Treatment of Recurrent Refractory Pediatric Low-Grade Glioma (pLGG)

Guest host Cassie Kline, MD, MAS, presents a three-year update from the phase 2 FIREFLY-1 trial evaluating tovorafenib, a weekly oral type II RAF inhibitor, in recurrent or refractory pediatric low-grade glioma. She emphasizes the importance of incorporating clinically meaningful endpoints into future trials, as they may better reflect real-world patient benefit than radiographic criteria alone. 

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. 

Moderator: Hello, and welcome to the Oncology Learning Network. I’m your host Jenny Lamberts with today’s podcast episode about emerging clinical endpoints in pediatric low-grade glioma. 

In this segment, I'm joined by Dr Cassie Kline, a pediatric neuro-oncologist at the Children’s Hospital of Philadelphia and Director of Clinical Research for the Pediatric Neuro-Oncology Group. Dr Kline discusses updated three-year data from the phase 2 FIREFLY-1 study evaluating tovorafenib in children with recurrent or refractory pediatric low-grade glioma, with a focus on how emerging, clinically meaningful endpoints can add important context when interpreting treatment durability. 

To start, Dr Kline will walk us through the updated three-year analysis from the FIREFLY-1 study and highlight the key findings that stood out with longer follow-up. 

Dr Kline: So, to start, 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. 

Moderator: With that overview in mind, we’ll next turn to how these data challenge some of our traditional assumptions about response and progression. Dr Kline, why doesn’t radiographic progression—particularly RAPNO-defined progression—always tell the full clinical story, and what can be learned from patients who continued therapy beyond protocol-defined progression? 

Dr Kline: 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, again utilizing RAPNO low-grade glioma criteria, 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. 

Moderator: Building on that concept, why might alternative endpoints such as time to next treatment and treatment-free interval provide a more clinically relevant perspective on durability than radiographic response alone, especially when evaluating long-term outcomes in pediatric low-grade glioma? 

Dr Kline: 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.   

Moderator: What happens after treatment discontinuation, including tumor rebound, baseline comparisons, and early evidence supporting retreatment activity? 

Dr Kline: Additionally, when we look at low-grade glioma outcomes, and certainly when we look at what happens when patients stop targeted treatment, we also want to look at rebound tumor growth, so how quickly does the tumor grow once you take the brakes off with the targeted therapy or stopping? And what we found was that there was minimal tumor rebound in patients when we followed them for 6 months off therapy. Again, we're looking at that N of 38 that entered the drug-free observation period.   

So specifically, we saw about a third or 12 patients out of the 39 that had an increase in tumor signs of at least 25% in the first 6 months. Of those 4 were BRAF V600E patients. But what's important to note is that even in the setting of the rebound growth, the majority of patients actually still had tumor size and tumor change that was below the baseline of their tumor size when they came into the study.   

And then we had 8 patients that did go on to have retreatment with tovorafenib, and of those, we were able to see some early signs of repeat efficacy. When we look at the maximal tumor change, after restarting tovorafenib, we saw a tumor shrinkage median value of about 38% and patients that were being treated for a median duration of about 9 months or 10.5 cycles of tovorafenib therapy.   

And then when we look at treatment-free interval, once patients have entered the drug-free observation period, the majority or 77% were able to achieve at least a 12-month treatment-free interval, and the end point of the treatment-free interval was actually not reached when we looked at this analysis.   

In conclusion, the updated 3-year analysis for FIREFLY-1, which looked at tovorafenib as a type II RAF inhibitor given once weekly in children, adolescents, and young adults with recurrent/refractory pediatric low-grade glioma showed us that 77% of patients who went into an observation period had a treatment-free interval of at least 12 months or more. They had a prolonged median time to next treatment of 42.6 months with minimal tumor rebound after drugs stop, early evidence of tovorafenib retreatment activity and no new safety signals. All of which is hopefully coming together to support tovorafenib as an effective therapy for recurrent refractory pediatric low-grade glioma. 

Moderator: Thank you, Dr Kline, for joining me, and thank you to our audience for listening to this Oncology Learning Network educational segment. This discussion highlights how the interpretation of progression and durability endpoints can meaningfully shape clinical assessment in pediatric low-grade glioma.