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Hopp Children's Cancer Center (KiTZ), Heidelberg, GermanyHeidelberg University Hospital, Heidelberg, GermanyGerman Cancer Research Center, Heidelberg, Germany
Antwerp University Hospital, Antwerp, BelgiumPaediatric Committee of the European Medicines Agency, (EMA), NetherlandsFederal Agency for Medicines and Health Products, Brussels, Belgium
Mitogen-activated protein kinase pathway is an important target in glioma, Langerhans cell histiocytosis, neurofibroma and leukaemia
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Mitogen-activated protein kinase inhibitors can address many unmet needs and have demonstrated activity
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Combination development and monotherapy optimisation is required
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New clinical/functional end-points should be agreed prospectively with regulators
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Inclusion in front-line studies and generating regulatory data are priorities
Abstract
As the mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers, it is an important therapeutic target. Currently, a range of targeted MAPK pathway inhibitors are being developed in adults. However, MAPK signals through many cascades and feedback loops and perturbing the MAPK pathway may have substantial influence on other pathways as well as normal development. In view of these issues, the ninth Paediatric Strategy Forum focused on MAPK inhibitors.
Development of MAPK pathway inhibitors to date has been predominantly driven by adult indications such as malignant melanoma. However, these inhibitors may also target unmet needs in paediatric low-grade gliomas, high-grade gliomas, Langerhans cell histiocytosis, juvenile myelomonocytic leukaemia and several other paediatric conditions. Although MAPK inhibitors have demonstrated activity in paediatric cancer, the response rates and duration of responses needs improvement and better documentation. The rapid development and evaluation of combination approaches, based on a deep understanding of biology, is required to optimise responses and to avoid paradoxical tumour growth and other unintended consequences including severe toxicity. Better inhibitors with higher central nervous systempenetration for primary brain tumours and cancers with a propensity for central nervous system metastases need to be studied to determine if they are more effective than agents currently being used, and the optimum duration of therapy with MAPK inhibition needs to be determined.
Systematic and coordinated clinical investigations to inform future treatment strategies with MAPK inhibitors, rather than use outside of clinical trials, are needed to fully assess the risks and benefits of these single agents and combination strategies in both front-line and in the refractory/relapse settings. Platform trials could address the investigation of multiple similar products and combinations. Accelerating the introduction of MAPK inhibitors into front-line paediatric studies is a priority, as is ensuring that these studies generate data appropriate for scientific and regulatory purposes. Early discussions with regulators are crucial, particularly if external controls are considered as randomised control trials in small patient populations can be challenging.
Functional end-points specific to the populations in which they are studied, such as visual acuity, motor and neuro psychological function are important, as these outcomes are often more reflective of benefit for lower grade tumours (such as paediatric low-grade glioma and plexiform neurofibroma) and should be included in initial study designs for paediatric low-grade glioma. Early prospective discussions and agreements with regulators are necessary.
Long-term follow-up of patients receiving MAPK inhibitors is crucial in view of their prolonged administration and the important involvement of this pathway in normal development.
Further rational development, with a detailed understanding of biology of this class of products, is crucial to ensure they provide optimal benefit while minimising toxicity to children and adolescents with cancer.
Activating somatic mutations of the mitogen-activated protein kinase (MAPK) pathway are frequently associated with paediatric tumours and malignancies where there are currently unmet needs [
The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy.
Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa study.
A phase I and pharmacokinetic study of oral dabrafenib in children and adolescent patients with recurrent or refractory BRAF V600 mutation-positive solid tumors.
Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.
], but definitive activity in other paediatric tumours has not been clearly demonstrated. The complexity and differences in the (epi)genomic landscape of different childhood tumours likely predict this variation in response to MAPK pathway (RAS, MEK, ERK) inhibition with targeted agents [
In view of the importance of the MAPK pathway in paediatric tumours and malignancies and the number of targeted pathway inhibitors currently being evaluated in adults and children, it was considered timely to hold a Paediatric Strategy Forum to focus on the role of these inhibitors in children. The Forum was organised by ACCELERATE [
] in collaboration with the European Medicines Agency (EMA) with the participation of the Food and Drug Administration (FDA) and built on the format and ethos of previous Forums aiming to evaluate science, facilitate dialogue and share information [
ACCELERATE and European medicines agency paediatric strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.
Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.
Second paediatric strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies ACCELERATE in collaboration with the European medicines agency with the participation of the Food and drug administration.
Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.
The Paediatric Strategy Forum focused on the key issues in the ongoing development of inhibitors of the MAPK pathway in paediatric oncology. Specifically, it addressed: (i) What are the unmet needs with existing MAPK pathway inhibitors?; (ii) How to better utilise existing MAPK pathway inhibitors (duration, schedule, alone or in combinations)?; (iii) What are the best endpoints for MAPK pathway inhibitor trials for different indications?; (iv) Can predictive biomarkers for treatment response and resistance be identified to answer these questions and answers? The Forum also highlighted the crucial importance of formulation and different pharmacokinetic and pharmacodynamic properties, including central nervous system (CNS) penetration and short- and long-term toxicities of these targeted agents.
The meeting was held virtually on 28 and 29 March 2022 with 206 participants: 98 international paediatric oncology experts from Europe, US, Canada, Australia, South America, Japan and India; 47 representatives from ten pharmaceutical companies in Europe and the US (Alexion/AstraZeneca, BioMed Valley Discoveries, Boehringer-Ingelheim, Day One Biopharmaceuticals, Merck & Co., Inc. Rahway, NJ, USA, Novartis¸ Pierre Fabre, Roche, SpringWorks Therapeutics); 14 patient advocates from Europe, the US and Canada (representatives from Andrew McDonough B+ Foundation, Children's Cancer Cause, Coalition Against Childhood Cancer, HistioCure Foundation, Histiocytosis Association, Imagine for Margo, NGO Karkinaki Awareness for Childhood and Adolescent Cancer, Paediatric Brain Tumour Foundation, Solving Kids' Cancer, Solving Kids' Cancer UK, Swedish Childhood Cancer Fund, Zoé4life and Childhood Cancer International–Europe); 25 regulators from the EMA (including the Paediatric Committee [PDCO]) and national competent authorities within the EU regulatory network, European Health Technology Assessment [HTA] bodies, US FDA and Health Canada as observers; the ACCELERATE Operations Coordinator. An overview of the biology of the MAPK pathway and a review of the current trials, plans and unmet needs in pLGG, pHGG, LCH and leukaemia were presented by academic experts. The details of seventeen inhibitors of the MAPK pathway were presented by industry representatives. The Forum concluded with the patient advocate perspectives and a multi-stakeholder strategic discussion.
2. Biology of the MAPK pathway
The MAPK signalling cascade is commonly altered in cancer and is crucial in normal development [
]. MAPK signalling also impacts many other pathways and feedback loops, especially the PI3K/AKT/mTOR pathway (Fig. 1). Therefore, perturbing the MAPK pathway may have substantial influence on other pathways.
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.
]. Neurofibromatosis type 1 (NF1), the most frequent hereditary cancer predisposition syndrome associated with MAPK pathway activation, is a genetic disease characterised by having a heterozygous pathogenic NF1 variant [
pLGG is an example of a disease of aberrant MAPK signalling with BRAF being the most frequently altered gene. In most tumours, there is only one driver event, which is most commonly a structural variant that leads to pathway activation; less frequently, oncogenic BRAF point mutations occur [
]. The most common BRAF rearrangement results in loss of the N’ terminal negative regulatory domain and replacement by another gene, most commonly KIAA1549, with the fused gene resulting in an activated BRAF kinase [
]. The next most frequent alteration is the BRAFV600E hotspot mutation which results in constitutive activation of the BRAF kinase. Alterations in the FGFR family represent the second most common group of somatic alterations and affect FGFR1 or FGFR2 [
]. Alterations in the FGFR1 gene include tandem duplications, point mutations and fusions. Tumours with FGFR1 point mutations frequently have co-occurring point mutations that are predicted to activate the MAPK or mTOR signalling pathway, which often include PTPN11, PIK3CA or loss-of-function NF1 alterations. In addition, oncogene-induced senescence (robust and sustained antiproliferative response brought about by oncogenic signalling resulting from an activating mutation of an oncogene, or the inactivation of a tumour-suppressor gene [
]) and its associated secretory phenotype, as well as the tumour microenvironment, are important modulators of tumour growth, behaviour and response to therapy.
