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

108: Updates in the Management of BRAF and MEK Inhibitors in Pediatric Solid Tumors (HOPA 2026) - "This session will provide an overview of these new agents and formulations and their use in the pediatric population. UAN: 0465-0000-26-025-L01-P Knowledge or Application Based: Knowledge Learning Objectives: Evaluate recent literature exploring the use of selumetinib and trametinib/dabrafenib in pediatric solid tumorsDiscuss key clinical trials leading to the approval of mirdametinib and tovorafenib in the pediatric populationIdentify available dosage forms of BRAF/MEK pathway inhibitors and associated administration challenges in the pediatric populationDevelop strategies to monitor and manage adverse effects of BRAF/MEK pathway inhibitors in pediatric patients"

Clinical • Oncology • Pediatrics • Solid Tumor

Characterization of intrinsic and acquired resistance to KRASG12C inhibitors across a broad collection of cancer cell line models (AACR 2026) - "Although PTEN loss was restricted to OV56, both OV56 and SW1573 were resistant to inhibitors of various MAPK pathway components, including RAF (tovorafenib, belvarafenib), MEK (trametinib), and ERK (ulixertinib), suggesting MAPK pathway independence. Cross-resistance to adagrasib, sotorasib and divarasib was also observed in the acquired resistant models.Intrinsically KRASG12C inhibitor-resistant cell lines, along with acquired resistant models, represent valuable systems for evaluating next-generation KRAS inhibitors and identifying new drug combinations to optimize therapeutic benefit of KRASG12C inhibitors in patients."

Preclinical • Oncology • KRAS • PTEN

KiTZ-EPILOGUE-2024: Phase I/II combination umbrella trial in progressive/relapsed/refractory pediatric low-grade glioma (pLGG) (EPILOGUE) (clinicaltrialsregister.eu) - P1/2 | N=28 | Not yet recruiting | Sponsor: Universitaetsklinikum Heidelberg AR

New P1/2 trial • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor • BRAF • KIAA1549

KiTZ-EPILOGUE-2024: Phase I/II combination umbrella trial in progressive/relapsed/refractory pediatric low-grade glioma (pLGG) (EPILOGUE) (clinicaltrialsregister.eu) - P1/2 | N=31 | Not yet recruiting | Sponsor: Universitaetsklinikum Heidelberg AR

New P1/2 trial • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor • BRAF • KIAA1549

PNOC029_Tovorafenib for the treatment of newly diagnosed or recurrent craniopharyngioma in children and young adults (clinicaltrialsregister.eu) - P1/2 | N=5 | Not yet recruiting | Sponsor: Prinses Maxima Centrum voor Kinderoncologie B.V.

New P1/2 trial • Brain Cancer • CNS Tumor

Servier and Day One Biopharmaceuticals announce acquisition to expand Servier's rare oncology portfolio (PRNewswire.co.uk) - "Servier...and Day One Biopharmaceuticals, Inc...announced that they have entered into a definitive agreement for Servier to acquire Day One for $21.50 per share in cash, representing a total equity value of approximately $2.5 billion. The transaction remains subject to customary closing conditions and is expected to close in the second quarter of 2026...It strengthens Servier's portfolio and expands its oncology pipeline with programs ranging from early stage to phase 3."

M&A • Adenoid Cystic Carcinoma • Glioma

A Study to Assess a Medicine Called Tovorafenib in Japanese Children and Young Adults With Brain Tumours (clinicaltrials.gov) - P1 | N=6 | Not yet recruiting | Sponsor: Ipsen

New P1 trial • Brain Cancer • Glioma • Oncology • Pediatrics • Solid Tumor • BRAF • KIAA1549

From Diagnosis Delay to Targeted Therapy: A Retrospective Study of Pediatric DLGNT with a Comprehensive Literature Review. (PubMed, Cancers (Basel)) - "The median number of therapeutic lines was four: 82% received chemotherapy (weekly vinblastine in 55%, vincristine/carboplatin regimen in 45%), 64% received MAPK pathway-targeted therapy, and 18% underwent radiotherapy...Conventional low-grade glioma chemotherapy constitutes the current treatment backbone, while MAPK pathway-targeted therapies show promising potential. Further studies and the establishment of an international registry are crucial to better characterize aggressive subtypes and optimize management strategies."

