Tovorafenib Demonstrates Early, Positive Results in Patients with pLGG

Positive data comes from the initial data of the FIREFLY-1 clinical trial (NCT04775485). This data revealed a favorable overall response rate (ORR) and clinical benefit rate (CBR) using tovorafenib (DAY101) in the first 22 evaluable patients with relapsed or progressive pediatric low-grade glioma (pLGG).1

pLGG is the most common type of brain tumor found in children with cancer, and there are currently no approved treatments or standard of care to combat it.

In these first group of Response Assessment for Neuro-Oncology (RANO) evaluable patients, the ORR was 64%, and the CBR was 91%. Tovorafenib is a brain-penetrant and a highly selective type II pan-RAF kinase inhibitor, targeting a key enzyme in the MAPK signaling pathway.

FIREFLY-1 is an ongoing, single-arm, phase 2 trial which enrolled 25 patients between aged 6 months to 25 years with relapsed or progressive pLGG. The study drug, tovorafenib, is given orally to patients as a monotherapy once a week. The primary end point of the study is ORR according to RANO criteria and assessed by blinded independent central review (BICR).

Data from this patient population revealed 14 partial responses, 13 being confirmed responses and 1 being an unconfirmed response. The study saw 6 patients with stable disease, and all of these patients experienced tumor shrinkage between the range of 19% and 43%. Investigators also saw responses in patients with BRAF fusions and BRAF V600E mutations who received previous MAPK-targeted therapy. The 14 patients who responded remain on therapy. The median time to response was 2.8 months.

This patient group was heavily pretreated with a median of 3 prior lines of therapy (range, 1-9).

“These initial findings underscore the potential of tovorafenib monotherapy to become a significant and transformative new option for relapsed/progressive pLGG, a pediatric brain tumor with no approved treatments today,” Samuel Blackman, MD, PhD, co-founder and chief medical officer of Day One, said. “With the registrational cohort fully enrolled, patient follow-up is ongoing, and we look forward to the topline data from the complete study population in the first quarter of 2023. Based on these positive initial data, we plan to begin the pivotal Phase 3 FIREFLY-2 clinical trial evaluating tovorafenib as a front-line therapy in pLGG to evaluate whether tovorafenib can provide benefit early in the disease development.”

Tovorafenib was found to be well-tolerated. Most adverse events (AEs) were grade 1 or 2 with the most common treatment-related AEs (TRAEs) being increase in blood creatine phosphokinase, rash, and hair color change. Grade 3 or higher TRAEs were reported in 9 patients (36%); however, no patients discontinued treatment because of TRAEs.

“These initial data demonstrate significant anti-tumor activity in children with relapsed/progressive pLGG, including children who are refractory to available therapies. Pediatric low-grade glioma is a truly challenging disease in which children face years of aggressive regimens that can carry a long-term impact on learning, cognition, and quality of life,” Roger Packer, MD, senior vice president, Center for Neuroscience and Behavioral Medicine, and director, Brain Tumor Institute, Children’s National Hospital said.

A phase 3, registrational clinical trial (FIREFLY-2/LOGGIC) of tovorafenib in the front line for patients with pLGG is expected to begin in the third quarter of 2022. The developer, Day One, aims to present additional interim results in the second half of 2022. Day One also plans to release results for the full FIREFLY-1 study population in the first quarter of 2023. If these finding are positive and supportive, the company will submit a new drug application to the FDA in the first half of next year.

This planned phase 3 trial will evaluate the efficacy and safety of tovorafenib in patients harboring a known activating BRAF alteration. The study hopes to enroll approximately 400 patients between the ages of 6 months to 25 years across 100 different sites in the US, Europe, and Asia. The study drug will be compared with an investigator’s choice of standard of care chemotherapy options. The primary endpoint of FIREFLY-2 will be ORR based on RANO criteria and by BICR. Secondary end points will include safety, progression-free survival, duration of response, and quality of life.

_REFERENCE:

_{Day one announces positive initial data from pivotal FIREFLY-1 trial of tovorafenib (DAY101) in relapsed pediatric low-grade glioma. Press release. Day One Biopharmaceuticals; June 12, 2022. Accessed June 15, 2022.https://bit.ly/3xRkiTn}