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

Perfume trial: Phase II trial of binimetinib in patients with BRAF fusion-positive low-grade glioma or pancreatic cancer. (ASCO 2025) - P2 | "Recently, tovorafenib has been granted accelerated approval by the FDA for pediatric low-grade glioma (LGG) with BRAF alteration (including BRAF fusion)...Phase I/II trials with selumetinib or binimetinib have shown efficacy in patients with BRAF fusion-positive LGG...Enrollment started in March 2023 and is ongoing at 6 facilities in Japan. As of Dec 2024, 6 patients with LGG and 3 patients with PC were enrolled (Clinical trial information: jRCT2031230007, NCT06159478)."

Clinical • P2 data • Astrocytoma • Brain Cancer • CNS Tumor • Glioma • Oncology • Pancreatic Cancer • Pediatrics • Pilocytic Astrocytoma • Solid Tumor • BRAF

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. (ASCO 2025) - P2 | "Rashes were common in pts treated with tovorafenib in FIREFLY-1. They typically occurred early in treatment, most were G1 or G2, resolved within a median of ~3 mos, and were manageable with SOC treatment and/or tovorafenib dose modifications. A/P rashes occurred more frequently in pts ≥12 y/a; there were no other significant trends in rashes experienced between the two age groups."

Clinical • Retrospective data • Atopic Dermatitis • Brain Cancer • CNS Tumor • Dermatitis • Dermatology • Glioma • Immunology • Oncology • Pediatrics • Solid Tumor • BRAF

Growth recovery in patients with BRAF altered pediatric low-grade gliomas (LGG) after discontinuation of tovorafenib. (ASCO 2025) - P, P1, P2 | "Decreases in growth velocity were common during tovorafenib treatment. Majority of patients to date demonstrate AGV recovery as early as 3 months with signs of catchup within 6-12 months after stopping tovorafenib. Preliminary findings indicate tumor-associated precocious puberty/Tanner stage 4 in females may be a risk factor for slow AGV recovery."

Clinical • Brain Cancer • CNS Tumor • Endocrine Disorders • Glioma • Growth Hormone Deficiency • Growth Hormone Deficiency (Pediatric) • Musculoskeletal Diseases • Oncology • Orthopedics • Pediatrics • Solid Tumor • BRAF

A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Sep 2028 | Trial primary completion date: Jun 2026 ➔ Sep 2028

Trial completion date • Trial primary completion date • Langerhans Cell Histiocytosis • ALK • BRAF • ERBB3

Study for Patients With Hairy Cell Leukemia to Test the Targeted Agent Tovorafenib in Combination With Rituximab and Compare the Combination With Current Standard Treatment (clinicaltrials.gov) - P1/2 | N=78 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1/2 trial • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF

Response to a novel type II RAF inhibitor in diffuse leptomeningeal glioneuronal tumor with BRAF fusion. (PubMed, Oncologist) - "This case highlights the importance of tumor molecular characterization, particularly in rare tumors, whereby identification of the BRAF:KIAA1594 gene fusion led to an appropriate selection of a type II BRAF inhibitor."

Journal • Cardiovascular • Glioneuronal Tumor • Oncology • Rare Diseases • BRAF • KIAA1549

VICTORY: Pilot Study of Vinblastine and Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas (clinicaltrials.gov) - P1 | N=57 | Recruiting | Sponsor: Daniel Morgenstern | Trial primary completion date: Mar 2026 ➔ Mar 2027

Trial primary completion date • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor • BRAF

OncoKBTM, MSK's precision oncology knowledge base: 2024 updates (AACR 2025) - "OncoKB promoted BRAF fusions to Level 1 following inclusion as patient eligibility criteria in the FDA drug label for tovorafenib (low-grade glioma). Additionally, OncoKB included KRAS G12C in colorectal cancer and IDH1 mutations in myelodysplastic syndromes as Level 1 following FDA approval of adagrasib + cetuximab and ivosidenib, respectively...Lastly, novel biomarkers including FBXW7 and PPP2R1A alterations (endometrial and ovarian cancer), SMARCA4 mutations (non-small cell lung cancer and esophageal adenocarcinoma) and MTAP deletions (all solid tumors) were included in OncoKB based on compelling preclinical and emerging clinical evidence in association with lunresertib + camonsertib, PRT3789, and AMG193 and MRTX1719, respectively...OncoKB also implemented major software updates to support data integration into the EPIC platform. Future OncoKB efforts are focused on whole genome/exome curation, inclusion of biomarkers for non-NGS-based precision oncology therapies,..."

Tumor mutational burden • Brain Cancer • CNS Tumor • Colorectal Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Glioma • Hematological Malignancies • Lung Cancer • Microsatellite Instability • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF • FBXW7 • IDH1 • KRAS • MSI • MTAP • POLD1 • PPP2R1A • SMARCA4 • TMB

Day One Reports First Quarter 2025 Financial Results and Corporate Progress (GlobeNewswire) - "OJEMDA net product revenue was $30.5 million in the first quarter of 2025. U.S. OJEMDA net product revenue increased 11% from the fourth quarter of 2024. OJEMDA prescriptions increased to over 900 (+16%) in the first quarter of 2025. Achieved $87.7 million in OJEMDA net product revenue since launch, representing over 2,500 OJEMDA prescriptions."

