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

Tovorafenib is an oral, selective, CNS-penetrant, type II inhibitor of BRAF and CRAF. BRAF fusions and CRAF/RAF1 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 BRAF or CRAF.

Patients ≥12 years of age with a recurrent/refractory solid tumor with a BRAF fusion or CRAF 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 ≥2 lines of prior therapy. Fourteen patients had tumors with BRAF fusion, six CRAF fusion, two CRAF amplification, and one CRAF 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 BRAF fusions or CRAF 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.