Background
Pediatric low-grade glioma (pLGG) is a heterogeneous group of World Health Organization (WHO) grade 1 and 2 tumors comprising several subgroups and is the most frequent pediatric central nervous system (CNS) tumor diagnosis, with 1200 to 1500 new cases per year in the United States (US) [
1]. Although pLGG is a low-grade tumor with an excellent 10-year overall survival (OS) rate of 94%, the 10-year progression-free survival (PFS) rate in case of an indication for systemic treatment with standard of care (SoC) chemotherapy is only 44% [
2,
3]. Therefore, pLGG may be considered a chronic disease in patients whose tumors are unresectable or cannot be completely resected, who will often require several treatment lines throughout life [
4]. The late adverse effects of the disease and treatment of it in combination with the damage to important functional structures puts a heavy burden on patients and can lead to loss of visual function and impairment of neurologic, endocrine, and cognitive functioning [
5‐
7].
The current SoC first-line systemic treatment is chemotherapy, most commonly a combination of vincristine and carboplatin (V/C). Although the regimens used by the European Society for Paediatric Oncology—Brain Tumour Group—low-grade glioma working group (SIOPe-BTG LGG WG) and the Children’s Oncology Group (COG) differ slightly, both regimens show a similar outcome [
8,
9]. The SIOPe-BTG LGG WG reported a response rate of 29% (24 weeks after treatment start) and a five-year PFS rate of 45% [
9], whereas the COG reported a response rate of 35% (end of treatment) and a five-year event-free survival rate of 39% [
8]. A single-arm phase 2 study of single-agent vinblastine (VBL) resulted in a 19% response rate and a five-year PFS rate of 53% [
10]. Several countries/institutions now utilize VBL as first-line therapy on the basis of this trial.
Treatment with V/C or VBL may be accompanied by significant adverse effects, including bone marrow toxicity, neurotoxicity, hearing loss, renal dysfunction, and allergic reactions [
3]. The burden of toxicity, frequent hospital visits as well as a significant number of patients progressing after first-line treatment, motivated the search for alternative strategies. In addition, these chemotherapy regimens appear even less effective in infants with pLGG [
11], underscoring the need for novel treatment options in this particular subgroup of patients with poor prognosis [
9].
Pediatric low-grade glioma is predominantly a single pathway disease driven by alterations in the mitogen-activated protein kinase (MAPK) signaling pathway (also known as the RAS-RAF-MEK-ERK pathway).
KIAA1549::BRAF fusions, BRAF V600E mutations,
FGFR1 alterations and loss of function mutations of the neurofibromin 1 (
NF1) gene are the most frequent molecular alterations [
12‐
18]. In addition, oncogene-induced senescence and the senescence-associated secretory phenotype have recently been reported to play an important role in pLGG [
19,
20].
As a single pathway disease, pLGG is an ideal candidate for the development of targeted treatments. In a phase 2 trial comparing the combination of the type I BRAF inhibitor dabrafenib and the MEK inhibitor trametinib to chemotherapy in patients with BRAF V600E-mutated pLGG requiring first-line systemic treatment, an objective response rate (ORR) of 47% and a median PFS of 20.1 months were observed, whereas SoC chemotherapy treatment with V/C resulted in an ORR of 11% and a median of PFS 7.4 months [
21]. Subsequently, the US Food and Drug Administration (FDA) approved dabrafenib combined with trametinib as a systemic treatment for BRAF V600E-mutated pLGG [
22]. The use of type I BRAF inhibitors is limited to patients with tumors harboring a BRAF V600E mutation due to the risk of paradoxical activation of the MAPK pathway and accelerated tumor growth if used in patients with tumors harboring a
RAF fusion, such as those involving
BRAF or
CRAF/RAF1 [
23]. In recurrent or progressive disease, MEK inhibitors, such as selumetinib and trametinib, have shown activity [
24‐
26]. However, data generated from ongoing studies of various MAPK pathway inhibitors have shown that responses in pLGGs driven by either BRAF V600E mutations (treated with type I RAF inhibitors and/or MEK inhibitors) or
KIAA1549::BRAF fusions (treated with MEK inhibitors) are often only durable for as long as the drug can be administered [
27,
28]. Furthermore, while the ORRs of MEK inhibitors are encouraging, responses can be relatively slow [
25], and current MEK inhibitors are poorly brain-penetrant and associated with significant peripheral toxicities, mostly dermatological, but also cardiac and ophthalmological adverse events (AEs) [
29,
30]. Thus, high target selectivity, CNS penetration properties, short time to response, and favorable tolerability over a long course of treatment are key determinants of sustained clinical activity and therefore treatment success [
26].
