Dr Anders on the Investigation of CCR4 Antagonists in Advanced Cancers

Robert Albert Anders, MD, PhD, associate professor, pathology, oncology, Department of Oncology–Gastrointestinal Cancer, Department of Pathology–Gastroenterology and Liver Pathology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, discusses the rationale for developing CCR4 antagonists for use in patients with advanced cancers, including lymphoma and non–small cell lung cancer (NSCLC).

Across several tumor types, immune cells in the tumor microenvironment (TME) can suppress tumor cells, demonstrating that patients’ immune systems can be used to treat their cancers, Anders says. CCR4 is a receptor cell that is expressed on regulatory T cells, which can be immunosuppressive, Anders explains.

The CCR4 antagonist FLX475 is being investigated in the phase 1/2 FLX475-02 trial (NCT03674567) as monotherapy and in combination with pembrolizumab (Keytruda) in patients with advanced or metastatic cancer who are ineligible for standard therapies. The trial investigators hypothesize that FLX475 blocks the CCR4 receptor, thus suppressing the immune inhibitory effects of the regulatory T cells in the tumor without affecting healthy tissue, according to Anders.

In an interim analysis of FLX475-02, of 6 evaluable patients with Epstein–Barr virus–positive natural killer cell or T-cell lymphoma who received FLX475 monotherapy, 2 achieved complete responses. Additionally, of 13 evaluable patients with checkpoint inhibitor–naïve NSCLC who received the agent in combination with pembrolizumab, 4 achieved confirmed partial responses.

Furthermore, a biomarker analysis of data from patients who received FLX475 monotherapy demonstrated that the agent generated a small increase in the proportion of CD25-positive, CD127-negative/low, and CD4-positive regulatory T cells by day 8 of treatment. An immunohistochemistry analysis of FLX475-treated tumor biopsies also revealed a trend toward an increase in the ratio of CD8-positive and FOXP3-positive cells in the TME.

This trial may also support the use of FLX475 in patients with other advanced tumors because the ligands CCL17 and CCL22, which interact with the CCR4 receptor, are often present in inflamed malignancies, Anders concludes.