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

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 (7Suppl): Abstract nr CT062.