Tovorafenib (formerly DAY101, TAK-580, MLN2480) is an investigational, oral, brain-penetrant, selective, small molecule, type II RAF inhibitor. In contrast to the approved type I RAF inhibitors, tovorafenib inhibits both wild-type BRAF and CRAF/RAF1 kinases and, importantly, hyperactivated signaling resulting from
BRAF fusions, including the
KIAA1549::BRAF fusion [
31].
Tovorafenib was shown to inhibit the kinase activity of BRAF kinase domain fusions with various 5′ gene partners, most notably fusion with the
KIAA1549 gene. In cellular assays, tovorafenib inhibited
KIAA1549::BRAF fusion kinase activity with comparable potency to inhibition of BRAF V600E and without the paradoxical activation of the MAPK pathway reported for type I BRAF inhibitors [
32]. Tovorafenib blocked downstream pERK signaling and had less severe dermatological, cardiac, or ophthalmological toxicities compared to other RAF or MEK inhibitors [
33‐
35]. Finally, tovorafenib had greater CNS penetration compared with the type I RAF inhibitor dabrafenib [
32]. The clinical activity of tovorafenib in the currently ongoing phase 2 FIREFLY-1 (PNOC026) study in pediatric patients with
BRAF-altered, recurrent, or progressive pLGG harboring a
BRAF fusion or BRAF V600E mutation was recently reported. In the registrational arm (69 evaluable patients), the ORR primary endpoint as determined by Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria per independent radiology review committee (IRC) was 67% [
33,
35]. Responses were observed in patients with tumors harboring BRAF V600E mutations who had received prior MAPK-targeted therapy. Finally, the median time to response was 2.8 months according to RANO-HGG criteria [
33,
35], which is shorter in comparison to MEK inhibitors [
25] and may have beneficial impact on the functional outcomes of patients.
The promising tovorafenib activity, manageable safety profile, oral availability, once weekly (QW) dosing as well as strong scientific rationale are the basis for the ongoing LOGGIC/FIREFLY-2 trial. The purpose of this trial is to evaluate the efficacy, safety, and tolerability of oral tovorafenib monotherapy versus SoC intravenous chemotherapy in patients with pLGG harboring an activating
RAF alteration requiring first-line systemic therapy. The primary efficacy endpoint, ORR, will be evaluated for tovorafenib versus SoC chemotherapy as determined by an IRC using RANO-LGG criteria [
36]. In addition, PFS will be a key secondary endpoint tested in a hierarchical manner following ORR for the final assessment of efficacy. Importantly, this study also includes endpoints to evaluate improvements in neurologic outcomes, visual function in patients with optic pathway glioma (OPG), and patient-reported outcomes to better describe the overall impact on patients’ lives and activities of daily living. Lastly, independent of this trial, tumor material will be submitted to the molecular platform LOGGIC Core BioClinical Data Bank [
37], by sites participating in this parallel study, to explore the identification of prognostic and predictive molecular biomarkers including the recently described MAPK inhibitor sensitivity score [
38].
Discussion
Patients with pLGG are in need of alternative, effective treatments with less toxicity, deeper and more durable activity and importantly, better neurologic, visual, and patient-reported outcomes. In the registrational arm (Arm 1) of the phase 2 FIREFLY-1 trial evaluating tovorafenib in pediatric patients with pLGG, rapid responses were observed with a median time to response of 2.8 months (RANO-HGG), 5.5 months (RAPNO-LGG [pending adjudication]) and 4.2 months (RANO-LGG), as of a December 22, 2022 data cutoff. Overall response rates of 67% (RANO-HGG, confirmed complete response [cCR] or partial response [PR], includes three unconfirmed partial responses [uPRs]), 51% (RAPNO-LGG, cCR, PR or minor response [MR] [pending adjudication], includes four uPR and four unconfirmed MR [uMR]), and 49% (RANO-LGG, cCR, PR or MR, includes eight uPR and two uMR) were observed with a clinical benefit rate of 93% (RANO-HGG, cCR, PR or stable disease [SD]), 87% (RAPNO-LGG, cCR, PR, MR or SD [pending adjudication]) and 83% (RANO-LGG, cCR, PR, MD or SD) [
33]. No difference in response rate was noted for patients that had previously been treated with MAPK pathway inhibitors. Furthermore, of 136 patients treated in Arms 1 and 2 (safety analysis set), only five discontinued treatment due to AEs (of those, four were treatment related); 39 required dose reductions or treatment interruptions due to treatment-related AEs [
33,
35].
