Tovorafenib Maintains Durable Clinical Benefit in Relapsed/Refractory Pediatric Low-Grade Glioma: Part 1

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Cassie Kline, MD, MAS, reviews the phase 2 FIREFLY-1 study and provides a 3-year update on time-to-next treatment and treatment-free interval with tovorafenib for pediatric low-grade glioma.

Dr Kline is a pediatric neuro-oncologist at the Children's Hospital of Philadelphia and is the director of clinical research for the pediatric neuro-oncology group. 

Hi, I'm Dr Cassie Kline. I'm one of the pediatric neuro-oncologists at the Children's Hospital of Philadelphia and the Director of Clinical Research for the pediatric neuro-oncology group there. Today, I'm going to be talking about the updated 3-year analysis from the phase 2 study, FIREFLY-1, which explored tovorafenib in the treatment of recurrent/refractory pediatric low-grade glioma.  

As a bit of background, tovorafenib is a selective, CNS-penetrant type II pan-RAF inhibitor administered orally once weekly with or without food. It was FDA approved in 2024 for pediatric refractory/recurrent BRAF-altered low-grade glioma.  

And again, this is really going to focus on the 3-year update from the FIREFLY-1 study wherein we were able to update the median study duration to 40.6 months for arm 1, which is the pediatric low-grade glioma registrational cohort of 77 patients.  

Some of the things that we updated with this data included time to next treatment. Out of the 76 evaluable patients, we looked at the time from their first dose of tovorafenib to the time of their next anticancer therapy, which could have been in this case retreatment with tovorafenib. We also had 39 patients that entered in a drug-free observation period. And what we looked at with that cohort was their treatment-free interval, so the time from last dose of tovorafenib to anticancer therapy. And those patients would have already completed 26 cycles of tovorafenib before entering the drug-free observation period. And of course, we'll also be looking at outcomes in the context of progression-free survival as defined by RAPNO low-grade glioma criteria during a central review.  

What is important, but we won't spend much time on in this update is that there were no additional safety signals that we noted with further follow-up, and everything seemed very much in line with previous publications and previous outcomes in terms of earlier data cutoff. 

When we look though at our RAPNO central review outcomes, we did identify an objective response rate in the tumors of about 53% with a median change in tumor size of about 47% tumor shrinkage, a median duration of response of 19.4 months, and a median time to response of 5.4 months. Additionally, we found that on central review, we did have 38 patients that experienced RAPNO-defined progressive disease while on therapy. And of those, 100% of the patients went on to continue to tovorafenib therapy after the RAPNO-defined progressive disease, and that was in line with central or local site, I should say, determination of ongoing benefit and radiographic review.  

What's interesting to know is that of those 38 patients, 45% went on to have ongoing tumor shrinkage after the RAPNO-defined progressive disease indicating ongoing medication benefit. Now, what we have traditionally looked at for most of our trial outcomes are things like overall or progression-free survival. So how long is the patient alive after therapy or on therapy, and how long perhaps are they alive without having the tumor progress?  

And certainly, we did look at both progression-free survival as defined by RAPNO criteria in this cohort. And RAPNO criteria identifies both radiographic progression-free survival, but then also incorporates functional outcomes like visual injury or vision decline as part of that progression definition. And so, we looked at both RAPNO-defined progression-free survival, and we also looked at radiographic progression-free survival. And when we look at those metrics, we identified that the median progression-free survival was 16.6 months.  

What's interesting though is that when we looked at progression-free survival based on clinical symptoms only, and then we also looked at time to next treatment—so again, time from first dose of tovorafenib therapy to the time to next anticancer therapy—we found that we were actually able to extend this period quite drastically. The median time to next treatment was actually 42.6 months, and that curve much more closely aligned with the clinically defined progression-free survival.  

And so perhaps what we were able to isolate here is that when we utilize radiographic definitions or RAPNO definitions, which compare to the smallest tumor size while on study, you're perhaps missing some of the more clinically relevant outcomes. And certainly, when you're thinking about time to next treatment and it's close following of clinical progression-free survival, you're perhaps missing a more closely aligned definition of progression that follows clinician-defined intervention criteria. Which I think is an important outcome when we're moving beyond just radiographic definitions of progression and onto outcomes that are relevant to patients, which are treatment-free intervals perhaps or time to next treatment. So, giving patients a long period of disease control without needing that next anticancer therapy.  

Source:  

Kline C, Hargrave D, Khong-Quang D-A, et al. Clinical stability following tovorafenib treatment in relapsed/refractory pediatric low-grade glioma: Updated results from the phase 2 FIREFLY-1 trial. Presented at: 2025 Society of Neuro-Oncology Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTP-17.