Novel Small Molecule +/- Pembrolizumab Induces Responses in Various Solid Tumors


The oral small molecule FLX475 demonstrated promise when administered either alone or in combination with the immune checkpoint inhibitor pembrolizumab in multiple solid tumors, according to findings from a phase 1/2 dose-escalation and expansion study.

Scott Antonia, MD, PhD

The oral small molecule FLX475 demonstrated promise when administered either alone or in combination with the immune checkpoint inhibitor pembrolizumab (Keytruda) in multiple solid tumors, according to findings from a phase 1/2 dose-escalation and expansion study.

Developer of FLX475, RAPT Therapeutics, Inc, announced in a press release that preliminary observations of the study data showed clinical activity as monotherapy and in combination with pembrolizumab. Additionally, biomarker data from the study support the mechanism of action of the small molecule.

“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. 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,” said Scott Antonia, MD, PhD, professor of Medicine and director of the Duke Cancer Institute Center for Cancer Immunotherapy and a member of RAPT’s Scientific Advisory Board, in a statement.

The phase 1 portion of the study enrolled 37 patients. The histologies assessed included non–small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, nasopharyngeal carcinoma, metastatic triple-negative breast cancer (mTNBC), urothelial carcinoma, gastric cancer, esophageal carcinoma, cervical cancer, and classical Hodgkin lymphoma. In the phase 1 portion of the study, patients received FX475 monotherapy at 25 mg, 50 mg, 75 mg or 100 mg once daily. Eighteen patients in the study received dose levels of 50 mg, 75 mg or 100 mg once daily. For those who received the combination of FLX475 and pembrolizumab, the immune checkpoint inhibitor was administered at the standard dose.

Out of 17 evaluable patients in the monotherapy arm, 14 had disease control, which was determined by achievement of a confirmed partial response, complete response, or stable disease. Notably, 1 of the patients who demonstrated disease control had relapsed metastatic cervical cancer.

There were 14 evaluable patients in the combination arm, of whom 13 had disease control. It was noted in the press release that of the responses observed,2 were confirmed partial responses which occurred in a patient with NSCLC who had previously progressed the checkpoint inhibitor atezolizumab (Tecentriq), as well as a patient with urothelial cancer with no prior checkpoint inhibitor therapy. The patient with NSCLC remains on the study for 18 months of treatment, and the patient with urothelial cancer remained for over nine months of treatment.

The initial data from this study also showed an increase in the CD8 to Treg ratio after treatment, hinting that the hypothesis leading to this study was correct. The investigators set out to show that a CCR4 antagonist has the ability to block the recruitment of tumor Treg, increase the CD8 to Treg ratio and enhance antitumor immunity.

Safety results from the preliminary analysis showed a favorable profile for FLX475. The maximum tolerated dose of the agent was not reached. In the monotherapy arm, 2 dose-limiting toxicities (DLTs) were observed, which were both asymptomatic QTc prolongation at the 75 mg and 100 mg dose levels. There were not DLTs observed with the combination of FLX475 and pembrolizumab. Based on the safety results of the phase 1 portion of the study, the recommended dose for the phase 2 portion is 100 mg.

In the phase 2 study, a minimum of 80 patients will be enrolled in to eight cohorts. The cohorts will include 4 cohorts ofFLX475 monotherapy and 4 ofFLX475 and pembrolizumab. The tumor types that will be evaluated will include, Epstein-Barr Virus- or Human Papillomavirus-associated cancers such as nasopharyngeal cancer, cervical cancer, and subsets of Hodgkin and non-Hodgkin lymphomas as well as head and neck cancer. The study will also included patients with NSCLC and TNBC.

Patients are eligible to enroll in the study given they have advanced or metastatic cancer that is ineligible for standard therapies, an ECOG performance status of 0 or 1, evaluable disease at baseline, and available tumor tissue for biopsy. The study excludes patients who have a history of allergy or severe hypersensitivity to biologic agents, have experiencedgrade 3 or 4 immune-related adverse events leading to discontinuation of prior immunotherapy drug, have active autoimmune disease or serious autoimmune disease within the past 2 years that required systemic therapy.

Patients were also excluded have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, pneumonitis that required steroids but was not infectious, or symptoms of active pneumonitis, those who had prior allogeneic hematopoietic stem cell transplant within 5 years, or prior allogeneic organ transplant, and those with active graft-versus-host disease.

“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,” said Brian Wong, MD, PhD, president and chief executive officer, RAPT Therapeutics, Inc, in a statement. “Based on these encouraging data, we have determined that three cancer indications, EBV-positive 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. RAPT Therapeutics. November 16, 2020. Accessed November 17, 2020.

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