Loan Tran*1, Anna Largajolli*2, YuWei Lin*2, A. Yin Edwards2, Katrina Hui2, Sophia Yui Kau Fong2, Peter Manley1, Elly Barry1, S. Y. Amy Cheung+2, Jing Wang+1
1Day One Biopharmaceuticals, Inc, 2Certara Drug Development Solutions
Objectives: Genetic alterations and dysregulation of the mitogen-activated protein kinase (MAPK) pathway have been found in many different types of adult and pediatric cancers [1]. One of the most frequently altered genes in this pathway is v-Raf murine sarcoma viral oncogene homolog B (BRAF) [2]. Tovorafenib is an oral, selective, central nervous system-penetrant, type II RAF kinase inhibitor that received US FDA accelerated approval for patients =6 months of age with r/r BRAF-altered pLGG based on results from the phase 2 FIREFLY-1 trial (NCT04775485). Here we describe the development of a PPK model for tovorafenib in adults and pediatrics and the assessment of clinical relevance of covariate effects. Methods: Data from 2 clinical trials (phase 1 C28001 [NCT01425008] and phase 1b C28002 [NCT02327169]) in adults with advanced solid tumors were used in the initial PPK analysis for the tablet formulation. One-, two-, and three-compartment models with different absorption models were tested. Covariate effects were assessed using stepwise covariate modelling. The preliminary PPK model was then updated with data from 2 additional studies—FIREFLY-1, in which patients 6 months to 25 years of age received tovorafenib either as a tablet or powder for oral suspension (PfOS), and a phase 1 trial in healthy adults examining the relative bioavailability (rBA) of the PfOS vs the tablet tovorafenib formulation and the effect of food on the tablet formulation. These studies provided additional data on the PfOS formulation and pediatric patients. Both the structural and covariate models were evaluated to update the PPK model for both adult and pediatric populations. The relative importance of covariate effects included in the updated PPK model was evaluated with univariate analyses using forest plots of the relative changes in model-predicted tovorafenib steady-state exposure. Results: The initial tovorafenib PK data in adult patients who received the tablet formulation was adequately described by a 1-compartment model with a 3-compartment transit absorption model and linear elimination. Sex was identified as a covariate of the apparent clearance (CL/F) and body surface area (BSA) as a covariate of CL/F and apparent central volume of distribution (Vc/F). With the additional data from FIREFLY-1 and the phase 1 rBA study, the PPK model was updated to include a first-order absorption model with no transit compartment for the PfOS formulation. Similar to the preliminary PPK model, BSA was included as a covariate of tovorafenib CL/F and Vc/F. The allometric exponents on CL/F and Vc/F increased with a wider range of BSA compared with the preliminary PPK model, which suggested an even stronger influence of body size on the PK in pediatric patients and the appropriateness of using a BSA-based dosing strategy. CL/F was associated with sex, where males were estimated to have a 21.5% higher CL/F than females. For subjects who received the tablet formulation, the consumption of high-fat food was estimated to have a 54.3% lower absorption rate constant compared to those under the fasted state. The effects of formulation (tablet vs PfOS) and food (fasted vs fed) on model-predicted tovorafenib steady-state exposure were within the 0.8 to 1.25 exposure ratio interval and were not considered to be clinically meaningful. Conclusions: The PK of tovorafenib was well characterized by a 1-compartment model with 3-transit absorption model for the tablet formulation and first-order absorption model with no transit compartment for the PfOS formulation. Simulations suggested that tovorafenib exposure was not impacted by formulation types, supporting the comparable relative bioavailability between the tablet and PfOS formulations. The inclusion of pediatric data also confirmed that a BSA-based dosing strategy was appropriate to account for the influence of body size on the PK in pediatric patients. *joint first authors, +joint senior author
1. Yaeger R, Corcoran RB. Targeting alterations in the RAF-MEK pathway. Cancer Discov. 2019;(3):329-341. 2. Sholl M A narrative review of BRAF alterations in human tumors: diagnostic and predictive implications. Precis Cancer Med. 2020;3:26.
Reference: PAGE 33 (2025) Abstr 11476 [www.page-meeting.org/?abstract=11476]
Poster: Drug/Disease Modelling - Oncology