Abstract CT062: A phase 1 study of tamnorzatinib (ONO-7475), an Axl/Mer dual inhibitor, alone and in combination with nivolumab in patients with advanced or metastatic solid tumors
Authors: Katsuya Yuki , Yonemori Kan , Shimizu Toshio , Koyama Takafumi , Kitano Sigehisa , Sudo Kazuki , Kondo Shunsuke , Sato Jun , Hozumi Hiroaki , Yamamoto Noboru 
Published: April 2024

Abstract
Background: Tamnorzatinib (ONO-7475) is an orally active small molecule Axl/Mer dual inhibitor that not only directly acts on cancer cells to suppress their proliferation, but also on immune cells and exerts characteristics of cancer immunotherapy.
Methods: We performed a phase 1 study to assess the tolerability, safety, and pharmacokinetics of ONO-7475 alone (Part A) and in combination with nivolumab (NIVO) (Part B) in Japanese patients (pts) with advanced or metastatic solid tumors (NCT03730337). Patients received once-daily ONO-7475 (3-10 mg, orally) as a monotherapy or in combination with NIVO (240 mg, i.v., every 2 weeks).
Results: Twelve pts in both Part A and Part B (three each at 3 and 6 mg, and six at 10 mg ONO-7475) received the study treatment. Baseline characteristics, safety, and efficacy outcomes are summarized in the Table. While one of six pts in the Part B 10-mg cohort developed dose-limiting toxicities of grade 4 nephritis, grade 3 colitis, and grade 3 hepatic function abnormal, no others did. In biomarker analyses, activation of T cell function and an increase in T cell number, an increase in inflammatory (M1) macrophages/immunosuppressive (M2) macrophages ratio, and suppression of epithelial-to-mesenchymal transition were observed after treatment.
Conclusion: ONO-7475 was tolerated at repeated once-daily oral doses up to 10 mg as a monotherapy and in combination with NIVO in pts with advanced or metastatic solid tumors.

TABLE 1. NAND Table. Baseline Characteristics, Safety Outcomes, and Efficacy Outcomes Part A (ONO-7475 alone) N = 12 Part B (ONO-7475 + NIVO) N = 12 Baseline Characteristics Median age, years (range) 63.5 (31–76) 56.0 (39–72) Female, n (%) 8 (66.7) 9 (75.0) ECOG PS, n (%) 0 8 (66.7) 10 (83.3) 1 4 (33.3) 2 (16.7) Safety Outcomes Number of patients with AEs (%) Any grade 11 (91.7) 11 (91.7) Glade ≥3 0 2 (16.7) *2 Number of patients with SAEs (%) 2 (16.7) *1 1 (8.3) *3 *1 Pyrexia and diverticulitis (1 patient each) *2 Grade 4 neutrophil count decreased (1 patient), grade 4 lymphocyte count decreased and nephritis (1 patient each), and grade 3 colitis, enterocolitis infectious, device related infection, anemia, hyperglycemia, and hepatic function abnormal (1 patient) *3 Colitis, hepatic function abnormal, and nephritis Efficacy Outcomes Objective Response Rate, n (%) [95% CI] 0 [0.0, 26.5] 1 (8.3) [0.2, 38.5] Disease Control Rate, n (%) [95% CI] 3 (25.0) [5.5, 57.2] 4 (33.3) [9.9, 65.1] Best Overall Response, n (%) [95% CI] Complete Response 0 [0.0, 26.5] 0 [0.0, 26.5] Partial Response 0 [0.0, 26.5] 1 (8.3) [0.2, 38.5] Stable Disease 3 (25.0) [5.5, 57.2] 3 (25.0) [5.5, 57.2] Progressive Disease 9 (75.0) 5 (41.7) Not Evaluable 0 3 (25.0) Median OS, months [95% CI] 12.21 [4.93, not reached] 16.99 [5.98, not reached] Median PFS, months [95% CI] 1.86 [0.92, 3.84] 2.17 [0.95, 3.78]
Citation Format: Yuki Katsuya, Kan Yonemori, Toshio Shimizu, Takafumi Koyama, Sigehisa Kitano, Kazuki Sudo, Shunsuke Kondo, Jun Sato, Hiroaki Hozumi, Noboru Yamamoto. A phase 1 study of tamnorzatinib (ONO-7475), an Axl/Mer dual inhibitor, alone and in combination with nivolumab in patients with advanced or metastatic solid tumors [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 CT062.