Ojemda (tovorafenib) / Takeda, Day One Biopharma, Xoma, Ipsen - LARVOL DELTA

Emerging Targeted Therapies and Ongoing Clinical Trials in Pediatric Brain Tumors (PubMed, No Shinkei Geka) - "Dabrafenib plus trametinib has shown superiority over chemotherapy in pediatric low-grade gliomas and activity against high-grade diseases. Larotrectinib and entrectinib provide tumor-agnostic options for NTRK-fusion-positive tumors with central nervous system penetration. Selumetinib offers clinical benefits in NF1-associated plexiform neurofibromas and shows promise for treating NF1-related low-grade gliomas. Tovorafenib, a type II RAF inhibitor active in BRAF-altered tumors (including BRAFKIAA1549 fusion), achieved robust responses, thereby leading to FDA approval. ONC201 (dordaviprone) has received accelerated approval for the treatment of H3 K27M-mutant diffuse midline gliomas, with Japanese trials and patient-initiated programs expanding access. Abemaciclib, a CDK4/6 inhibitor, is under phase II evaluation for pediatric high-grade glioma and diffuse midline glioma, including sites in Japan. Neurosurgeons play a pivotal role in securing high-quality biopsies, thus..."

Journal • Review • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • High Grade Glioma • Neurofibromatosis • Oncology • Pediatrics • Solid Tumor • BRAF • KIAA1549 • NF1 • NTRK

Molecularly-guided phase 2 umbrella trial for children and young adults with newly-diagnosed high-grade glioma (HGG) including diffuse intrinsic pontine glioma (DIPG): CONNECT TarGeT (Targeted pediatric HGG therapy) trial in progress (WFNOS 2025) - P, P2 | "The following TarGeT treatment arms (most involving upfront radiotherapy), are open or soon to open, selected based on prevalence of targets in HGG/DIPG, relevant pre-clinical and clinical data, established pediatric safety data, and prioritizing combinations: (A) ribociclib and everolimus (target: cell cycle or PI3K//mTOR pathway alterations) [NCT05843253], (A-2) ribociclib and temozolomide (H3G34 mutation) (B) tovorafenib (MAPK pathway alterations), (D) olutasidenib and temozolomide (IDH1 mutation) [NCT06161974], (F) nivolumab and relatlimab (high tumor mutational burden, mismatch repair deficiency), (L) lorlatinib (+/- chemotherapy or radiation) (ROS1, ALK fusion). Development of additional treatment arms is underway, with possibility of incorporating new arms as supporting data allows."

Clinical • P2 data • Tumor mutational burden • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Pediatrics • Solid Tumor • ALK • IDH1 • ROS1 • TMB

Molecularly-guided phase 2 umbrella trial for children and young adults with newly-diagnosed high-grade glioma (HGG) including diffuse intrinsic pontine glioma (DIPG): CONNECT TarGeT (Targeted pediatric HGG therapy) trial in progress (SNO 2025) - P, P2 | "The following TarGeT treatment arms (most involving upfront radiotherapy), are open or soon to open, selected based on prevalence of targets in HGG/DIPG, relevant pre-clinical and clinical data, established pediatric safety data, and prioritizing combinations: (A) ribociclib and everolimus (target: cell cycle or PI3K//mTOR pathway alterations) [NCT05843253], (A-2) ribociclib and temozolomide (H3G34 mutation) (B) tovorafenib (MAPK pathway alterations), (D) olutasidenib and temozolomide (IDH1 mutation) [NCT06161974], (F) nivolumab and relatlimab (high tumor mutational burden, mismatch repair deficiency), (L) lorlatinib (+/- chemotherapy or radiation) (ROS1, ALK fusion). Development of additional treatment arms is underway, with possibility of incorporating new arms as supporting data allows."

Clinical • P2 data • Tumor mutational burden • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • ALK • IDH1 • ROS1 • TMB

What Are the Likely PICOs for Tovorafenib and Lifileucel as the First Products to Go Through the JCA? (ISPOR-EU 2025) - "Based on the clinical trials of tovorafenib and lifileucel, predicting the PICOs in tovorafenib will be easier for the manufacturer than for lifileucel, primarily due to the lack of treatment options in LGG. The PICOs used in the tovorafenib trial are therefore closer to our predictions, however this study did not look at all member states, which is a limitation."

