Tovorafenib Presents Opportunity for Tumor Reduction in Pediatric Low-Grade Glioma

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Treatment with tovorafenib elicited encouraging and fast onset responses in heavily pretreated pediatric patients with low-grade glioma regardless of response assessment criteria, according to data from the phase 2 FIREFLY-1 trial that were presented at the 2023 ASCO Annual Meeting.

 Lindsay Kilburn, MD

Lindsay Kilburn, MD

Treatment with tovorafenib (DAY101) elicited encouraging and fast onset responses in heavily pretreated pediatric patients with low-grade glioma regardless of response assessment criteria, according to data from the phase 2 FIREFLY-1 trial (NCT04775485) that were presented at the 2023 ASCO Annual Meeting. The agent was also well tolerated, with a discontinuation rate of only 4%.

In the registrational arm (n = 69), the objective response rate (ORR) was 67% per RANO-HGG criteria. The clinical benefit rate (CBR), defined by confirmed complete response (CR), confirmed or unconfirmed partial response (PR), or stable disease (SD), was 93%. Among patients who experienced SD for at least 12 months, the CBR was 68%. Best overall responses included CR (6%), PR (61%), SD (26%), and progressive disease (PD; 6%); 1 patient was not evaluable. The median independent radiology review committee (IRC)–assessed duration of response (DOR) was not yet reached (95% CI, 9.0-not estimable).

When assessed by RANO-LGG criteria (n = 76), the ORR was 49%, and the CBR was 83%. CBR in the population of patients who experienced SD for at least 12 months was 47%. Best overall responses included PR (26%), minor response (MR; 22%), SD (34%), PD (14%), or were not evaluable (3%).

Response was also evaluated with RAPNO-LGG criteria, and in this population (n = 69), the ORR was 51%, with CBRs or 87% and 46% in patients who experienced SD at any time and those who experienced SD for at least 12 months, respectively. Best overall responses included PRs (25%), MRs (26%), SD (36%), and PD (12%); 1 patient was not evaluable.

“Clinically meaningful and rapid tumor responses to monotherapy tovorafenib [were] seen on both T1-Gd+ and T2/FLAIR sequences in this heavily pretreated population,” lead study author and Lindsay Kilburn, MD, a neuro-oncologist at Children’s National in Washington, DC, said in a presentation of the data.

Pediatric low-grade gliomas comprise approximately 30% of central nervous system tumors, representing the most common brain tumor in children with substantial disease- and treatment-associated morbidity.

The majority (70%) of pediatric low-grade gliomas are driven by BRAF alterations, which allow for activation of the protein as a monomer or dimer.

Tovorafenib is an investigational, oral, selective, central nervous system–penetrant, type II RAF inhibitor with activity against monomeric and dimeric forms of RAS signaling. Unlike type I BRAF inhibitors, tovorafenib does not lead to paradoxical activation of the MAPK pathway. Additionally, the agent can be administered in tablet form and as an oral suspension with once-weekly dosing.

The phase 2 FIREFLY-1 trial enrolled patients aged 6 months to 25 years with a RAF-altered tumor who had radiographic progression on at least 1 line of systemic therapy. Prior MAPK pathway targeted therapy was allowed.

The trial was divided into 3 arms. Arm 1 comprised the registrational low-grade glioma arm (n = 77), which enrolled children and young adults with recurrent or progressive low-grade glioma harboring a known activating BRAF alteration, including BRAF fusions and BRAF V600 mutations. Patients in this arm received between 420 mg/m2 and 600 mg/m2 of tovorafenib every week in 28-day cycles.

Arm 2 comprised the low-grade glioma extension cohort (n = 59). In this arm, patients had to have a RAF alteration, including a BRAF or CRAF/RAF1 fusion or BRAF V600E mutation. Finally, arm 3 enrolled patients with a locally advanced or metastatic solid tumor harboring a known activating RAF fusion that had relapsed or progressed or was nonresponsive to available treatment.

Efficacy was evaluated in arm 1 and safety analyses were based on pooled data from arms 1 and 2, which have fully accrued and closed for enrollment. Arm 3 continues to accrue patients.

Patients in arms 1 and 2 received treatment for a planned period of 26 cycles (approximately 1 year), after which they could choose to continue or stop study therapy.

