Type II RAF Inhibitor Tovorafenib in Recurrent/Refractory Melanoma or Other Solid Tumors With <i>BRAF</i> Fusions or <i>CRAF/RAF1</i> Fusions or Amplification: Phase II FIRELIGHT-1 Substudy.

Abstract

Tovorafenib is an oral, selective, CNS-penetrant, type II inhibitor of BRAF and CRAF. <i>BRAF</i> fusions and <i>CRAF/RAF1</i> fusions and amplifications are rare oncogenic drivers in many solid tumors. The phase II DAY101-102a substudy of FIRELIGHT-1 (ClinicalTrials.gov identifier: NCT04985604) investigated the efficacy and safety of tovorafenib monotherapy in recurrent/refractory solid tumors with structural alterations in <i>BRAF</i> or <i>CRAF</i>. Patients &#x2265;12 years of age with a recurrent/refractory solid tumor with a <i>BRAF</i> fusion or <i>CRAF</i> fusion or amplification were enrolled into a melanoma cohort or tumor-agnostic cohort. The primary end point was overall response rate (ORR), as assessed by investigators. Tovorafenib was administered at 600 mg once weekly (adult dose), continuously, in 28-day cycles. Twenty-three patients were enrolled; eight in the melanoma cohort and 15 in the tumor-agnostic cohort. The median age was 53 years (range, 21-71), and 57% of patients had &#x2265;2 lines of prior therapy. Fourteen patients had tumors with <i>BRAF</i> fusion, six <i>CRAF</i> fusion, two <i>CRAF</i> amplification, and one <i>CRAF</i> fusions and amplification. The median duration of tovorafenib treatment was 5.3 months (range, 0.8-22.5). The ORR was 43% (10/23 patients), including 50% (4/8) in patients with melanoma and 40% (6/15) in patients with other tumors. The median time to response was 1.8 months. The median duration of response was 9.2 months. The most common treatment-related adverse events (any grade) were anemia (39%), pruritus (30%), increased creatine phosphokinase (26%), and rash (26%). Tovorafenib demonstrated single-agent clinical activity in solid tumors with <i>BRAF</i> fusions or <i>CRAF</i> fusions or amplification and had a manageable safety profile. Tovorafenib may offer a new targeted treatment option for adult patients with tumors harboring these rare genomic driver alterations.