LGG-09. CLINICAL ACTIVITY OF PAN-RAF INHIBITOR TOVORAFENIB IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY

Genomic alterations of BRAF are common oncogenic drivers in pediatric low-grade glioma (pLGG). Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II panRAF inhibitor. FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 includes patients 6 months-25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m(2) (≤600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by RANO criteria and determined by blinded independent review. As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2-21). Patients had received a median of 3 prior lines of systemic therapy (range: 1-9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a tumor BRAF fusion/rearrangement (83%) and 13 (17%) a V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7-16.8); 59 patients (77%) remained on treatment at data cutoff. ORR in 69 RANO-evaluable patients was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Two patients (3%) discontinued tovorafenib due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented. Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with refractory BRAF-altered LGG.