tivumecirnon (FLX475) / Hanmi, GSK - LARVOL DELTA

North American Adult T-Cell Leukemia/Lymphoma Has Frequent Mutations in CCR4 and Responds in Vitro to a Small Molecule CCR4 Antagonist, CCR4-351 (ASH 2023) - P1/2 | "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."

IO biomarker • Preclinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CCL2 • CCL22 • CCR4 • CD4 • CD7 • CD8

North American Adult T-Cell Leukemia Lymphoma Has Frequent Mutations in CCR4 and Responds in Vitro to a Small Molecule CCR4 Antagonist (ASH 2024) - P1/2 | "Furthermore, a CCR4-targeting therapy, Mogamulizumab, was reported to have clinical efficacy in J-ATLL but not NA-ATLL patients although the underlying mechanism is unknown. CCL22 but not CCL17 induced strong chemotaxis in NA-ATLL cell lines, which can be 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 tivumecirnon may be an effective therapeutic approach for this devastating disease."

IO biomarker • Preclinical • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CCL2 • CCL22 • CCR4 • CD4 • CD7 • CD8

Discovery of Tivumecirnon (FLX475), a Potent and Selective CCR4 Antagonist That Inhibits the Migration of Immunosuppressive Regulatory T Cells into the Tumor Microenvironment to Restore Antitumor Immunity. (PubMed, J Med Chem) - "We have developed novel CCR4 antagonist small molecules that selectively and potently inhibit the migration of Treg to the TME (hTreg CTX IC50: 27 nM) and have culminated in our clinical candidate (14, FLX475, Tivumecirnon). The discovery of this potent, selective, and orally bioavailable CCR4 antagonist and its characterization in several preclinical models is described herein."

Biomarker • Journal • Oncology • CCL2 • CCL22 • CCR4

A combined mregDC and Treg signature associates with antitumor efficacy of CCR4 antagonist tivumecirnon FLX475 (AACR 2024) - P1/2 | "Our clinical study (NCT03674567) demonstrated that tivumecirnon can block the local accumulation of Treg in the TME and has clinical activity as monotherapy as well as in combination with pembrolizumab. Furthermore, the levels of mregDC and Treg may be used as a biomarker for selection of patients more likely to respond to tivumecirnon in combination with anti-PD-1. Additional studies are required to confirm these results"

Clinical • IO biomarker • Oncology • CCL2 • CCL22 • CCR4 • GZMB • IFNG • PTPRC

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 (AACR 2024) - P1/2 | "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."

Checkpoint inhibition • Clinical • P2 data • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Natural Killer/T-cell Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • T Cell Non-Hodgkin Lymphoma • CCR4 • PD-L1

Structure basis for C-C chemokine receptor 4 modulation by orthosteric and allosteric antagonists. (PubMed, Proc Natl Acad Sci U S A) - "Tivumecirnon (FLX475) and Zelnecirnon (RPT193), two clinical-stage investigational drugs, bind to the orthosteric site of CCR4, blocking the chemokine recognition site 1. In contrast, AZD2098 and GSK2239633A occupy an allosteric site near the TM7-H8 turn, presumably interfering with G-protein coupling. Further analyses reveal that the therapeutic antibody mogamulizumab binds to the N-terminal region of CCR4 without competing with CCL17, suggesting that its antagonistic effect is mediated exclusively through antibody-dependent cellular cytotoxicity. Together, these structural insights elucidate distinct modes of CCR4 inhibition and provide a framework for the rational design of next-generation therapeutics targeting chemokine receptors."