The promising phase 2 tovorafenib activity data in combination with the tolerability and safety of this oral monotherapy in patients with pLGG led to the decision of the SIOPe-BTG LGG WG to nominate tovorafenib for a comparison with SoC chemotherapy in the first-line phase 3 trial. This resulted in a collaboration with Day One Biopharmaceuticals who became the sponsor of the LOGGIC/FIREFLY-2 trial. Pediatric oncology drug development is hampered by many hurdles and challenges, especially in pediatric neuro-oncology, and the collaboration between an academic group and a biopharmaceutical company as in the LOGGIC/FIREFLY-2 trial accelerates accessibility of innovative drugs for children with cancer and at the same time provides opportunities for the scientific advancement of the field [
45].
In the context of pLGG being a chronic disease, in addition to radiologic responses, functional endpoints such as neurologic outcomes, visual function in OPG, and patient-reported outcomes are of extreme importance and will be assessed throughout this study. As this is a registrational trial, the primary efficacy endpoint in this study is based on RANO-LGG criteria, the same criteria used in registrational study CDRB436G2201 (NCT02684058) of dabrafenib in combination with trametinib in pediatric patients with pLGG harboring a BRAF V600 mutation [
36,
46]. Radiologic response will also be measured by RAPNO-LGG criteria [
41] as a secondary endpoint; data from this trial will contribute towards the clinical validation of the existing RAPNO working group consensus recommendations.
Although not in the study protocol, tissue can be sent from participating sites for molecular profiling via the LOGGIC Core BioClinical Databank [
37]. This will not only confirm the mandatory activating
RAF alterations but will also allow for exploration and correlation of complex biomarkers based on RNA sequence analysis and clinical outcomes. To this aim, a novel MAPK inhibitor sensitivity score was recently developed to guide biomarker driven future trials, such as those investigating relapse and/or combination therapy [
38].
The ongoing LOGGIC/FIREFLY-2 trial will determine how the promising phase 2 activity data in combination with the tolerability and safety of tovorafenib will translate when compared with SoC chemotherapy in the first-line treatment setting [
47]. Compared with most currently applied chemotherapy regimens, which require in-clinic intravenous treatment, patients randomized to tovorafenib will receive an oral drug that is taken at home once weekly, that is available in both tablet and a pediatric friendly oral suspension that can be also given via a nasogastric or gastric tube, allowing continuation of daily activities such as attending school. For future patients, the efficacy and safety data generated from this study can potentially address the unmet clinical need in the treatment of pLGG and aims at defining the new SoC treatment for this disease in a global effort.
Declarations
Ethics approval and consent to participate
The study was conducted in compliance with ICH Good Clinical Practice guidelines and ethical principles described in the Declaration of Helsinki. The study protocol and all amendments were reviewed by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for each participating study center. Study centers as of Sept. 6, 2023 include: Perth Childrens Hospital (Nedlands, Australia), Sydney Children’s Hospital (Randwick, Australia), The Royal Children’s Hospital – Children’s Cancer Centre (Parkville, Australia), Women’s and Children’s Health Network (North Adelaide, Australia), Medizinische Universität Wien (Innsbruck, Austria), Cliniques Universitaires Saint-Luc (Brussels, Belgium), Universitair Ziekenhuis Gent (Ghent, Belgium), Centre Hospitalier de l’Université Laval et Centre Mère-Enfant Soleil (Québec, Canada), CHU Sainte-Justine (Québec, Canada), The Montreal Children’s Hospital (Québec, Canada), Fakultní nemocnice Brno—Dětská, Nemocnice (Brno, Czechia), Motol University Hospital (Prague, Czechia), Rigshospitalet (Copenhagen, Denmark), Tampereen Yliopistollinen Sairaala (Tampere, Finland), Hôpital de le Timone (Marseille, France), Institut Curie (Paris, France), Charite Universitätsmedizin Berlin (Berlin, Germany), Evangelische Klinikum Bethel (EvKB) (Bielefeld, Germany), Universitätsklinikum Hamburg-Eppendorf (Hamburg, Germany), Universitätsklinikum Heidelberg (Heidelberg, Germany), Universitätsklinikum Erlangen (Ulm, Germany), Aghia Sofia General Children’s Hospital (Athens, Greece), Athens General Children’s Hospital (Athens, Greece), Semmelweis Egyetem Tűzoltó utcai ll. Sz. Gyermekgyógyászati Kliniká (Budapest, Hungary), Prinses Máxima Centrum Kinderoncologie (Utrecht, Netherlands), Starship Paediatric Blood & Cancer Center (Grafton, New Zealand), Seoul National University Hospital (Seoul, South Korea), Severance Hospital, (Seoul, South Korea), SingHealth Group—KK Women’s and Children’s Hospital (Singapore), Univerzitetni Klinini Center Ljubljana (Ljubljana, Slovenia), Hospital Universitari Vall d’Hebrón (Barcelona, Spain), Hospital Sant Joan de Déu Barcelona (Barcelona, Spain), Hospital Infantil Universitario Niño Jesús (Madrid, Spain), Hospital Universitario Virgen del Rocío (Sevilla, Spain), Hospital Universitari I Politècnic La Fe (Valencia, Spain), Astrid Lindgrens Barnsjukhus Solna (Stockholm, Sweden), Centre Hospitalier Universitaire Vaudois Lausanne (Lausanne, Switzerland), Universitaets—Kinderspital Zürich (Zürich, Switzerland), Ann & Robert H. Lurie Childrens Hospital of Chicago, (Illinois, United States), Arnold Palmer Hospital for Children (Florida, United States), Children’s Hospital Colorado (Colorado, United States), Children’s Hospital Los Angeles (California, United States), Childrens National Medical Center (The District of Columbia, United States), Dana-Farber Cancer Institute (Massachusetts, United States), Duke Cancer Institute (North Carolina, United States), New York University Langone Health (New York, United States), Phoenix Children’s Hospital (Arizona, United States), Riley Hospital for Children at Indiana University Health (Indiana, United States), St. Louis Childrens Hospital (Missouri, United States), Texas Children’s Hospital (Texas, United States), University of Michigan – C.S. Mott Children’s Hospital (Michigan, United States), University of Rochester (New York, United States), and University of Texas Southwestern Medical Center (Texas, United States). Written, informed consent/pediatric assent will be obtained by the investigator and designated site staff and withdrawal of consent/assent will be available at all times during the study.
Competing interests
The authors wish to declare the following competing interests: C.M.vT has participated in advisory boards for Novartis, Bayer, and Alexion. L.B.K has received consulting fees from Blueprint Medicine and contracted research from Novartis, Regeneron Pharmaceuticals, Day One Biopharmaceuticals, Spring Works Therapeutics, Bristol Myers Squibb, and SonALAsense and also is a stock shareholder at Onconova Therapeutics. S.P has participated in advisory boards for Bayer, Alexion, and Esai and received research support from Novartis, Bayer, and Roche. A.A.A has participated in an advisory board for Alexion and received travel and scientific grants from Alexion. M.Z has participated in an advisory board for AstraZeneca. K.S has participated in advisory boards for Alexion, Servier, Jazz Pharmaceuticals, Novartis, Roche, Bayer, and NovoNordisk. A.S has participated in advisory boards for Alexion, AstraZeneca Rare Disease, and Day One Biopharmaceuticals. E.O has participated in an advisory board for Alexion/AstraZeneca Rare Disease. P.HD has participated in an advisory board and consultancy for Alexion. D.S.Z has received consulting fees from Bayer, AstraZeneca, Accendatech, Novartis, Day One Biopharmaceuticals, FivePhusion, Amgen, Alexion, and Norgine and also received research support from Accendatech. D.C is a co-founder and shareholder for Heidelberg Epignostix GmbH and receives royalties for sale of BRAF V600E specific antibody VE1. F.S has received honoraria from Bayer and Illumina and is a co-founder and shareholder for Heidelberg Epignostix GmbH. J.Q, L-P.T, S.C.B, and P.M are all employees of Day One Biopharmaceuticals and have received Day One Biopharmaceuticals stock and stock options. T.M has received research grants from Day One Biopharmaceuticals and Biomed Valley Discovery. D.T.W.J is a co-founder and shareholder for Heidelberg Epignostix GmbH. D.H has participated in advisory boards for Alexion/AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Day One Biopharmaceuticals, Janssen, Novartis, and Roche and also received research grants from Alexion/AstraZeneca and Roche. O.W has participated in advisory boards for Novartis, Janssen, Roche, Bristol Myers Squibb, and AstraZeneca and also received research grants from Day One Biopharmaceuticals, Biomed Valley Discovery, Bristol Myers Squibb, Syndax, and PreComb. The following authors have no competing interests to declare: R.S, O.C, A. Y. N. SvM, S.A, A.K, and R.W.
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