Brain Cancer • Glioma • Hematological Disorders • Melanoma • Pediatrics • Solid Tumor

Eco-conscious AQbD-guided stability-indicating RP-UPLC method for analysing Tovorafenib in bulk and dosage forms. (PubMed, Sci Rep) - "Assessment with green chemistry tools yielded favourable eco-scores (ComplexMoGAPI 90, AGREE 0.61, BAGI 70, RAPI 92.5, EVG Q2, and RGBfast 97.5%). This validated RP-UPLC procedure offers reliable, sensitive, and sustainable Tovorafenib analysis, supporting both efficient pharmaceutical quality control and environmental sustainability."

Journal • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor • BRAF

High-Grade Astrocytoma with Piloid Features: An institutional experience (SNO 2025) - "Systemic therapies were administered in 5/8 (lomustine, bevacizumab, pembrolizumab, temozolomide, trametinib, tovorafenib). While the optimal management of this newly recognized entity has yet to be established, our cohort demonstrates a clinical behavior consistent with CNS WHO grade 3, aligning with current WHO interpretations."

Clinical • Astrocytoma • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ATRX • BRAF • CDKN2A • CDKN2B • FGFR1 • KIAA1549 • NF1 • NTRK2

High-Grade Astrocytoma with Piloid Features: An institutional experience (WFNOS 2025) - "Systemic therapies were administered in 5/8 (lomustine, bevacizumab, pembrolizumab, temozolomide, trametinib, tovorafenib). While the optimal management of this newly recognized entity has yet to be established, our cohort demonstrates a clinical behavior consistent with CNS WHO grade 3, aligning with current WHO interpretations."

Clinical • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • ATRX • BRAF • CDKN2A • CDKN2B • FGFR1 • KIAA1549 • NF1 • NTRK2

Clinical stability following tovorafenib treatment in relapsed/refractory pediatric low-grade glioma: updated results from the phase 2 FIREFLY-1 trial (SNO 2025) - P2 | "Tovorafenib induces durable responses with evidence of clinical stability off treatment in patients with recurrent BRAF-altered pLGG. Progression can occur after cessation, but retreatment is feasible."

Clinical • P2 data • Brain Cancer • Glioma • Pediatrics • Solid Tumor • BRAF

Use of tovorafenib for BRAF mutant or altered CNS tumors in adults: a single institution case series (SNO 2025) - "Tovorafenib is a promising new treatment for CNS tumors with BRAF mutations or alterations. Our single institution case series suggests the efficacy of this drug for multiple tumor types in adults. Certain tumor subtypes such as KIAA1549 fusions may be more likely to benefit from this treatment."

Clinical • Astrocytoma • Brain Cancer • CNS Tumor • Fibrosarcoma • Glioblastoma • Glioma • Hematological Disorders • Musculoskeletal Pain • Oncology • Pilocytic Astrocytoma • Pleomorphic Xanthoastrocytoma • Rare Diseases • Sarcoma • Solid Tumor • BRAF • KIAA1549

Feasibility of CSF and plasma ctDNA in BRAF-altered glioma during treatment with plixorafenib: trial in progress (SNO 2025) - "Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy (excluding tovorafenib) are eligible to be screened and consented for the study prior to surgery...Patients will initiate the study drug (oral plixorafenib 900mg daily with cobicistat 150mg daily) when clinically recovered from surgery...MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. The study is open and one participant has been successfully enrolled."

Circulating tumor DNA • Brain Cancer • Glioma • Solid Tumor • BRAF

Day One Announces Three Year Follow-Up Data From OJEMDA (tovorafenib) Phase 2 FIREFLY-1 Trial at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting (GlobeNewswire) - "In 76 evaluable patients from Arm 1, 44 (58%) completed 26 or more cycles of treatment (approximately 24 months). Amongst the key primary endpoints, the overall response rate was 53% (40/76), the median duration of response was 19.4 months (95% CI [13.8-27.2]), and the time to response was 5.4 months (range [1.6-17.5])....39 patients entered a treatment-free observation period: 77% (30/39) were treatment-free for a minimum of 12 months....The median time to next treatment (TTNT) following initiation of OJEMDA exceeded 3.5 years."

