Updated Three-Year FIREFLY-1 Findings Highlight the Role of Emerging Clinical Endpoints in pLGG

Pediatric low-grade glioma (pLGG) remains the most common type of brain tumor in children, characterized by a chronic disease course and repeated therapeutic interventions. The advent of targeted MAPK-pathway inhibitors has initiated a paradigm shift in the management of pLGG, offering new hope for patients with BRAF-altered tumors. These therapies have prompted renewed evaluation of how to measure treatment benefit in pLGG. While overall response rate (ORR) and progression-free survival (PFS) remain foundational trial benchmarks, they may not fully capture clinically meaningful durability of benefit in pLGG, particularly in the context of long-term disease control. Now, updated data from the phase 2 FIREFLY-1 trial provide insights into the potential advantages of incorporating new clinical endpoints into practice.^1-3  

FIREFLY-1 (NCT04775485) is an open-label, multicenter phase 2 study evaluating once-weekly oral tovorafenib in children and young adults with relapsed or refractory BRAF-altered pLGG.² In Arm 1 of the study, the registrational cohort included 77 patients who had received at least 1 prior systemic therapy.² Eligible patients were identified as having tumors with BRAF fusion, rearrangement, or V600 mutation.² Responses were assessed through independent central review using RAPNO (Response Assessment in Pediatric Neuro-Oncology) low-grade glioma criteria.² In addition to standard RAPNO criteria, FIREFLY-1 uniquely incorporated time to next treatment (TTNT) and treatment-free interval (TFI) endpoints to better capture clinically relevant treatment durability beyond radiographic change.^1,2   

In the updated 3-year analysis, with a median follow-up of 40.6 months, tovorafenib demonstrated antitumor activity consistent with that observed in earlier analyses.³ Efficacy outcomes include an ORR of 53%, with a median reduction in tumor size of 47%, and a median duration of response (DOR) of 19.4 months.³ Notably, median radiographic PFS was 16.6 months with a median TTNT of 42.6 months, meaning that patients went for more than 3 years before requiring another line of therapy.^1,3 No new safety signals were identified in the extended follow-up, though continued monitoring remains important given the chronic treatment course in pLGG.³ This divergence between radiographic PFS and TTNT highlights how emerging clinical endpoints may better reflect clinically meaningful durability of benefit, particularly when treatment decisions are not driven by imaging alone.  

Of the 77 patients enrolled, 39 elected to enter a drug-free observational period after completing 26 cycles of tovorafenib.³ Among them, 77% achieved a TFI of ≥12 months, and the median TFI was not reached at the time of data cutoff.³ Tumor rebound was minimal, with 12 out of the 39 patients experiencing ≥25% growth in the first 6 months of observation, with most remaining below baseline tumor size.³ For patients who experienced RAPNO-defined disease progression, re-treatment with tovorafenib resulted in meaningful tumor shrinkage, indicating the feasibility of treatment re-initiation.³ These observations underscore the limitations of relying exclusively on rigid radiographic criteria when interpreting long-term disease control in pLGG.  

Taken together, the updated FIREFLY-1 results underscore the importance of emerging endpoints, such as TTNT and TFI, in future clinical trials. TTNT and TFI capture treatment-relevant decision points and periods of off-therapy stability, which may help better quantify the multidimensional benefits experienced by patients and their families. While radiographic PFS and objective response rate (ORR) remain foundational in neuro-oncology research, clinicians increasingly recognize their limitations in assessing treatment for pLGG.  

Long-term FIREFLY-1 results demonstrate how emerging endpoints, such as TTNT and TFI, can complement traditional radiographic measures in interpreting the durability of benefit in pLGG. These data support a broader shift toward incorporating patient-centered endpoints that provide additional context for understanding treatment durability beyond radiographic progression alone. 

References  

1. Day One Biopharmaceuticals. Three-year follow-up data from OJEMDA™ (tovorafenib) phase 2 FIREFLY-1 trial. News release. Day One Biopharmaceuticals, Inc; November 24, 2025. 

2. Day One Biopharmaceuticals, Inc. A study to evaluate tovorafenib in pediatric and young adult participants with relapsed or progressive low-grade glioma and advanced solid tumors (FIREFLY-1). ClinicalTrials.gov identifier: NCT04775485. Updated April 10, 2025. Accessed December 19, 2025. https://clinicaltrials.gov/study/NCT04775485 

3. Kline C, Hargrave D, Khong-Quang DA, et al. Clinical stability following tovorafenib treatment in relapsed/refractory pediatric low-grade glioma: updated results from the phase 2 FIREFLY-1 trial. Neuro Oncol. 2025;27(suppl 5):v149.