Journal • Adult T-Cell Leukemia-Lymphoma • Cutaneous T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CCL2 • CCL22 • CCR4

CCR-CCL axes as key upstream influencers of pancreatic ductal adenocarcinoma: CCR2-CCL2, CCR5-CCL5, CCR4-CCL17/22, CCR6-CCL20, CCR7-CCL19/21. (PubMed, Front Immunol) - "We further detail past and ongoing therapeutic efforts and trials addressing these axes in both PDAC and relevant non-PDAC settings via several small-molecule antagonists and monoclonal antibodies: BMS-813160, Maraviroc, Leronlimab, FLX475, PF-07054894, IDOR- 1117-2520, and CAP-100. Despite continuous advances in the field, the current body of evidence remains limited and presents significant research gaps in areas such as spatial profiling, stage-specific analyses, and general mechanistic validation in PDAC-specific settings. Addressing these shortcomings will be key to developing a more comprehensive knowledge of the field and improving future therapeutic strategies to overcome PDAC."

IO biomarker • Journal • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CCL19 • CCL2 • CCL20 • CCR2 • CCR4 • CCR6 • CCR7

RAPT Therapeutics Reports First Quarter 2025 Financial Results (RAPT Therapeutics Press Release) - "Research and development expenses for the first quarter of 2025 were $12.0 million, compared to $24.8 million for the same period in 2024. The decrease in research and development expenses was primarily due to decreases in costs related to development of zelnecirnon and tivumecirnon, personnel, lab supplies, non-cash stock-based compensation and facilities, partially offset by increases in costs related to development of RPT904 and early-stage programs."

Commercial • Oncology

Hanmi Pharmaceutical Confirms ‘Complete Remission’ in Phase 1/2 Study of Its Innovative Selective CCR4 Antagonist (Hanmi Press Release) - P2 | N=20 | NCT04768686 | Sponsor: Hanmi Pharmaceutical Company Limited | "At the 2025 ASCO Gastrointestinal Cancers Symposium, Hanmi unveiled the final results of a Phase 2 clinical trial demonstrating the excellent antitumor efficacy and tolerability of Tivumecirnon (FLX475) in combination with KEYTRUDA in patients with Epstein-Barr Virus (EBV)-positive gastric cancer. In Cohort 1, which consisted of 10 patients with EBV-negative gastric cancer, no objective response rate (ORR) was observed, although two patients achieved stable disease (SD). By contrast, the results in Cohort 2 were far more promising. Among the 10 patients with EBV-positive gastric cancer, an ORR of 60% was achieved, including one complete response (CR) and five partial responses (PR)."

P2 data • Gastric Cancer

A phase 2 study to assess the safety and efficacy of FLX475 (tivumecirnon) combined with pembrolizumab in patients with advanced or metastatic gastric cancer. (ASCO-GI 2025) - P2 | "The combination of FLX475 with pembrolizumab was well-tolerated and showed promising anti-tumor activity and durable responses in patients with advanced or metastatic EBV-positive GC."

Clinical • IO biomarker • Metastases • P2 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CCL2 • CCL22 • CCR4

KEYNOTE-877: Dose Escalation and Expansion Study of FLX475 Monotherapy and in Combination with Pembrolizumab (clinicaltrials.gov) - P1/2 | N=323 | Completed | Sponsor: RAPT Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial primary completion date: Sep 2024 ➔ Dec 2024

Monotherapy • Trial completion • Trial primary completion date • Breast Cancer • Cervical Cancer • Classical Hodgkin Lymphoma • Esophageal Cancer • Gastric Cancer • Head and Neck Cancer • Hematological Malignancies • Hodgkin Lymphoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

RAPT Therapeutics Reports Third Quarter 2024 Financial Results (GlobeNewswire) - "Third Quarter Ended September 30, 2024...Research and development expenses for the third quarter of 2024 were $13.3 million, compared to $27.0 million for the same period in 2023. The decrease in research and development expenses was primarily due to lower development costs related to zelnecirnon, tivumecirnon and early stage programs, as well as decreased expenses for personnel, consultants and lab supplies....Research and development expenses for the nine months ended September 30, 2024 were $60.8 million, compared to $74.2 million for the same period in 2023. The decrease in research and development expenses was primarily due to decreases in development costs related to zelnecirnon, tivumecirnon and early-stage programs, as well as lab supplies, partially offset by increased expenses for personnel, consultants, facilities and non-cash stock-based compensation."