P2 data • Low Grade Glioma

Clinical stability following tovorafenib treatment in relapsed/refractory pediatric low-grade glioma: updated results from the phase 2 FIREFLY-1 trial (WFNOS 2025) - P2 | "Tovorafenib induces durable responses with evidence of clinical stability off treatment in patients with recurrent BRAF-altered pLGG. Progression can occur after cessation, but retreatment is feasible."

Clinical • P2 data • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor • BRAF

Feasibility of CSF and plasma ctDNA in BRAF-altered glioma during treatment with plixorafenib: trial in progress (WFNOS 2025) - "Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy (excluding tovorafenib) are eligible to be screened and consented for the study prior to surgery...Patients will initiate the study drug (oral plixorafenib 900mg daily with cobicistat 150mg daily) when clinically recovered from surgery...MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. The study is open and one participant has been successfully enrolled."

Circulating tumor DNA • Brain Cancer • Solid Tumor • BRAF

Use of tovorafenib for BRAF mutant or altered CNS tumors in adults: a single institution case series (WFNOS 2025) - "Tovorafenib is a promising new treatment for CNS tumors with BRAF mutations or alterations. Our single institution case series suggests the efficacy of this drug for multiple tumor types in adults. Certain tumor subtypes such as KIAA1549 fusions may be more likely to benefit from this treatment."

Clinical • Astrocytoma • Brain Cancer • Fibrosarcoma • Glioblastoma • Glioma • Hematological Disorders • Musculoskeletal Pain • Oncology • Pilocytic Astrocytoma • Pleomorphic Xanthoastrocytoma • Rare Diseases • Sarcoma • Solid Tumor • BRAF • KIAA1549

Day One Biopharmaceuticals…announced it will present new OJEMDA durability and clinical stability data from the registrational FIREFLY-1 study at the 30th Annual Meeting & Education Day of the Society for Neuro-Oncology (SNO)… (GlobeNewswire) - "In an oral presentation, Dr. Cassie Klein...will report results with >36-months follow up from the pivotal Phase 2 FIREFLY-1 trial evaluating tovorafenib as once-weekly oral monotherapy in patients aged 6 months to 25 years with relapsed or progressive pediatric Low-Grade Glioma (pLGG) harboring a known activating BRAF alteration. Dr. Klein will also provide an update on the treatment-free interval (TFI) achieved in patients who stopped treatment after completing the full 26 cycles (~24 months) of tovorafenib."

P2 data • Low Grade Glioma

Day One Reports…Corporate Progress (GlobeNewswire) - "Three-year data from the pivotal FIREFLY-1 trial will be presented in an oral presentation titled ‘Clinical stability following tovorafenib treatment in relapsed/refractory pediatric low-grade glioma: updated results from the phase 2 FIREFLY-1 trial’ on Sunday, Nov. 23 at 11:49 a.m. HST during the 2025 Society for Neuro Oncology Annual Meeting."

P2 data • Glioma

OJEMDA Commercial Performance (GlobeNewswire)

Sales • Glioma

New and Emerging Therapies for Patients with Low-Grade Glioma. (PubMed, CNS Drugs) - "This review will highlight the molecular and genetic underpinnings of these tumors and how targeted therapeutic strategies led to the US Food and Drug Administration's approvals of combination therapy with dabrafenib and trametinib for pediatric patients with BRAF V600E mutant low-grade glioma; tovorafenib, a pan-RAF inhibitor, for pediatric BRAF mutant glioma; and vorasidenib, an inhibitor of mutant IDH1/2 enzymes, for patients with mutant IDH low-grade glioma. Integration of these targeted therapies into currently accepted treatment paradigms remains to be fully understood, along with the long-term impact on patient quality of life and prognosis."

