Dr Brahmer on the Investigation of FLX475 in NSCLC

Julie Renee Brahmer, MD, co-director, Upper Aerodigestive Department, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, professor, oncology, Johns Hopkins Medicine, discusses the investigation of FLX475 in patients with advanced non–small cell lung cancer (NSCLC).

At the 2023 ASCO Annual Meeting, investigators presented data from a phase 1/2 trial (NCT03674567) evaluating the clinical and biological activity of FLX475, an oral CCR4 antagonist, in patients with advanced cancers, such as NSCLC. Investigators found that FLX475 monotherapy induced beneficial changes in the tumor microenvironment consistent with its proposed mechanism of action. Moreover, the investigational agent modified the tumor microenvironment to respond to PD-1 and PD-L1 inhibitors, highlighting this drug’s potential as a promising treatment option for patients with advanced cancers.

These are exciting data, Brahmer begins, saying that FLX475, when used as a single-agent therapy, has demonstrated notable responses, particularly in cases of Epstein-Barr virus (EBV)–positive lymphoma. It is believed that the mechanism of action of this agent directly influences its response to virally driven tumors, she notes. In this study, 2 out of 6 patients with EBV-positive lymphoma achieved a complete response when treated with FLX475 as a standalone therapy, Brahmer explains.

Furthermore, the study explored the combination of FLX475 with the PD-1 inhibitorpembrolizumab (Keytruda), Brahmer expands. Ligands may be upregulated when patients receive PD-1 inhibitor monotherapy, Brahmer says. Blocking CCR4 can potentially exclude or downregulate regulatory T cells, preventing their recruitment. This allows CD8-positive T cells to infiltrate the tumor more effectively when FLX475 is combined with a PD-1 inhibitor, Brahmer emphasizes.

In a group of immunotherapy-naïve patients with advanced NSCLC, promising results emerged, with 4 out of 13 patients achieving partial responses, Brahmer continues. Given the initial success seen with FLX475 as monotherapy and in combination therapy, forthcoming results with this agent in other cancer types, such as head and neck cancer, are awaited, as are data from larger cohorts of patients with various cancers, Brahmer concludes.