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1. Compare the objective response rate (ORR) assessed per RANO-LGG criteria by Independent Review Committee (IRC) of tovorafenib monotherapy versus standard of care (SoC) chemotherapy (Time Frame - Up to 60 months): ORR, per RANO-LGG criteria, defined as the proportion of patients with overall confirmed
response of complete response (CR) or partial response (PR)
Secondary outcome:
1. Compare the progression-free survival (PFS) assessed by IRC of tovorafenib monotherapy versus SoC chemotherapy per RANO-LGG criteria (Time Frame - Up to 60 months): PFS per RANO-LGG criteria, defined as time from randomization to PD or death from any
cause
2. Compare the duration of response (DOR) assessed by IRC of tovorafenib monotherapy versus SoC chemotherapy per RANO-LGG criteria (Time Frame - Up to 60 months): DOR per RANO-LGG criteria, defined as time from confirmed response to PD or death from any
cause for patients with confirmed response
3. Compare the overall survival (OS) of tovorafenib monotherapy versus SoC chemotherapy (Time Frame - Up to 60 months): OS, defined as time from randomization up to death from any cause
4. Compare the safety and tolerability of tovorafenib monotherapy versus SoC chemotherapy (Time Frame - Up to 60 months): Type, frequency, and severity of treatment-emergent adverse events
5. Compare the safety and tolerability of tovorafenib monotherapy versus SoC chemotherapy (Time Frame - Up to 60 months): Measured by incidence of clinically significant laboratory abnormalities
6. Evaluate changes in neurological function and adaptive behavior between tovorafenib versus SoC (Time Frame - Up to 60 months): Change from baseline in the Vineland Adaptive Behavior Composite Scales [age-adjusted
standard scores range between 20 to 140, with a mean of 100 and standard deviation of 15,
and lower scores indicate worse functional outcomes]
7. Compare changes in visual function outcomes of tovorafenib monotherapy versus SoC chemotherapy in patients with optic pathway glioma (OPG) (Time Frame - Up to 60 months): Measured by Teller Acuity Cards® or alternative
8. Compare the ORR of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RANO-HGG and Response Assessment in Pediatric Neuro-Oncology (RAPNO-LGG) criteria (Time Frame - Up to 60 months): ORR, defined as the proportion of patients with overall confirmed response per RANO-HGG,
RANO-LGG, or RAPNO-LGG criteria.
9. Compare the clinical benefit rate (CBR) of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RANO-LGG, RANO-HGG and RAPNO-LGG criteria (Time Frame - Up to 60 months): CBR, defined as the proportion of patients with radiological tumor stabilization or
regression per RANO-LGG, RANO-HGG or RAPNO-LGG criteria, as applicable
10. Compare time to response (TTR) of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RANO-LGG, RANO-HGG and RAPNO-LGG criteria (Time Frame - Up to 60 months): Measured by the time to first response following initiation of therapy in patients with
best overall confirmed response per RANO-LGG, RANO-HGG or RAPNO-LGG criteria, as
applicable
11. Compare the PFS of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RAPNO-LGG and RANO-HGG criteria (Time Frame - Up to 60 months): PFS per RANO-HGG or RAPNO-LGG (as applicable), defined as time from randomization to
progressive disease (PD) or death from any cause
12. Compare the DOR of tovorafenib monotherapy versus SoC chemotherapy as assessed by IRC per RAPNO-LGG and RANO-HGG criteria (Time Frame - Up to 60 months): DOR, defined as time from confirmed response to PD or death from any cause for patients
with confirmed response per RANO or RAPNO criteria, as applicable
13. Evaluate the health-related quality of life (HRQoL) in tovorafenib versus SoC chemotherapy using Patient-Reported Outcomes Measurement Information System (PROMIS) test battery (Time Frame - Up to 60 months): Measured by change from baseline in Total Score at 1, 2, 5 years
Active Comparator: Arm #2 Investigator's choice of one of the following current standard of care for pediatric
patients with low-grade gliomas:
1. Children's Oncology Group - Vincristine/Carboplatin (COG-V/C)
2. International Society for Paediatric Oncology - Low-Grade Glioma
Vincristine/Carboplatin (SIOPe-LGG-V/C)
3. Vinblastine (VBL)
