Monoclonal antibodies can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal (CRC) and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced CRC or HNSCC. Treatment consisted of cetuximab 500 mg/m2 i.v. every two weeks with lenalidomide given orally days 1-21 on a 28 day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcγRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. 22 patients were enrolled (19 CRC, 3 HNSCC). Fatigue was the only dose limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m2 with lenalidomide 25 mg daily days 1-21. Correlative studies demonstrated a dose dependent increase in NK cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well-tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of anti-tumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted.
- Received November 13, 2015.
- Revision received June 27, 2016.
- Accepted June 28, 2016.
- Copyright ©2016, American Association for Cancer Research.