p></p><p>This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in <i>KRAS</i>-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa) to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb) to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day) and intravenous cetuximab (400 mg/m² followed by weekly 250 mg/m²) in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in <i>KRAS</i>-mutant metastatic colorectal cancer patients.</p><p>Trial Registration</p><p>Clinicaltrials.gov <a href="http://clinicaltrials.gov/ct2/results?term=NCT01032291" target="_blank">NCT01032291</a></p></div