Commercial • Inflammation • Oncology • Solid Tumor

KEYNOTE-B83: FLX475 Combined with Pembrolizumab in Patients with Advanced or Metastatic Gastric Cancer (clinicaltrials.gov) - P2 | N=20 | Completed | Sponsor: Hanmi Pharmaceutical Company Limited | Trial completion date: Oct 2023 ➔ Aug 2024 | Trial primary completion date: Oct 2023 ➔ Aug 2024

Metastases • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

RAPT Therapeutics Reports Second Quarter 2024 Financial Results (GlobeNewswire) - "RAPT Therapeutics...reported financial results...Second Quarter Ended June 30, 2024...Research and development expenses for the second quarter of 2024 were $22.6 million...The increase in research and development expenses was primarily due to higher development costs related to zelnecirnon, as well as increased expenses for personnel, consultants, facilities and non-cash stock-based compensation, partially offset by decreases in development costs related to tivumecirnon and early-stage programs as well as lab supplies costs...Research and development expenses for the six months ended June 30, 2024 were $47.4 million....The increase in research and development expenses was primarily due to increased expenses for personnel, consultants, facilities and non-cash stock-based compensation, partially offset by decreases in development costs related to zelnecirnon, tivumecirnon, early-stage programs and lab supplies costs."

Commercial • Asthma • Atopic Dermatitis • Hematological Malignancies • Immunology • Oncology • Respiratory Diseases • Solid Tumor

Dr Muzaffar on the Evaluation of FLX475 Plus Pembrolizumab in HNSCC (OncLive) - "Jameel Muzaffar, MD, discusses a study of FLX475 plus pembrolizumab in patients with head and neck squamous cell carcinoma."

Video

Tivumecirnon Plus Pembrolizumab Shows Activity in Checkpoint Inhibitor–Exposed Recurrent/Metastatic HNSCC (OncLive) - "'For patients [with HSNCC] who have [progressed on] checkpoint blockers, there's really no standard of care,' lead study author Jameel Muzaffar, MD, said in an interview with OncLive. 'Therefore, having these newer combinations come up and show such promising responses is encouraging. It tells us that we're going in the right direction.'"

Audio • Interview

RAPT Therapeutics Announces Promising Results from Phase 2 Trial of Tivumecirnon in Combination with Anti-PD-1 Immunotherapy in CPI-Experienced Head and Neck Cancer Patients (GlobeNewswire) - P1/2 | N=323 | NCT03674567 | Sponsor: RAPT Therapeutics, Inc. | "The results were presented at the American Association for Cancer Research (AACR) Annual Meeting....The AACR poster highlighted data from the 32-patient CPI-experienced HNSCC cohort in the trial evaluating tivumecirnon, an oral small molecule CCR4 antagonist designed to block the migration of regulatory T cells, in combination with pembrolizumab. Patients in this cohort had heavily pretreated disease, with 69% of patients having received three or more (up to six) prior lines of treatment. In the entire cohort, confirmed responses were observed in 5/32 patients (15.6%) regardless of PD-L1 or HPV status. In the 23 patients known to have PD-L1+ disease (CPS ≥1), an ORR of 17.4% (4/23) was observed, and in the 18 patients known to have HPV+ disease, an ORR of 22.2% (4/18) was observed."

