tivumecirnon (FLX475)

P1/2, N=323, Active, not recruiting, RAPT Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Jan 2025 | Trial primary completion date: Jul 2023 --> Sep 2024

P2, N=20, Completed, Hanmi Pharmaceutical Company Limited | Recruiting --> Completed | N=90 --> 20 | Trial completion date: Dec 2025 --> Oct 2023 | Trial primary completion date: Nov 2025 --> Oct 2023

This is because, although an anti-CCR4 mAb, mogamulizumab, has been approved in Japan to treat ATLL, this therapy failed in a Phase 2 trial among patients outside of Japan. CCL22 but not CCL17 induced strong chemotaxis behavior in NA-ATLL cell lines, which was potently inhibited by a small molecule CCR4 antagonist, CCR4-351. Since extramedullary presentation is frequently seen in NA-ATLL and central nervous system involvement is an adverse prognostic feature, inhibiting chemotaxis with a CCR4 antagonist such as FLX475 may be an effective therapeutic approach.

Conclusions FLX475, an oral CCR4 antagonist, has previously demonstrated clear monotherapy and encouraging combination activity with pembrolizumab. 2 3 In this completed Phase 2 cohort of subjects with CPI-naïve NSCLC, FLX475 in combination with pembrolizumab was shown to be well tolerated and has demonstrated encouraging clinical activity compared to pembrolizumab monotherapy in PD-L1+ NSCLC (based on historical results) – in both subjects with low (TPS 1-49%) and those with high (TPS ≥50%) PD-L1 expression – supporting the continued development of this combination therapy for NSCLC.

In a cohort enrolling subjects with non-small-cell lung cancer (NSCLC) not previously treated with checkpoint inhibitor, 4/13 subjects (31%) have had confirmed partial responses (PRs), including several ongoing for over 6 months, meeting criteria to proceed to Stage 2 enrollment. Conclusions In this ongoing phase 1/2 trial of the oral CCR4 antagonist, FLX475, as monotherapy and in combination with pembrolizumab, antitumor activity including complete responses to FLX475 monotherapy and encouraging combination activity have been observed with an acceptable safety profile.

Treg depletion via systemic ablation or inhibition of trafficking, resulted in augmentation of the antitumor effects of CAR T cells in our pre-clinical immunocompetent solid tumor model. If generalizable, these data support further investigation as to whether the orally bioavailable CCR4 antagonist currently in clinical development, FLX475, may be used to augment human CAR T cell therapy for solid tumors.

Enrollment into Phase 2 expansion cohorts has been initiated. Research Funding: RAPT Therapeutics