Discussion
toxicity, rash, LGGs, tumors, gliomas
SOLID TUMORS, TUMORS, SKIN AND SUBCUTANEOUS TISSUE DISORDER, GLIOMAS
This first-in-human dose escalation study allowed the determination of the MTD of tovorafenib administered either Q2D or QW and has shown that the overall safety profiles on both schedules are acceptable. The most common TEAEs leading to dose reduction were skin and subcutaneous tissue disorders, which have previously been noted as common side effects of first-generation BRAF inhibitors [The dose expansion phase provided a preliminary indication of tovorafenib efficacy. Partial responses were seen in 8 (50%) of 16 patients in the The PK analyses showed that tovorafenib has a moderately fast absorption rate, with an overall median The QW dose escalation and expansion cohorts were introduced by protocol amendment as it was anticipated that higher unit doses would be possible on such a schedule, which would lead to higher tovorafenib concentrations for part of the treatment period. This proved to be the case, with a higher Weekly administration of tovorafenib as monotherapy has been further explored in a pediatric phase 1 study in patients with radiographically recurrent/progressive low-grade gliomas (LGGs) harboring MAPK pathway alterations [Tovorafenib on a QW schedule is also currently being evaluated as monotherapy and in combination with other therapies in the phase 1b/2 FIRELIGHT-1 umbrella study in patients ≥ 12 years of age with recurrent, progressive, or refractory solid tumors harboring MAPK pathway aberrations (NCT04985604). In particular, given non-overlapping toxicity profiles, this study will explore combining tovorafenib with a MEK inhibitor, which outside the specific setting of tumors with In conclusion, we have defined the MTD of tovorafenib for adults on Q2D and QW schedules. The dose expansion phase of our phase 1 study shows that the safety profile of tovorafenib is acceptable in both cases, and in line with other BRAF-targeted agents. Of note, tovorafenib appears to have antitumor activity in the setting of BRAF alterations without the clinical manifestations of paradoxical activation seen with type I BRAF inhibitors, such as the development of cutaneous squamous cell carcinoma or keratoacanthoma. In addition, there is evidence of MAPK pathway inhibition without the class effects seen with MEK inhibitors (e.g., decreased left ventricular ejection fraction, retinal vein obstruction/central serous retinopathy, acneiform rash, paronychia).The long plasma half-life of tovorafenib affords use with a QW dosing schedule, while still maintaining a steady state trough plasma concentration above the protein binding adjusted pERK EC