Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma

作者：Drew Rasco, Theresa Medina, Pippa Corrie, Anna C. Pavlick, Mark R. Middleton, Paul Lorigan, Chris J. Hebert, Ruth Plummer, James Larkin, Sanjiv S. Agarwala, Adil Daud, Jiaheng Qiu, Viviana Bozón, Michelle Kneissl, Elly Barry, Anthony J. Olszanski · 发表于：Cancer Chemotherapy and Pharmacology · 年份：2023 · DOI：10.1007/s00280-023-04544-5 · 被引用次数：44 · 研究领域：Melanoma and MAPK Pathways、Cutaneous Melanoma Detection and Management、Brain Metastases and Treatment

PURPOSE: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. METHODS: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. RESULTS: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable ...