Tovorafenib Shows Manageable Low-Grade Rashes in BRAF-Altered R/R pLGG

The first-in-class type II pan-RAF inhibitor, tovorafenib (Ojemda) improves accessibility to targeted therapies for patients with BRAF-altered, relapsed or refractory pediatric low-grade glioma (pLGG) while maintaining low-grade and manageable dermatologic adverse effects (AEs), according to Andrea Franson, MD, MS. In addition to showing low-grade and manageable rashes in patients, tovorafenib, which was approved by the FDA in April 2024, can be given as a pill or liquid formulation, a helpful bonus when dealing with pediatric patients.¹

In a post-hoc analysis of the phase 2 FIREFLY-1 trial (NCT04775485), which was presented at the 2025 ASCO Annual Meeting, patients were treated with one or more weekly 420 mg/m² doses of tovorafenib (n = 137).^2,3 Maculopapular, erythematous or eczematous (M/E/E) rashes were mostly low grade in patients who experienced 1, 2, 3, or 4 or more episodes, at rates of 51% (n = 58), 32% (n = 36), 12% (n = 14), and 5% (n = 6), respectively. Acneiform or pustular (A/P) rashes were also largely low grade in patients who experienced them, with 88% (n = 45) experiencing 1 episode and 12% (n = 6) experiencing 2. The median time to onset of a patient’s first rash episode was 0.6 months (range, 0.03-22.0) for M/E/E rashes and 1 month (range, 0.1-29.5) for A/P rashes. Moreover, first rash episodes typically happened within the first cycle of treatment, and all treatment-emergent rashes resolved within 3 months.

Updated 3-year results from FIREFLY-1, which were presented at the 2025 Society for Neuro-Oncology Annual Meeting, showed that patients who had received tovorafenib in the registrational arm (n = 77) achieved a prolonged median time to next treatment of 42.6 months (95% CI, 36.7-not evaluable).⁴ Additionally, 77% of patients who entered post-treatment observation (n = 39) had a treatment-free interval of at least 12 months.

“There is a shift in the pLGG paradigm with tovorafenib having received FDA approval in this specific patient population. [Tovorafenib] is becoming an option at the time of recurrence and a second-line therapy for patients who have had tumor growth or recrudescence after initial upfront therapies,” Franson, a clinical associate professor of pediatrics and fellowship director of Pediatric Hematology/Oncology at the University of Michigan Medical School in Ann Arbor, said in an interview with OncLive®.

In the interview, Franson broke down the data from FIREFLY-1 and elaborated on how they position tovorafenib in the current and future pLGG treatment paradigm.

OncLive: What is the mechanism of action of tovorafenib, and what general class-related toxicities is this agent associated with?

Franson: Tovorafenib is first in class at least on the clinical side for a pan-RAF inhibitor, inhibiting part of the Ras-Raf-MEK-ERK pathway, which also has a different mechanism of action than previous type I RAF inhibitors. [Tovorafenib] is a type II [RAF inhibitor].

Studies have shown, [which has been corroborated by] our clinical experience, that there are certain organ classes that seem [to be affected more], and [tovorafenib] may be similar to other drugs that hit other aspects of the [Ras-Raf-MEK-ERK pathway]. Skin AEs often come to the top of the list of toxicities that may occur in this patient population as well as some laboratory changes, some of which are asymptomatic. Hematologic AEs are also looked at, [because] there can be a dip in hemoglobin with some anemia that occurs with continuous, long-term use of [tovorafenib]. Aside from [these AEs] there are some rarer AEs and some levels of fatigue that are reported as well in these patients.

What types of rashes were most common with tovorafenib based on the post-hoc analysis from FIREFLY-1?

When preparing patients to potentially take tovorafenib, it is hard to predict what [type of rash] may occur. Some of the common [rash-related AEs] that are seen are dry skin–type rashes, sometimes [accompanied by] intense itching. [These rash-related AEs] often occur when patients are starting the medication and often get better over time with continued doses and/or supportive care. In patients who are older, post-pubescent, or young adults, acne distribution rashes are a possibility. However, there are different levels of supportive care that can help patients through [these AEs]. [Dry skin and acne distribution] are the most common rashes, but there is a wider range of dermatologic events that can happen with these types of medicines in my experience.

What did this analysis show about the incidence and severity of these rashes?

