On May 25, 2023 RAPT Therapeutics, Inc. (Nasdaq: RAPT), a clinical-stage, immunology-based therapeutics company focused on discovering, developing and commercializing oral small molecule therapies for patients with significant unmet needs in inflammatory diseases and oncology, reported biomarker data for FLX475 from its ongoing FLX475-02 Phase 1/2 clinical trial which corroborate the clinical activity of FLX475 reported in Epstein-Barr virus-positive (EBV+) lymphoma, EBV+ gastric cancer and non-small cell lung cancer (NSCLC), as well as the mechanism of this novel CCR4 antagonist (Press release, RAPT Therapeutics, MAY 25, 2023, https://investors.rapt.com/news-releases/news-release-details/rapt-therapeutics-present-biomarker-data-corroborating [SID1234632070]). These data will be presented in a poster at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting taking place next week at the McCormick Place Convention Center in Chicago, IL.
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FLX475 is a potent and selective CCR4 antagonist, designed to block the recruitment of immunosuppressive regulatory T cells (Treg) into tumors without affecting healthy tissues. In December 2022 at ESMO (Free ESMO Whitepaper)-IO, a clinical update from the Phase 1/2 trial reported evidence of monotherapy and combination activity. FLX475 monotherapy induced confirmed complete metabolic responses in two of the six evaluable patients with EBV+ NK/T cell lymphoma. In patients with checkpoint inhibitor naïve NSCLC, the overall confirmed objective response rate was 31% (4/13 patients), and the confirmed objective response rate in PD-L1+ tumors was 38% (3/8 patients) following treatment with FLX475 plus pembrolizumab.
As part of the clinical trial protocol, the company analyzed peripheral blood and tumor tissue biomarker data from patients with a broad range of tumor types treated with FLX475 monotherapy. These data substantiate the mechanism of action and support the combination of FLX475 with pembrolizumab. In peripheral blood, FLX475 monotherapy resulted in a small, but significant, increase in the proportion of circulating Treg, consistent with blocking the migration of Treg into the TME. In tumor tissues, changes in the TME conducive to anti-PD(L)1 response were observed. First, FLX475 monotherapy resulted in a decrease in Treg cell populations and an increase in the distance between CD8+ effector T cells and Treg in the TME. Second, transcriptomic profiles from tumors after FLX475 monotherapy exhibited significant changes known to be correlated with an enhanced response to checkpoint inhibitor therapy.
"These biomarker data provide further evidence that FLX475 reduces Treg in the tumor and promotes a permissive environment that should enhance immune-based therapy including checkpoint inhibitors," said Dirk Brockstedt, Ph.D., chief scientific officer of RAPT. "In addition to inhibiting the recruitment of regulatory T cells, which are highly potent suppressors of an antitumor immune response, we saw a concomitant increase in cancer fighting effector T cells and additional beneficial changes in the tumor microenvironment that have been shown to correlate with a favorable response to anti-PD(L)1 therapy. These data are consistent with and support the clinical activity we’ve seen with FLX475 as monotherapy and in combination therapy with pembrolizumab."
About FLX475
FLX475 is a small molecule CCR4 antagonist designed to block the migration of regulatory T cells (Treg) specifically into tumors, but not healthy tissues. Treg represent a dominant pathway for downregulating the immune response, generally correlate with poor clinical outcomes, and may limit the effectiveness of currently available therapies such as checkpoint inhibitors. FLX475 may restore naturally occurring antitumor immunity alone and may synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators, cancer vaccines, and adoptive T cell therapy.