The primary end point was ORR rate by RANO-HGG criteria per IRC. Secondary end points included safety, ORR by RAPNO-LGG criteria per IRC, DOR, progression-free survival, time to response, and CBR.

Baseline characteristics showed that the median patient age was 8 years (range, 2-21) and most patients were male (52%) and White (53%). The median number of prior lines of therapy was 2 (range, 1-9), although most patients had received at least 3 prior lines of therapy (49%). Prior MAPK pathway inhibition was reported in 60% of patients.

Among 77 patients with a BRAF alteration, 83% had BRAF fusions and 17% had BRAF V600E mutations. Represented tumor locations were the optic pathway (51%), cerebral hemisphere (8%), brain stem (8%), deep midline structures (12%), cerebellum (6%), and other (16%).

In the registrational arm, the median duration of tovorafenib treatment was 10.8 months, and most patients (74%) remained on treatment at data cutoff. Median IRC-assessed DOR per RANO-HGG criteria was not reached (95% CI, 9.0 months-not estimable).

“Tumor response [occurred] independent of histologic subtype, BRAF alteration type, number of prior lines of therapy, or prior MAPK inhibitor use,” Kilburn said.

Kilburn also presented a case study of a patient with KIAA1549-BRAF fusion optic pathway glioma, illustrating the efficacy of the agent. The patient was an 8-year-old boy with relapsed pilomyxoid astrocytoma of the optic pathway, suffering from visual loss in the right eye, visual field loss in the left eye, fatigue, intermittent nausea/vomiting, intermittent headaches, anorexia, and temperature regulation disorder.

The patient received tovorafenib at 400 mg/week after 3 prior lines of therapy. At cycle 3, the patient experienced a PR, with an 88% reduction in tumor size per RANO-HGG criteria and MR of -32% and -40% by RAPNO-LGG and RANO-LGG criteria, respectively.

“Sustained criteria [were] met in visual acuity,” Kilburn said. “[Although] PD criteria [were] met with RANO-HGG at cycle 15, [the patient] continued treatment as [the] investigator deemed [there was] no radiographic progression with subsequent reduction in target lesion.”

In terms of safety, the patient experienced grade 2 drug eruption and CPK elevation and grade 1 hair color change, paronychia, and growth retardation.

Overall safety was evaluated in 136 patients. Treatment-related adverse effects (TRAEs) occurring in at least 25% of patients included hair color changes (any grade, 71%; grade ≥3, 0%), fatigue (40%; 3%), vomiting (18%; 2%), maculopapular rash (38%; 7%), headache (20%; 0%), pyrexia (11%; 1%), nausea (15%; 0%), dry skin (25%; 0%), dermatitis acneiform (26%; 1%), constipation (21%; 0%), decreased appetite (18%; 2%), and epistaxis (16%; 0%).

The most frequent laboratory abnormalities were CPK elevation, anemia, hypophosphatemia, and AST elevation. Kilburn noted that almost all events were clinically unidentifiable and did not require intervention or change in treatment.

Five patients discontinued treatment because of an AE (treatment-related, n = 4), owing to autoimmune hemolytic anemia, hemolysis, ventricular extrasystoles, growth retardation, shunt malfunction, and tumor hemorrhage.

Twenty-nine percent of patients required dose reductions or interruptions because of TRAEs.

The agent will be studied further as frontline therapy in patients with low-grade glioma in the phase 3 LOGGIC-FIFEFLY-2 trial. As of March 2023, the first patient had received treatment with tovorafenib.

Disclosures: Dr Kilburn disclosed employment with Kaiser Permanente, stock ownership in Onconova Therapeutics, consulting or advisory role with Blueprint Medicines, and research funding from Blaze Bioscience (Inst), Bristol Myers Squibb/Celgene (Inst), Day One Biopharmaceuticals (Inst), Epizyme (Inst), Helsinn Therapeutics (Inst), Novartis (Inst), Regeneron (Inst), and SpringWorks Therapeutics (Inst).


Kilburn L, Khuong-Quang DA, Nysom K, et al. Clinical activity of pan-RAF inhibitor tovorafenib in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY (PNOC026) study. J Clin Oncol. 2023;41(suppl 16):10004. doi:10.1200/JCO.2023.41.16_suppl.10004

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