Ongoing Phase 1/2 Trial of FLX475 Shows Promising Activity in Multiple Cancer Indications


The results demonstrated preliminary evidence of monotherapy activity, encouraging efficacy in combination with the PD-1 checkpoint inhibitor pembrolizumab (Keytruda), and biomarker data supporting FLX475’s mechanism of action.

Results from the ongoing phase 1/2 trial of FLX475 in multiple cancer indications demonstrated preliminary evidence of monotherapy activity, encouraging efficacy in combination pembrolizumab (Keytruda), and biomarker data supporting FLX475’s mechanism of action, according to RAPT Therapeutics, the developer of the agent.

As of November 10, 2020, the initial study observations also found that FLX475 revealed a favorable safety profile, both as monotherapy and in combination with pembrolizumab.

“FLX475 is a potent non-depleting CCR4 antagonist that is designed to block regulatory T cells that interfere with an effective anti-tumor immune response,” Scott Antonia, MD, PhD, professor of Medicine and director of the Duke Cancer Institute Center for Cancer Immunotherapy, as well as a member of RAPT’s Scientific Advisory Board, explained in a press release. “These data are particularly impressive as the immunotherapy field has long recognized Treg as important targets in oncology, but until FLX475, others have not been able to selectively target these cells in the tumor microenvironment without affecting beneficial cells. These data demonstrate that RAPT’s oral small molecule approach with FLX475 holds promise in treating a variety of charged cancers.”

The dose escalation phase 1 portion of the trial enrolled a total of 37 patients with various types of cancers. In total, 19 patients were treated with 1 of 4 doses (25 mg, 50 mg, 75 mg, or 100 mg once daily) of FLX475 monotherapy and 18 were treated with 1 of 3 doses (50 mg, 75 mg, or 100 mg once daily) of FLX475 in combination with the standard dose of pembrolizumab.

Disease control, defined as a best response of stable disease (SD), an unconfirmed or confirmed partial response (PR), or complete response (CR), was reported in 14 of the 17 evaluable patients treated with monotherapy, including an unconfirmed PR in a patient with relapsed metastatic cervical cancer. In the combination cohorts, disease control was observed in 13 of the 14 evaluable patients, including 2 confirmed partial responses: a patient with NSCLC who had progressed on prior checkpoint treatment with atezolizumab (Tecentriq) and who remains on study after 18 months of treatment and a patient with checkpoint inhibitor-naïve urothelial cancer who was on study for over 9 months of treatment.

Additionally, preliminary data demonstrated an increase in the CD8 to Treg ratio following treatment, which is consistent with the hypothesis that a CCR4 antagonist can block the recruitment of tumor Treg, increase the CD8 to Treg ratio and possibly improve antitumor immunity.

Moreover, the phase 1 results also found that FLX475 had a favorable safety profile, with no maximum tolerated dose reached. Overall, 2 dose-limiting toxicities (DLTs) of asymptomatic QTc prolongation were observed in the monotherapy cohorts, 1 in the 75 mg cohort and 1 in the 100 mg cohort. However, no DLTs were observed in the Phase 1 combination cohorts.

Based on the phase 1 data, 100 mg was selected as the recommended phase 2 dose for both the monotherapy and combination therapy cohorts.

The ongoing phase 2 portion of the trial plans to enroll a minimum of 80 patients with several types of charged tumors, with 10 patients in each of 8 cohorts. Four cohorts are evaluating FLX475 as a monotherapy and 4 cohorts are evaluating FLX475 in combination with pembrolizumab.

The charged cancers include Epstein-Barr Virus (EBV)- or Human Papillomavirus (HPV)-associated cancers such as nasopharyngeal cancer, cervical cancer, and subsets of Hodgkin and non-Hodgkin lymphomas as well as head and neck cancer. Other charged tumor types include non-small cell lung cancer and triple-negative breast cancer.

Notably, the study protocol calls for expansion of cohorts to generate additional data based on promising clinical activity. RAPT has selected 3 cancer indications for expansion, including EBV+ lymphoma, checkpoint inhibitor-naïve nasopharyngeal cancer, and checkpoint inhibitor naïve head and neck cancer.

“We are pleased with the early evidence of clinical activity of FLX475, both as monotherapy and in combination with pembrolizumab in multiple charged tumor types,” Brian Wong, MD, PhD, president and CEO of RAPT, said in a press release. “Based on these encouraging data, we have determined that 3 cancer indications, EBV+ lymphoma, nasopharyngeal cancer, and head and neck cancer, have generated sufficient early evidence of efficacy to advance into expanded phase 2 evaluation. We continue to enroll patients and generate data in this multi-cohort, multi-indication trial and look forward to providing updates on all remaining cohorts and additional go-forward decisions next year.”


RAPT Therapeutics Reports Positive Initial Data from Ongoing Phase 1/2 Clinical Trial of FLX475 in Multiple Cancer Indications [news release]. South San Francisco, California. Published November 16, 2020. Accessed November 17, 2020.

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