In a post-hoc analysis of incidence of rash data and dermatologic toxicities from FIREFLY-1, rashes were common but [the data] varies in how it presents. [We also saw that rashes] were relatively low grade, often resolving over a period that we can provide supportive care for.Timing of first rash episode was also looked at, and most of them resolved relatively quickly from the start of the first episode to resolution. Although, there were some patients that had rashes that persisted longer while remaining low grade. Many patients can get through rashes with supportive care without dose reduction, although dose reduction is a possibility for patients with higher [grade events] while still maintaining efficacy. From what [data are available] nice tumor responses are still seen with dose reductions for skin-related toxicities. Additionally, skin-related toxicities have been the most common AEs that we have had to dose reduce for.

Where does tovorafenib fit into the current pLGG treatment paradigm? Could tovorafenib’s role change in the future?

There is still ongoing work trying to understand where tovorafenib and other targeted therapies fall within [the pLGG] treatment paradigm, but the [current role] for [tovorafenib] would be at the time of recurrence for pediatric RAF-altered low-grade glioma [based on the] FDA approval.

Data from the phase 3 FIREFLY-2 trial [NCT05566795] will be important in understanding whether tovorafenib can have an earlier role in the pLGG paradigm.⁵ FIREFLY-2 will be an upfront randomization between standard, physician’s choice chemotherapy and tovorafenib. I am hopeful that tovorafenib will have a role in the upfront setting in part due to the burden of using traditional chemotherapy. Until then there will be a lot of speculation and active work to be able to answer these questions in a large population of patients.

How does tovorafenib seem to compare with similar agents in the space?

Tovorafenib is given once a week which is a large benefit compared with many other targeted therapies in terms of compliance and patients being able to stick to that kind of schedule. Even though there are skin-related AEs that have come out of these studies, the intensity of tovorafenib is not always as strong as targeted therapies like MEK inhibitors.

Other than [skin-related AEs, differences] come down to formulation. From the beginning tovorafenib has had both a pill and a powder to liquid formulation which is good for small children. In the past a lot of these therapies have been in forms that [are prohibitive for] small patients. Thankfully, [accessibility for smaller patients] is increasing for other targeted therapies, and being able to use tovorafenib in smaller patients is a positive.

What other data are important to keep in mind with respect to tovorafenib?

The 3-year data update from FIREFLY-1 presented at the SNO 2025 meeting was focused on both time to next treatment and treatment-free interval.⁴ These are important measures that have not always been included as end points in studies. Time to next treatment was around 40 months. These data mean that there is some amount of time where patients were on tovorafenib and did not immediately need another line of therapy. This is encouraging since there are patients who go through lines of therapy quickly with tumors that do not seem to respond.

Additionally, this comparison vs radiographic changes were looked at, particularly time of progression per RAPNO and RANO criteria. [Time of progression] may look shorter [with tovorafenib] but times when clinicians intervened and needed to give the next line of therapy did not happen as soon. In pLGG imaging is important to have but is not always a cause for action since these tumors can wax and wane. [This means] patients [don’t necessarily have] to commit to other lines of therapy, and these data showcase this nicely.

References

1. FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. FDA. Updated May 22, 2024. Accessed January 2, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tovorafenib-patients-relapsed-or-refractory-braf-altered-pediatric
2. Witt O, Chi SN, Kang HJ, et al. Post hoc analysis of rashes reported in patients (pts) with BRAF-altered relapsed/refractory (r/r) pediatric low-grade glioma (pLGG) treated with the type II RAF inhibitor tovorafenib in FIREFLY-1. J Clin Oncol. 2025;43(suppl 16):10037. doi:10.1200/JCO.2025.43.16_suppl.10037
3. A study to evaluate tovorafenib in pediatric and young adult participants with relapsed or progressive low-grade glioma and advance solid tumors (FIREFLY-1). ClinicalTrials.gov. Updated April 10, 2025. Accessed January 2, 2026. https://www.clinicaltrials.gov/study/NCT04775485
4. 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. Presented at 2025 Society for Neuro-Oncology Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTP-17.
5. DAY101 vs. standard of care chemotherapy in pediatric participants with low-grade glioma requiring first-line systemic therapy (LOGGIC/​FIREFLY-2). ClinicalTrials.gov. Updated November 6, 2025. Accessed January 2, 2026. https://clinicaltrials.gov/study/NCT05566795