FLX475 Alters TME to Enhance Anti–PD-1/PD-L1 Response in NK/T-cell Lymphoma

Dirk G. Brockstedt, PhD

Single-agent treatment with the novel CCR4 antagonist FLX475 led to changes in the tumor microenvironment (TME) to a phenotype more associated with responses to anti–PD-1/PD-L1 therapy in patients with natural killer (NK)/T-cell lymphoma, according to data from a biomarker analysis of a phase 1/2 trial (NCT03674567) presented at the 2023 ASCO Annual Meeting.¹

­Findings showed that FLX475 monotherapy generated a small increase in the proportion of circulating regulatory T cells. An increase in the ratio of CD8-positive and FOXP3-positive cells was also observed in the TME from baseline to after 2 cycles of treatment. Furthermore, the percentage of CD8-positive cells within 25 µm of FOXP3-positive cells also decreased.

A decrease in regulatory T cells, endothelial cell gene signatures, and cancer-associated fibroblasts was also observed. Moreover, investigators noted an increase in hotness and activation of innate immune pathways.

Following treatment with FLX475, gene expression changes resembled the TME of patients who have responded to anti–PD-1 monotherapy. Through an increase in these genes associated with response to immune checkpoint inhibition, FLX475 was found to condition the TME for anti–PD-1/PD-L1 therapy.

“Consistent with the clinical activity observed to date with FLX475 monotherapy in Epstein–Barr virus–positive [EBV] NK/T-cell lymphoma and with FLX475 plus pembrolizumab [Keytruda] in checkpoint inhibitor–naïve non–small cell lung cancer [NSCLC], biomarker studies have demonstrated several lines of evidence supporting the proposed mechanism of action of CCR4 antagonism,” lead study author Dirk G. Brockstedt, PhD, chief scientific officer at Rapt Therapeutics, and colleagues, wrote in a poster presentation of the data.

CCR4 is the primary chemokine receptor expressed on human regulatory T cells. Two ligands for CCR4 (CCL1 and CCL22) are highly expressed in tumor cells and other cells in the TME in the response to inflammation, leading to the migration of regulatory T cells into tumors, which can repress the antitumor activity of effector T cells.

The potent, oral, small-molecule, CCR4 antagonist, FLX475, is designed to prohibit regulatory T cells from being drawn into tumors, promoting a shift in the balance of regulatory and effector T cells to promote tumor killing. Notably, FLX475 is not expected to cause autoimmunity due to nonspecific regulatory T-cell depletion, or cause immunosuppression through the depletion of CCR4-positive effector cells.

In previously reported clinical data from the phase 1/2 trial, FLX475 monotherapy elicited responses in 4 of 6 patients with EBV-positive NK/T cell lymphoma, including 2 durable complete metabolic responses (CMRs).² Additionally, 1 patient experienced an unconfirmed CMR, and another patient had an unconfirmed partial metabolic response.

In 4 of these patients who crossed over to receive FLX475 plus pembrolizumab following disease progression, 1 experienced a PMR following a CMR with FLX475 monotherapy, 1 had a PMR after a PMR with single-agent treatment, 1 had a PMR after no response to monotherapy, and 1 experienced progressive disease after no response to FLX475 monotherapy.

Additionally, among 13 patients with immune checkpoint inhibitor–naïve NSCLC treated with FLX475 plus pembrolizumab, 5 responded, including 4 confirmed PRs and 1 unconfirmed PR.

Regarding safety, 20% of evaluable patients treated with FLX475 monotherapy (n = 25) experienced serious treatment-emergent adverse effects (TEAEs), although TEAEs did not lead to death or discontinuation in any patients. Among those treated with FLX475 plus pembrolizumab (n = 39), serious TEAEs were reported in 49% of patients. TEAEs led to treatment discontinuation in 3% of patients and death in 8% of patients.

The ongoing trial is enrolling patients with documented advanced or metastatic cancer who are ineligible for standard therapies. For the dose-escalation portion of the study, patients are required to have NSCLC, head and neck squamous cell carcinoma (HNSCC), nasopharyngeal carcinoma, metastatic triple-negative breast cancer (TNBC), urothelial carcinoma, gastric cancer, esophageal carcinoma, cervical cancer, or classical Hodgkin lymphoma. The dose-expansion portion is including those with nasopharyngeal carcinoma, lymphoma, HNSCC, cervical cancer, NSCLC, or TNBC.³

All patients are also required to have evaluable disease at baseline, including at least 1 measurable target lesion for patients in dose-expansion cohorts; an ECOG performance status of 0 or 1; and tumors available for biopsy.

The trial is excluding patients with a history of grade 3/4 immune-related AEs that led to discontinuation of a prior immune-oncology treatment, those with active autoimmune disease or serious autoimmune disease within past 2 years requiring systemic therapy, patients who received an allogeneic stem cell transplant within 5 years of enrollment or prior allogeneic organ transplant at any time; and select patients with a history of pneumonitis.

In both dose escalation and expansion, patients are being treated with FLX475 alone once per day, or once per day in combination with 200 mg of intravenous pembrolizumab once every 3 weeks. In the dose-escalation monotherapy arm, patients received FLX475 at doses of 25 mg, 50 mg, 75 mg, and 100 mg. In the combination arm, the doses of FLX475 were 50 mg, 75 mg, and 100 mg. The recommended phase 2 dose of FLX475 is 100 mg once per day.²

The primary end points of the study are the safety and tolerability of FLX475 alone and in combination with pembrolizumab, and overall response rate for both single-agent and combination therapy.³

References

1. Brockstedt DG, Grant A, Adamik J, et al. Clinical and biological activity of FLX475, an oral CCR4 antagonist, in advanced cancer. J Clin Oncol. 2023;41(suppl 16);2625. doi:10.1200/JCO.2023.41.16_suppl.2625
2. Lin C, Kim TM, Desai P, et al. Phase 1/2 study of the oral CCR4 antagonist, FLX475, as monotherapy and in combination with pembrolizumab in advanced cancer. Ann Oncol. 2022;16(suppl 1):100104. doi:10.1016/iotech/iotech100104
3. Dose escalation and expansion study of FLX475 monotherapy and in combination with pembrolizumab. ClinicalTrials.gov. Updated July 7, 2023. Accessed July 12, 2023. https://clinicaltrials.gov/ct2/show/NCT03674567