P2 data • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

KEYNOTE-877: Dose Escalation and Expansion Study of FLX475 Monotherapy and in Combination With Pembrolizumab (clinicaltrials.gov) - P1/2 | N=323 | Active, not recruiting | Sponsor: RAPT Therapeutics, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2023 ➔ Jan 2025 | Trial primary completion date: Jul 2023 ➔ Sep 2024

Combination therapy • Enrollment closed • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

RAPT Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results (GlobeNewswire) - "RAPT Therapeutics, Inc...reported financial results for the fourth quarter and year ended December 31, 2023...Research and development expenses for the fourth quarter of 2023 were $26.8 million, compared to $19.5 million for the same period in 2022. The increase in research and development expenses was primarily due to higher development costs related to zelnecirnon, as well as increased expenses for personnel, lab supplies, consultants, facilities and stock-based compensation, partially offset by lower development costs related to tivumecirnon and early-stage programs...Research and development expenses for the year ended December 31, 2023 were $101.0 million, compared to $67.1 million in 2022. The increase in research and development expenses was primarily due to higher development costs related to zelnecirnon....partially offset by lower development costs related to tivumecirnon and early-stage programs."

Commercial • Asthma • Hematological Malignancies • Immunology • Inflammation • Oncology • Respiratory Diseases • Solid Tumor

RAPT Therapeutics Announces Multiple Late-Breaking Presentations at the Upcoming American Association for Cancer Research (AACR) Annual Meeting (GlobeNewswire) - "RAPT Therapeutics...announced the acceptance of three late-breaking abstracts for poster presentation, including a poster presentation for tivumecirnon (FLX475), its lead oncology drug candidate, highlighting phase 2 clinical data in head and neck squamous cell carcinoma (HNSCC), at the American Association for Cancer Research (AACR) Annual Meeting which will take place April 5-10, 2024 in San Diego, CA."

Clinical data • Late-breaking abstract • P2 data • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

KEYNOTE-B83: FLX475 Combined With Pembrolizumab in Patients With Advanced or Metastatic Gastric Cancer (clinicaltrials.gov) - P2 | N=20 | Completed | Sponsor: Hanmi Pharmaceutical Company Limited | Recruiting ➔ Completed | N=90 ➔ 20 | Trial completion date: Dec 2025 ➔ Oct 2023 | Trial primary completion date: Nov 2025 ➔ Oct 2023

Enrollment change • Metastases • Trial completion • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

CCR4 Antagonists May Bolster Immune Responses With Checkpoint Inhibitors in PD-L1+ NSCLC (OncLive) - "In an interview with OncLive®, Anders discussed the how unique mechanism of CCR4 antagonists such as tivumecirnon could improve immune responses when administered alongside checkpoint inhibitors; early results with tivumecirnon in patients with NSCLC, particularly those with PD-L1–high status; and the potential use of tumor-driven biomarkers for patient stratification and prediction of benefit with this approach for this patient population."

Interview

RAPT Therapeutics Announces Positive Data, Including Objective Response Rates and Progression-Free Survival, from its Phase 2 Trial of FLX475 in Combination with a Checkpoint Inhibitor in Patients with Advanced NSCLC (BioSpace) - P1/2 | N=375 | (NCT03674567) | Sponsor: RAPT Therapeutics, Inc. | "The data were presented today in a poster at the Society for Immunotherapy of Cancer (SITC) 38th Annual Meeting being held in San Diego. The presenting author was Julie Brahmer, M.D..."

Checkpoint inhibition • P1/2 data

Phase 2 safety and efficacy of oral CCR4 antagonist FLX475 (tivumecirnon) plus pembrolizumab in subjects with non-small cell lung cancer not previously treated with checkpoint inhibitor (SITC 2023) - P1/2 | "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."

Checkpoint inhibition • Clinical • IO biomarker • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCR4

Biological activity of FLX475, an oral CCR4 antagonist, as monotherapy and in combination with pembrolizumab in advanced cancer (SITC 2023) - P1/2 | "FLX475 monotherapy appears to modify the TME toward a phenotype associated with response to anti-PD-(L)1. Baseline markers associated with favorable outcome are different for the combination treatment compared to anti-PD-1 monotherapies suggesting that more patients might benefit from FLX475/pembrolizumab combination than pembrolizumab alone."

Combination therapy • IO biomarker • Metastases • Monotherapy • Oncology • CCL2 • CCL22 • CCR4 • CD4 • CD8 • FOXP3 • IL2RA • IL7R