Ojemda (tovorafenib)

P1/2, N=168, Active, not recruiting, Day One Biopharmaceuticals, Inc. | Recruiting --> Active, not recruiting

Clinical development of tovorafenib is underway in numerous countries worldwide. This article summarizes the milestones in the development of tovorafenib leading to this first approval for relapsed or refractory pLGG with an activating BRAF alteration.

This review discusses the development of targeted therapies for these tumors, examining the effectiveness of first-generation BRAF inhibitors such as Vemurafenib, Dabrafenib and Encorafenib, while addressing the challenges posed by paradoxical ERK activation. The advent of pan-RAF inhibitors, notably Tovorafenib, offers a promising advance, demonstrating enhanced efficacy and better penetration of the blood-brain barrier, without the issue of paradoxical activation. Nevertheless, continued research is essential to refine therapeutic strategies for BRAF-mutated gliomas, given the evolving nature of targeted therapy development.

P1, N=57, Recruiting, Daniel Morgenstern

P1, N=22, Terminated, Millennium Pharmaceuticals, Inc. | Phase classification: P1b --> P1

P1/2, N=168, Recruiting, Day One Biopharmaceuticals, Inc. | Phase classification: P1b/2 --> P1/2

The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG.

P2, N=29, Recruiting, National Cancer Institute (NCI) | Initiation date: Jan 2024 --> Apr 2024

No abstract available

Further, we discuss treatment strategies for refractory/relapsed (R/R) LCH, with a focus on MAPK inhibitors' efficacy and challenges (ie, the unknown): long-term toxicity in children, optimal duration, if they are curative, whether it is safe to combine them with chemotherapy, and their high price tag. Lastly, emerging strategies, such as the new panRAF inhibitor (Day 101) in patients with R/R LCH, ERK1/2 or CSF1R inhibition in patients with MEK1/2 inhibitor resistance, and targeting the microenvironment (checkpoint plus MEK inhibition) or senescent cells (mTOR or BCL-XL inhibitors) in R/R patients, are also examined.

P3, N=400, Recruiting, Day One Biopharmaceuticals, Inc.

These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .

Tovorafenib provided clinically meaningful tumor responses, including those with a best response reported of SD or PD using another MAPKi, in patients with BRAF-altered pLGG regardless of prior MAPKi therapy, and has a manageable safety profile.

Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.

P2, N=140, Recruiting, Day One Biopharmaceuticals, Inc. | Trial completion date: Feb 2024 --> Jun 2024 | Trial primary completion date: Mar 2023 --> Apr 2024

Patient 2 is a 30-year-old Asian female enrolled in FL-1 with metastatic undifferentiated spindle cell sarcoma harboring an APPL2-RAF1 fusion previously treated with radiation, multiple surgical resections, and 2 lines of systemic therapy (cisplatin + etoposide [best response of stable disease] followed by docetaxel + gemcitabine [best response of partial response {PR} but progressed after 6 cycles]). Tovorafenib has clinical activity and a manageable safety profile in these two AYA patients with RAF fusion sarcoma. These reports provide additional evidence of the antitumor activity of tovorafenib in RAF fusion-driven tumors beyond pLGG Early tumor shrinkage minimizing potential morbidities facilitated curative tumor resection in one patient where surgical intervention was not previously possible and a continued rapid, durable tumor response in another. Genomic analysis of all sarcomas is warranted to identify rare oncogenic gene fusions, especially when such alterations are targetable.

According to the phase III INDIGO trial, vorasidenib, an IDH1/2 inhibitor, significantly benefited adults with IDH1/2-mutant low-grade gliomas, reducing progression risk and delaying the need for chemoradiotherapy. Meanwhile, in a pediatric low-grade glioma cohort of FIREFLY-1, a phase II trial, robust responses to the type II pan-RAF inhibitor tovorafenib were seen.

No abstract available

The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.

Selective inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as Pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class.

P2, N=28, Recruiting, National Cancer Institute (NCI)

Previous therapy with pembrolizumab provided a best response of stable disease (SD) after 11 weeks of therapy...Patient 2 is a 35-year-old white male with a TRIM33-BRAF fusion malignant melanoma, and progressed after treatment with radiation, nivolumab, and nivolumab + ipilimumab... Early results from the first three patients of this ongoing trial showed tovorafenib is generally well tolerated and has encouraging antitumor activity in BRAF-fusion melanoma.

P=N/A, Available, Day One Biopharmaceuticals, Inc.

P2, N=140, Recruiting, Day One Biopharmaceuticals, Inc. | N=60 --> 140

P1/2, N=43, DOT Therapeutics-1 Inc. (Day One)

P1, N=44, Active, not recruiting, Karen D. Wright MD | Recruiting --> Active, not recruiting

He was treated with 3 cycles of ifosfamide, doxorubicin and dexrazoxane...The patient was consequently started on the MEK inhibitor trametinib in May 2019...Pending molecular test results, which again identified the SNX8:BRAF fusion, the patient started gemcitabine and docetaxel as second-line therapy for recurrent disease...The patient developed grade 2 rash after the first dose of DAY101, which resolved in 1 day after a dose of diphenhydramine... Tumors with IFS-like morphology need to undergo comprehensive genomic profiling to identify novel oncogenic fusions. DAY101 is potentially an effective treatment in pediatric patients with soft tissue sarcomas harboring BRAF fusions and warrants further investigation in other BRAF fusion-driven solid tumors.

In addition, TAK-580 enhanced the cytotoxicity of KPT-330 against MM cells even in the presence of IGF-1. Taken together, our results demonstrate that a combination of pan-RAF inhibitor and XPO1 inhibitor is a potential therapeutic option in treating MM.

P1b/2, N=43, Recruiting, Day One Biopharmaceuticals, Inc. | Not yet recruiting --> Recruiting

P2, N=60, Recruiting, Day One Biopharmaceuticals, Inc. | Not yet recruiting --> Recruiting

Accordingly, the tool compound TAK-632, which exhibits comparable biochemical and cellular potency to DAY101, was used alternatively as needed for in vitro assays.Single-agent anti-proliferative activity was observed in a melanoma BRAF fusion PDX model treated with TAK-632 ex vivo, with less sensitivity observed in models beyond melanoma harboring other BRAF fusions. Inhibition of both RAF monomers and dimers by DAY101 enables a broader indication selection strategy, beyond LGG and BRAF alterations. Ongoing translational work will highlight the potential utility of DAY101 in adult tumors harboring RAS or RAF alterations, both as a single agent and in hypothesis-driven combinations.

P2, N=60, Not yet recruiting, Day One Biopharmaceuticals, Inc.

P2, N=60, DOT Therapeutics-1 Inc. (Day One)

In this study, we examined the anti-tumor effects of TAK-580 used as monotherapy or in combination with bortezomib, lenalidomide, or other novel agents in multiple myeloma (MM) cells in vitro. TAK-580 monotherapy potently targeted proteins in the RAS-RAF-MEK-ERK signaling pathway and induced potent cytotoxicity and apoptosis in MM cell lines and myeloma cells from patients with newly diagnosed and relapsed and/or refractory MM, compared with a representative RAF inhibitor, dabrafenib...Importantly, TAK-580 also enhanced lenalidomide-induced cytotoxicity and apoptosis in MM cells. Taken together, our results provide the rationale for TAK-580 monotherapy and/or treatment in combination with novel agents to improve outcomes in patients with MM.