Journal • Retrospective data • Brain Cancer • CNS Tumor • Glioma • Glioneuronal Tumor • Oncology • Pediatrics • Solid Tumor • BRAF • KIAA1549

DAY101 vs. Standard of Care Chemotherapy in Pediatric Participants With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2) (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Day One Biopharmaceuticals, Inc. | Trial completion date: Mar 2030 ➔ Jun 2031 | Trial primary completion date: Feb 2026 ➔ Jun 2027

Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Fibrosarcoma • Glioma • Oncology • Pediatrics • Sarcoma • Solid Tumor

Ipsen receives positive CHMP opinion for Ojemda for the treatment as monotherapy of children with relapsed or refractory BRAF-altered pediatric low-grade glioma (GlobeNewswire) - "The CHMP’s positive opinion is based on data from the pivotal Phase II FIREFLY-1 study, which evaluated tovorafenib in 137 children and young adults with relapsed or refractory BRAF-altered pLGG who had received at least one prior systemic therapy....Following this positive opinion, the European Commission will review the CHMP’s recommendation, with a final decision on marketing authorization expected in the coming months."

CHMP • Low Grade Glioma

PNOC014: DAY101 In Gliomas and Other Tumors (clinicaltrials.gov) - P1 | N=44 | Completed | Sponsor: Karen D. Wright, MD | Active, not recruiting ➔ Completed

Trial completion • Brain Cancer • Glioma • Oncology • Solid Tumor • NF1

Understanding Pharmacokinetic-Drug Interactions With Drugs Approved by the US Food and Drug Administration in 2024 to Better Manage the Risk of Drug Interactions With Concomitant Medications: A Review of Clinical Data From New Drug Applications. (PubMed, Curr Ther Res Clin Exp) - "Of these, 7 drugs were substrates of CYP3A, 3 of CYP2C9, one of CYP1A2, and one of CYP2C8, including the sensitive substrates vanzacaftor (CYP3A) and vorasidenib (CYP1A2). As precipitants, 6 drugs (acoramidis, cefepime/enmetazobactam, givinostat, lazertinib, mavorixafor, and resmetirom) were clinical inhibitors of CYP enzymes (2C8, 2C9, 2D6, 2E1, and 3A), with mavorixafor being a CYP2D6 strong inhibitor. Two drugs (elafibranor and tovorafenib) showed weak induction of CYP3A. Regarding transporter data, 3 drugs were substrates of transporters, including seladelpar (BCRP and OAT3), sulopenem (OAT3), and vadadustat (OAT1/3), and 8 drugs (arimoclomol, danicopan, givinostat, lazertinib, mavorixafor, resmetirom, vadadustat, and vazacaftor/tezacaftor/deutivacaftor) were inhibitors of transporters...Several DDIs with an AUC change <2 also had labeling recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Mechanistic DDI..."

Clinical data • FDA event • Journal • NDA • PK/PD data • Review • CYP1A2 • CYP2C9

Tovorafenib: “The Committee discussed the issues identified in this application”; Low grade glioma (European Medicines Agency) - CHMP Final Minutes of the meeting on 21 - 24 Jul 2025: “The committee adopted the CHMP recommendation and scientific discussion together with the list of questions”

CHMP • Low Grade Glioma • Oncology

Aggressive infantile melanoma arising in a congenital nevus with rare BRAF and BCOR mutations: a case report and literature review of pediatric melanoma. (PubMed, Dermatol Reports) - "Treatment included surgery and systemic therapies (nivolumab and ipilimumab, followed later by tovorafenib). The patient's clinical course was marked by aggressive local progression and therapeutic challenges. This case highlights the rarity of such presentations and the need for further research into the clinicopathological and molecular features of infantile melanoma arising in congenital melanocytic nevus (CMN)."