Kinase inhibitors have been successful in the therapy of malignant melanoma, including BRAF, MEK and ERK inhibitors targeting the MAPK pathway; PI3K, AKT or mTOR inhibitors targeting the PI3K pathway and some newer FGFR inhibitors are in development [
]. However, it is essential to understand the biology of these oncogenic pathways, as there are risks of paradoxical signalling activation via feedback loops with targeting of some nodes. For example, preclinical studies of BRAF V600E-mutated pLGG cell lines treated with a type 1 BRAF inhibitor are effective in switching off MAPK signalling, while treatment with the same BRAF inhibitor in BRAF KIAA1549-rearranged cells can cause paradoxical pathway activation and an increase in cell growth [
]. Paradoxical activation of MAPK signalling led to unexpected tumour growth in a clinical trial evaluating the kinase inhibitor sorafenib for children with pLGGs, leading to early termination of the clinical trial [
The highly conserved MAPK pathway plays a critical role in the regulation of normal development across a large range of cell and tissue types, including (but not limited to) placental development, immune differentiation, angiogenesis, cardiovascular development and neurogenesis [
]. Conversely, the loss of MEK1 is embryonic lethal due to anomalies in placental development, while the combined loss of MEK1 and MEK2 is also incompatible with postnatal survival, with effects across several tissues. Similarly, the loss of specific RAS and RAF isoforms in knock-out mice are also associated with an array of developmental defects [
]. While the effects of MAPK signalling in development have been widely evaluated, the sequelae of MAPK inhibition and thus long-term effects on childhood development remain unknown.
In summary: (i) the MAPK pathway is one of the most commonly altered pathways across childhood cancers; (ii) drugs targeting different components of the pathway may enable precision medicine approaches; (iii) a deeper understanding of the biology of the pathway is required to prevent potential for paradoxical cancer cell growth and to select the patient populations most likely to benefit from treatment and to avoid toxicity.
2.1 MAPK pathway inhibitors in pLGG
Approximately 3500 patients present with pLGG per year in North America and Europe. Currently, 90% of these patients survive with 50% cured by surgery alone [
]. However, the 5-year progression-free survival (PFS), after chemotherapy, is less than 50% with many patients receiving multiple lines of therapies in an attempt to avoid radiotherapy and associated substantial long-term sequelae [
A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - a final report.
Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low-grade glioma patients-Report from the German SIOP-LGG 2004 cohort.
]. pLGG is one of the six paediatric malignancies in the World Health Organisation Global Childhood Cancer Initiative to be addressed to save one million lives of children with cancer by 2030 [
]. The current unmet needs in pLGG are to minimise morbidity and to maximise quality of life by replacing chemotherapy with presumably less toxic, more effective targeted therapy. In addition to overall survival and PFS, new clinical end-points have also been proposed by international cooperative groups for inclusion in trial designs. These include visual acuity, quality of life, motor and neuropsychological functioning since the majority of these children will survive well into adulthood yet may suffer significant risk for reduced quality of life and compromise function in these realms. The ongoing and completed trials of inhibitors of the MAPK pathway in pLGG are shown in Table 1, Table 2. The inhibition of MEK results in partial responses (≥50% tumour reduction by RANO criteria) in 30–40% of recurrent pLGG [
Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.
A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study.
Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa study.