Sales • Glioma

The efficacy of NST-628, a non-degrading pan-RAF/MEK molecular glue, and MEK inhibitors for overcoming acquired osimertinib resistance mediated by TRIM24-BRAF fusions in EGFR mutant NSCLC (AACR 2025) - "Next, we utilized a panel of compounds targeting the RAS/RAF/MAPK pathway including agents targeting pan-RAS (RMC-6236 and RMC-7977), SHP2 (RMC-4550), BRAF (dabrafenib, encorafenib, tovorafenib and vemurafenib), pan-RAF (TAK-632), MEK (binimetinib, cobimetinib, selumetinib and trametinib), pan-RAF/MEK (NST-628) and assessed whether targeting signal transduction molecule downstream of EGFR could overcome this adaptative resistance mechanism. TRIM24-BRAF expressing cells showed minimal sensitivity to BRAF, SHP2 or RAS targeting single agents. Taken together, our findings indicate that expression of TRIM24-BRAF fusion induce osimertinib resistance in EGFR mutant NSCLC and targeting the MEK pathway using trametinib or NST-628 can overcome osimertinib resistance in this setting."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR • TRIM24

Tovorafenib: Regulatory decision in EU for r/r pediatric low-grade gliomas (based on FIREFLY-1 trial) in 2026 (Ipsen) - Q1 2025 Results

EMA approval • Glioma • Oncology

Ipsen delivers strong sales in the first quarter 2025 and confirms its full-year guidance (GlobeNewswire) - "The regulatory filing for tovorafenib was accepted by EMA for review in the European Union, marking an important step forward in the development of this potential treatment for pediatric low-grade glioma and reinforcing Ipsen’s commitment to innovation in rare and difficult-to-treat cancers; Ipsen also initiated the entry in Phase I of IPN01195, a RAF inhibitor, complementing IPN01194, an ERK inhibitor, and tovorafenib, two other assets targeting the MAPK pathway."

EMA filing • Trial status • Glioma • Solid Tumor

Targeting the RAS pathway with MEK and pan-RAF inhibition in Philadelphia-like acute lymphoblastic leukemia (AACR 2025) - "Interestingly, addition of the pan-RAF inhibitor tovorafenib to trametinib did not have further therapeutic benefit. These findings begin to shed insight into novel targets for CRLF2-R ALL.Survival OutcomesMedian survival (days)Log-rank p-value to controlLog-rank p-value to combinationControl3Tovorafenib8**0.0035*0.0116Trametinib15**0.0035ns 0.4235Combination13**0.0035"

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CRLF2 • JAK2 • PTPRC

Properties of FDA-approved small molecule protein kinase inhibitors: a 2025 update. (PubMed, Pharmacol Res) - "Seven drugs (abrocitinib, baricitinib, deucravacitinib, deuruxolitinib, ritlecitinib, tofacitinib, upadacitinib) are prescribed for the management of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis)...The following four drugs received FDA approval in 2024 - deuruxolitinib (alopecia areata), ensartinib and lazertinib (non-small cell lung cancer), and tovorafenib (pediatric glioma) while mirdametinib was approved in 2025 for the treatment of type I neurofibromatosis (von Recklinghausen disease). Apart from netarsudil, temsirolimus, and trilaciclib, the approved protein kinase blockers are orally bioavailable. This article summarizes the physicochemical properties of all 85 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 39 of the 85..."

FDA event • Journal • Review • Alopecia • Atopic Dermatitis • Brain Cancer • Chronic Myeloid Leukemia • CNS Tumor • Dermatitis • Dermatology • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Glioma • Hematological Malignancies • Immunology • Inflammatory Arthritis • Inflammatory Bowel Disease • Leukemia • Lung Cancer • Neurofibromatosis • Non Small Cell Lung Cancer • Oncology • Pediatrics • Psoriasis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Solid Tumor • Ulcerative Colitis • MAP2K1

Sequencing MEK inhibitor therapy after tovorafenib in BRAF fusion-driven cancers: Preclinical evidence of sustained tumor regression (AACR 2025) - "Once individual tumors regrew to 100-200 mm3 size (within approximately 2 weeks), mice were treated for 14 days with a MEK inhibitor (trametinib; 0.3 mg/kg oral, once daily), or tovorafenib was resumed. In conclusion, our study provides evidence for the efficacy of sequencing MEK inhibitor treatment after tovorafenib in a PDX model of AGK::BRAF fusion melanoma. Furthermore, long-term efficacy was maintained with continuous dosing of tovorafenib in vivo, with no signs of emerging resistance preclinically, supporting the hypothesis that acquired resistance may be less common in BRAF fusion driven tumors treated with tovorafenib."