Journal • Melanoma • Nevi and Melanomas • Oncology • Pediatrics • Sarcoma • Solid Tumor • BCOR • BRAF

Gemcitabine and Nab-Paclitaxel Combined With Iparomlimab-Tuvorilimab for Advanced Gallbladder Cancer (ChiCTR) - P2 | N=44 | Not yet recruiting | Sponsor: Xinhua Hospital Affiliated to Shanghai Jiaotong University of Medicine; Xinhua Hospital Affiliated to Shanghai Jiaotong University of Medicine

New P2 trial • Gallbladder Cancer • Oncology • Solid Tumor

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. (PubMed, Nat Med) - P2 | "These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 ."

Journal • P2 data • Brain Cancer • CNS Tumor • Glioma • Hematological Disorders • Oncology • Pediatrics • Solid Tumor • BRAF

Phase IB study of tovorafenib for children with relapsed/recurrent low-grade gliomas and other MAPK pathway activated tumors. (ASCO 2024) - P1 | "Oral weekly tovorafenib is well tolerated and shows preliminary efficacy. Decreased GV was observed in pre-pubertal patients on drug and warrants further investigation to understand the mechanism of action. Based on the number of dose modifications required for toxicity, the chosen RP2D for weekly oral dosing of tovorafenib was 420 mg/m 2 ."

Clinical • P1 data • Astrocytoma • Brain Cancer • CNS Tumor • Fatigue • Glioma • Gynecology • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • BRAF • FGFR1 • KIAA1549

2025 OJEMDA Commercial Performance (GlobeNewswire) - "OJEMDA net product revenue was approximately $52.8 million and $155.4 million for the fourth quarter and full year 2025, respectively (unaudited). ~37% QoQ growth compared to Q3 2025; ~172% YoY growth vs. 2024, driven by momentum in patient demand, with prescription volumes increasing to 1,394 during the fourth quarter. 2026 OJEMDA U.S. net product revenue is projected to be between $225 million and $250 million, representing 53% year-over-year growth at the midpoint."

Sales • Low Grade Glioma

2026 Corporate Priorities and Key Milestones: OJEMDA (GlobeNewswire) - "(i) Deliver on 2026 OJEMDA net product revenue guidance, with a focus on increasing persistency and driving new patient starts to support continued OJEMDA adoption as standard of care (SOC) in 2L pediatric low-grade glioma (pLGG); (ii) Extend the OJEMDA commercial opportunity beyond the U.S. with global expansions via our partner; (iii) Complete enrollment in the pivotal Phase 3 FIREFLY-2 clinical trial in first-line pLGG in the first half of 2026, enabling a mid-2027 data readout and a potential approval in 2028."

Approval • Commercial • Enrollment status • P3 data • Low Grade Glioma

Clinical experience with tovorafenib in adults with treatment-refractory high- and low-grade gliomas. (PubMed, Neurooncol Pract) - "All patients had received prior BRAF-targeted therapy, and all patients with HGG had received prior radiation and temozolomide as well. Our experience with tovorafenib indicates some limited efficacy in HGG in combination with other standard treatments. These observations demonstrate the need for further clinical trials in patients with HGG to understand potential clinical utility, either earlier in the disease course or in combination with other therapies."

Journal • Brain Cancer • Glioma • Hematological Disorders • High Grade Glioma • Oncology • Pediatrics • Solid Tumor

Harnessing retinoic acid metabolism-related genes to identify lung adenocarcinoma subtype and establish a risk model for predicting prognosis and drug therapy response. (PubMed, Comput Biol Chem) - "RAMRGs serve as useful biomarkers to predict prognosis in LUAD patients, and may guide the immunotherapy regimen."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CYP17A1 • IGF2BP1 • IGFBP1 • TP53

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