Abstract CT226: Phase 2 study of oral CCR4 antagonist FLX475 (tivumecirnon) plus pembrolizumab in subjects with head and neck squamous cell carcinoma (HNSCC) previously treated with checkpoint inhibitor
Authors: Muzaffar Jameel , Kirtane Kedar , Redman Rebecca , Yang Muh-Hwa , Kim Tae Min , Liu Stephen , Lynch Ryan , Brahmer Julie , LoRusso Patricia , Henick Brian , Kim Sung-bae , Feng Yin-Hsun , Chisamore Michael , Kassner Paul , Brockstedt Dirk , Nasrah Nicole , Goyal Rakesh , Ho William Y. , Villaflor Victoria 
Published: April 2024

Abstract
BACKGROUND: FLX475 (tivumecirnon) is a selective CCR4 antagonist designed to block the recruitment of immunosuppressive regulatory T cells (Treg) into the tumor microenvironment. The FLX475-02 trial (NCT03674567) is a phase 1/2 study of FLX475 as monotherapy and in combination with pembrolizumab in subjects with advanced cancer. Early encouraging data on the biologic effects, safety and antitumor activity of FLX475 have previously been presented. We now present the results from the Phase 2 cohort of combination therapy in subjects with head and neck squamous cell carcinoma (HNSCC) previously treated with checkpoint inhibitor (CPI-experienced).
METHODS: Subjects with CPI-experienced, recurrent or metastatic (R/M) HNSCC received FLX475 100 mg orally once daily with pembrolizumab (200 mg IV Q3 weeks). The primary study objectives were safety and tolerability, and antitumor activity. The primary efficacy endpoint was objective response rate (ORR), based on RECIST 1.1 criteria. Additional efficacy endpoints included progression-free survival (PFS). Safety was evaluated as per CTCAE v4.03. Data cutoff was 11DEC2023.
RESULTS: For the 32 subjects with HNSCC evaluable for response, median follow-up was 14.8 months (range 2.2-40.1) and median lines of prior therapy were 3 (1-6). Median age of subjects was 59 yrs; 94% were male and 75% were Caucasian. Primary tumor location was oropharynx in 56%. As previously reported, the only adverse event clearly determined to be treatment related to FLX475 to date has been asymptomatic and reversible QT prolongation (managed by dose reduction). Among the subjects evaluable for response regardless of HPV or PD-L1 status (n=32), confirmed partial response (cPR) was observed in 5 subjects (ORR: 15.6%, 95% CI 6-32%). Among the subgroup of subjects whose tumors were HPV positive (n=18), 8 (44%) experienced reduction from baseline in target lesion measurements and cPR was observed in 4 (ORR: 22.2%, 95% CI 9-46%). Among the subgroup of subjects whose tumors expressed PD-L1 (combined positive score [CPS] ≥1%) (n=22), cPR was observed in 4 (ORR: 18.2%, 95% CI 7-39%). At data cutoff, the HPV-positive subgroup median PFS was 2.9 months (95% CI 2-10.3) and 3 subjects were still on treatment.
CONCLUSIONS: FLX475, an oral CCR4 antagonist, has previously demonstrated clear monotherapy activity in EBV+ extranodal NK/T-cell lymphoma and promising combination activity with pembrolizumab in EBV+ gastric cancer and CPI-naïve non-small cell lung cancer. In this completed Phase 2 cohort of subjects with CPI-experienced R/M HNSCC, FLX475 in combination with pembrolizumab was shown to be well tolerated and has demonstrated encouraging clinical activity particularly in those with HPV-positive tumors, supporting the continued development of this combination therapy for CPI-experienced HNSCC.
Citation Format: Jameel Muzaffar, Kedar Kirtane, Rebecca Redman, Muh-Hwa Yang, Tae Min Kim, Stephen Liu, Ryan Lynch, Julie Brahmer, Patricia LoRusso, Brian Henick, Sung-bae Kim, Yin-Hsun Feng, Michael Chisamore, Paul Kassner, Dirk Brockstedt, Nicole Nasrah, Rakesh Goyal, William Y. Ho, Victoria Villaflor. Phase 2 study of oral CCR4 antagonist FLX475 (tivumecirnon) plus pembrolizumab in subjects with head and neck squamous cell carcinoma (HNSCC) previously treated with checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT226.