Preclinical • Astrocytoma • Brain Cancer • CNS Tumor • Glioma • Melanoma • Oncology • Pleomorphic Xanthoastrocytoma • Solid Tumor • AGK • BRAF • KIAA1549

FIREFLY 1: A Study to Evaluate Tovorafenib in Pediatric and Young Adult Participants With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (clinicaltrials.gov) - P2 | N=141 | Recruiting | Sponsor: Day One Biopharmaceuticals, Inc. | Trial completion date: Jun 2024 ➔ May 2027 | Trial primary completion date: Dec 2022 ➔ May 2027

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioma • Oncology • Pediatrics • Solid Tumor • BRAF

Preclinical activity of the type II RAF inhibitor tovorafenib in tumor models harboring either a BRAF fusion or an NF1-loss of function mutation. (PubMed, Cancer Res Commun) - "In NF1-LOF tumor cells treated with tovorafenib, increase in phosphorylated-ERK (pERK) was observed at low concentrations, with inhibition of pERK at higher concentrations. When tovorafenib was combined with pimasertib in vitro, synergy was observed in a NF1-LOF embryonal rhabdomyosarcoma PDX model ex vivo and a NF1-LOF MPNST cell line in vitro, suggesting that vertical pathway inhibition is needed in the NF1-LOF mutant setting."

Journal • Preclinical • Melanoma • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • AGK • BRAF • NF1

XOMA Royalty Reports Fourth Quarter and Full Year 2024 Financial Results and Highlights Business Achievements (GlobeNewswire) - "The U.S. Food and Drug Administration (FDA) approved Day One's OJEMDA (tovorafenib) for use in patients with pediatric low-grade glioma (pLGG). XOMA Royalty earned a $9.0 million milestone upon the approval and recorded $2.7 million in income resulting from OJEMDA sales in 2024. In addition, XOMA Royalty received an $8.1 million payment related to Day One's sale of its priority review voucher."

Sales • Glioma

A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis (clinicaltrials.gov) - P2 | N=48 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Langerhans Cell Histiocytosis • ALK • BRAF • ERBB3

Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids. (PubMed, SLAS Discov) - "Additive and/or synergistic effects were observed with alpelisib or inavolisib or copanlisib in combination with a RAS/MEK/ERK pathway inhibitor, either selumetinib (MEK), ravoxertinib (ERK 1/2), or tovorafenib (DAY101, RAF). Combinations of each of these three PI3K inhibitors with the KRAS mutation specific inhibitors MTRX1133 (KRAS G12D) or sotorasib (KRAS G12C) had selective activity in cell lines harboring the corresponding target. Lastly, combination effects were observed from vertical inhibition of the PI3K/AKT/mTOR pathway with a PI3K inhibitor in combination with either the mTORC1/2 inhibitor sapanisertib or an AKT inhibitor, ipatasertib or afuresertib."

Journal • Oncology • KRAS

Day One Reports Fourth Quarter and Full Year 2024 Financial Results and Corporate Progress (GlobeNewswire) - "Program Highlights: OJEMDA net product revenues were $29.0 million and $57.2 million for the fourth quarter and full year ended December 31, 2024, respectively. OJEMDA net product revenues increased 44% from the third to fourth quarter of 2024....OJEMDA received the Exclusively Pediatric designation by the Centers for Medicare & Medicaid Services in the fourth quarter ended December 31, 2024, reducing its Medicaid and 340B minimum rebate percentage from 23.1% to 17.1%....Day One advanced enrollment in the global, pivotal Phase 3 FIREFLY-2 clinical trial, with full enrollment expected in the first half of 2026."

Commercial • Enrollment status • Glioma

A Study With Tovorafenib (DAY101) as a Treatment Option for Progressive, Relapsed, or Refractory Langerhans Cell Histiocytosis (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2025 ➔ Jun 2026 | Trial primary completion date: May 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Langerhans Cell Histiocytosis • ALK • BRAF • ERBB3

2025 Upcoming Milestones (GlobeNewswire) - "Ipsen anticipates several key milestones across its portfolio in 2025, including: Cabometyx (CABINET trial) – Regulatory decision in Europe for advanced neuroendocrine tumors (NETs), including pancreatic (pNETs) and extra-pancreatic (epNETs) neuroendocrine tumors; Tovorafenib (FIREFLY-1 trial) – Regulatory submission in Europe for pediatric low-grade glioma"

EMA approval • EMA filing • Glioma • Neuroendocrine Tumor • Pancreatic Cancer

Orphan Drug Designations and Approvals (FDA) - Generic Name: tovorafenib, Trade Name: Ojemda, Date Designated: 09/24/2020, Orphan Designation: Treatment of malignant glioma, Orphan Designation Status: Designated/Approved.

Orphan drug • Glioma

PNOC014: DAY101 In Gliomas and Other Tumors (clinicaltrials.gov) - P1 | N=44 | Active, not recruiting | Sponsor: Karen D. Wright, MD | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • NF1