Abstract
PURPOSE
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 AND METHODS
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.
RESULTS
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%).
CONCLUSION
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.