Journal • Review • Astrocytoma • Brain Cancer • Glioblastoma • Glioma • Oligodendroglioma • Oncology • Pediatrics • Solid Tumor • BRAF • IDH1 • IDH2

Clinical stability following tovorafenib treatment in relapsed/refractory pediatric low-grade glioma: updated results from the phase 2 FIREFLY-1 trial (WFNOS 2025) - P2 | "Tovorafenib induces durable responses with evidence of clinical stability off treatment in patients with recurrent BRAF-altered pLGG. Progression can occur after cessation, but retreatment is feasible."

Clinical • P2 data • Brain Cancer • Glioma • Pediatrics • Solid Tumor • BRAF

BGB3245-mediated RAF dimer disruption combined with MEK inhibition suppresses ERK reactivation in BRAF-mutant and ERK-dependent glioblastoma models (AACR-NCI-EORTC 2025) - "BGB3245 was evaluated alongside two mechanistically distinct BRAF inhibitors with different selectivity profiles: tovorafenib (DAY101), a type II pan-RAF inhibitor that targets both monomeric and dimeric forms of wild-type and mutant BRAF and CRAF proteins, and plixorafenib (PLX8394), a mutant-specific BRAF paradox breaker affecting monomeric and dimer-inducing mutations...To evaluate the benefits of enhanced vertical inhibition strategies, BGB3245 and other RAF inhibitors were evaluated as monotherapy or in combination with the MEK inhibitor mirdametinib... These findings support dual pan-RAF and MEK inhibition as a rational strategy for GBM subtypes addicted to ERK signaling, particularly in BRAF-mutant gliomas. Pan-RAF inhibitors may overcome some forms of resistance, though brain-penetrant RAF-dimer inhibitors are needed for optimal clinical translation."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BRAF • CDKN2A • CDKN2B • EGFR • NF1 • PTEN

Tovorafenib: Regulatory decision in EU for r/r pediatric low-grade gliomas (based on FIREFLY-1 trial) in 2026 (Ipsen) - Q3 2025 Results

EMA filing • Low Grade Glioma • Oncology

Testing the Combination of Anti-cancer Drugs, Tovorafenib Plus Rituximab, in Patients With Hairy Cell Leukemia (clinicaltrials.gov) - P1/2 | N=84 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Initiation date: Sep 2025 ➔ Jun 2026

Enrollment open • Trial initiation date • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF

CLINICAL EFFICACY/EFFECTIVENESS, SAFETY AND HEALTH-RELATED QUALITY OF LIFE ASSOCIATED WITH TREATMENTS FOR RELAPSED/REFRACTORY PAEDIATRIC LOW-GRADE GLIOMA: A SYSTEMATIC LITERATURE REVIEW (EANO 2025) - "Most clinical trials evaluated MAPK inhibitors (n = 15, including pan-RAF inhibitor tovorafenib [n = 2] and V-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor dabrafenib [n = 2]) or chemotherapy-based regimens (n = 13; 12 regimens). CONCLUSION The variety of therapies identified highlights a lack of standard of care for R/R pLGG and a need for specific, well-tolerated treatment options with proven efficacy/effectiveness that improve HRQoL/functional outcomes. Future studies that report molecular prognostic factors (e.g. BRAF alterations), employ consistent efficacy/effectiveness and safety assessments, and evaluate long-term treatment impact on HRQoL/functional outcomes are needed to guide treatment selection."

Clinical • HEOR • Review • Brain Cancer • Glioma • Oncology • Solid Tumor

Study of Tovorafenib in High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG) (clinicaltrials.gov) - P2 | N=79 | Not yet recruiting | Sponsor: Nationwide Children's Hospital

New P2 trial • Anaplastic Astrocytoma • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Pediatrics • Solid Tumor • BRAF

FIRELIGHT-1: Tovorafenib (DAY101) Monotherapy for Patients With Melanoma and Other Solid Tumors (clinicaltrials.gov) - P2 | N=23 | Terminated | Sponsor: Day One Biopharmaceuticals, Inc. | Phase classification: P1/2 ➔ P2 | N=168 ➔ 23 | Active, not recruiting ➔ Terminated; Sponsor decision

Enrollment change • Monotherapy • Phase classification • Trial termination • Astrocytoma • Bladder Cancer • Brain Cancer • Colorectal Cancer • Genito-urinary Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pilocytic Astrocytoma • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • Urothelial Cancer • BRAF • NF1 • RAF1