South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
University of Colorado Cancer Center, Aurora, CO, USA.
Cancer Chemother Pharmacol. 2023 Jul;92(1):15-28. doi: 10.1007/s00280-023-04544-5. Epub 2023 May 23.
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.
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.
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 patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg.
The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.
NCT01425008.
BRAF 和 NRAS 的基因组改变是恶性黑色素瘤和其他实体肿瘤的致癌驱动因素。托伐替尼是一种研究性、口服、选择性、穿透中枢神经系统的小分子、II 型泛 RAF 抑制剂。这是一项首次在人体中进行的 I 期研究，旨在探索托伐替尼的安全性和抗肿瘤活性。
这项在复发或难治性晚期实体肿瘤成人患者中进行的两部分研究包括剂量递增阶段和剂量扩展阶段，包括分子定义的黑色素瘤患者队列。主要目的是评估托伐替尼隔日（Q2D）或每周一次（QW）给药的安全性，并确定这些方案下的最大耐受和推荐的 II 期剂量（RP2D）。次要目的包括评估抗肿瘤活性和托伐替尼的药代动力学。
托伐替尼已用于 149 名患者（Q2D n=110，QW n=39）。托伐替尼的 RP2D 定义为 200mg Q2D 或 600mg QW。在剂量扩展阶段，Q2D 队列中 80 名患者中有 58 名（73%）和 QW 队列中 19 名患者中有 9 名（47%）发生了≥3 级不良事件。这些患者中最常见的是贫血（14 名患者，14%）和斑丘疹（8 名患者，8%）。在可评估的 68 名患者的 Q2D 扩展阶段中，有 10 名（15%）患者有反应，包括 16 名 BRAF 突变阳性、初治 RAF 和 MEK 抑制剂的黑色素瘤患者中有 8 名（50%）。在未接受 RAF 和 MEK 抑制剂治疗的 NRAS 突变阳性黑色素瘤患者的 QW 剂量扩展阶段，17 名可评估患者中无反应；9 名患者（53%）的最佳反应为疾病稳定。在 400-800mg 的剂量范围内，QW 剂量给药与托伐替尼在全身循环中的最小积累相关。
两种方案的安全性特征均可接受，QW 剂量为 600mg QW 的 RP2D 更适合未来的临床研究。托伐替尼在 BRAF 突变型黑色素瘤中的抗肿瘤活性有希望，并证明在多种情况下继续临床开发是合理的。
NCT01425008。