]. A randomised trial in BRAF V600–mutant pLGG has demonstrated superior overall response rate, clinical benefit rate and median PFS with dabrafenib and trametinib compared to carboplatin and vincristine [
]. However, not all patients remain in continuous partial response after stopping therapy and tumour rebound may occur following treatment cessation. Both better inhibitors, with, for example, higher CNS penetration and better combination therapies, are likely required to drive deeper and more durable responses. However, inhibitors with higher CNS penetration need to be studied to determine if they are more effective than agents currently being used. In addition, tumour microenvironmental factors including senescence-related pathways likely modulate treatment response to MAPK inhibitors and may provide opportunities for novel single agent and combination therapies [
], most clearly depicted in the difference between those pLGG arising in patients with NF1 compared to the rest of the population. This molecular heterogeneity demands that predictive biomarkers are discovered and understood to better select specific patients for tailored therapy. Understanding rebound and resistance are key future goals. At present, the optimal duration of therapy is unknown with response persisting in some patients after drug discontinuation whilst others experience tumour regrowth or progression. The current pragmatic approach is to treat clinical benefit until loss of clinical benefit or for a certain specific duration (typically approximately 2 years) and then stopping therapy. In view of the prolonged administration, the involvement of this pathway in normal development and the life expectancy of patients into adulthood, a better understanding of the late effects of patients receiving MAPK inhibitors is required. Ancillary and integrated biological studies will hopefully allow the understanding of which patients require further therapy. Currently, there are several studies open or in the late stages of planning for both newly diagnosed and recurrent pLGG and completed studies (Table 1, Table 2). For the future, an industry-supported, academic-sponsored international platform trial that provides clinical trial data that can be used for licensing purposes and with early input from regulators, could address the investigation of multiple similar products and combinations in small patient populations. Within the same overall trial structure, products from different pharmaceutical companies and different mechanisms of action could be evaluated using an adaptive design and products for further evaluation could be identified.
Table 1Summary of ongoing trials in newly diagnosed/recurrent pLGG with MAPK pathway inhibitors.
A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients with Neurofibromatosis and Low-Grade Glioma - https://clinicaltrials.gov/ct2/show/NCT03871257. (Accessed 6 September 2022).
A Study to Evaluate DAY101 in Pediatric and Young Adult Patients with Relapsed or Progressive Low-Grade Glioma (FIREFLY-1). https://clinicaltrials.gov/ct2/show/NCT04775485. (Accessed 6 September 2022).
A Trial of Dabrafenib, Trametinib and Hydroxychloroquine for Patients with Recurrent LGG or HGG with a BRAF Aberration. https://clinicaltrials.gov/ct2/show/NCT04201457. (Accessed 6 September 2022).
A Study to Compare Treatment with the Drug Selumetinib Alone Versus Selumetinib and Vinblastine in Patients With Recurrent or Progressive Low-Grade Glioma - https://clinicaltrials.gov/ct2/show/NCT04576117. (Accessed 6 September 2022).
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) - https://clinicaltrials.gov/ct2/show/NCT03155620. (Accessed 6 September 2022).
Trametinib and Everolimus for the Treatment of Pediatric and Young Adult Patients with Recurrent Low Grade Gliomas (PNOC021) - https://clinicaltrials.gov/ct2/show/NCT04485559. (Accessed 6 September 2022).
Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.
Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects with Cancer or Plexiform Neurofibromas and Trametinib in Combination with Dabrafenib in Subjects with Cancers Harboring V600 Mutations. https://clinicaltrials.gov/ct2/show/NCT02124772. (Accessed 6 September 2022).
Approximately 1150 patients present each year in North America and Europe with pHGG. Similar to pLGG, the classification of pHGG is evolving with inclusion of molecular data rather than simple morpholohistological grading [
]. BRAF V600E mutations occur in approximately 6% of pHGG (70 patients per year in Europe and North America) (mostly midline or hemispheric tumours) and confer a better prognosis [
]. The current unmet needs in BRAF-mutated pHGG are to identify more effective therapies that would increase survival and in the long-term, ultimately, to reduce or avoid radiation therapy entirely. In one study, BRAF inhibition with dabrafenib resulted in a maximum tumour reduction of ≥50% in 68% of patients with pHGG, but this was of short duration (median PFS 7.4 months) [
Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa study.
Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma. https://clinicaltrials.gov/ct2/show/NCT03919071. (Accessed 6 September 2022).
A Trial of Dabrafenib, Trametinib and Hydroxychloroquine for Patients with Recurrent LGG or HGG with a BRAF Aberration. https://clinicaltrials.gov/ct2/show/NCT04201457. (Accessed 6 September 2022).
]]). In newly diagnosed and recurrent pHGG, there has been a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated off-label with BRAF inhibitors with or without MEK inhibitors, confirming activity [
]. Responses were observed and the authors concluded that adjuvant randomised trials of BRAF inhibitors in adult and paediatric low-grade and high-grade gliomas were needed. Similarly to LGG, inhibitors with higher CNS penetration need to be evaluated. The key future focus is to improve overall survival of these patients by determining optimal inhibitor combinations and ascertain if treatment response/resistance [
]. In a condition where previously effective medical therapies were lacking, treatment with the MEK inhibitor, selumetinib, has resulted in 68% of patients achieving a confirmed partial response (tumour volume decreases from baseline of ≥20% by volumetric analysis of the MRI); 82% of these having a durable response (>1 year). The median time to initial response is 8 cycles (32 weeks) (range, 4 to 20) with a median time to best response being 16 cycles (range, 4 to 36) [
]. Selumetinib (Koselugo®) as monotherapy is indicated for the treatment of paediatric patients 2 years of age and older in the United States (and 3 years of age and older in the European Union) with NF 1 who have symptomatic, inoperable plexiform neurofibromas [
NF106: a neurofibromatosis clinical trials Consortium phase II trial of the MEK inhibitor mirdametinib (PD-0325901) in adolescents and adults with NF1-related plexiform neurofibromas.
]. The current unmet needs are to increase the number of patients who achieve partial response (as defined above), to obtain greater tumour volume reduction (as currently there are very few tumours which shrink more than 30%), to make responses more durable (most tumours regrow after stopping treatment), and to define schedules, e.g. intermittent dosing that reduce toxicity while maintaining efficacy with improved functional and quality of life outcomes, e.g. motor function and tumour-related pain. MAPK, including KRAS inhibitors, with better safety and efficacy profiles, used as monotherapy or in combination may also have a role.
2.4 MAPK pathway inhibitors in LCH
Approximately 800 children present each year in North America, Europe and Australia with LCH, which is similar in incidence to paediatric Hodgkin lymphoma and AML. LCH is therapeutically classified either as low-risk single system, low-risk multisystem and high-risk multisystem disease (classically involving spleen, bone marrow and/or liver) with response to initial chemotherapy guiding further treatment for patients with multi-focal disease [
] but disease eradication is achieved in <50% of patients with front-line therapy, and further attempts at curative therapy result in increased risk of morbidity and mortality [
]. LCH-neurodegenerative syndrome (dysarthria, dysmetria, learning and behaviour difficulties, and brain MRI changes) occurs in 5–10% of patients and currently does not have an effective therapy [
]. Conversely, some patients with low-risk disease may be over treated with conventional chemotherapy. The current unmet needs are to eliminate the risk of death in high-risk patients, improve treatment efficacy, reduce morbidity from treatment failure and/or chronic therapy and prevent and/or effectively treat LCH-neurodegenerative syndrome. Activating somatic MAPK pathway mutations are identified in almost all cases of LCH, with BRAF V600E as the most common, followed by activating mutations in MAP2K1 (which encodes MEK1). Alternative BRAF mutations, tyrosine kinase receptor gene mutations and ARAF mutations have also been reported [
] and additional or combination therapy is likely needed to eradicate subsets of mutated cells. A combination of BRAF and MEK inhibitors (trametinib with dabrafenib) has been evaluated [
Whitlock JA, Geoerger B, Roughton M, Choi J, Osterloh L, Russo M et al. Dabrafenib, alone or in combination with trametinib, in Pediatric patients with BRAF V600 mutation-positive Langerhans cell histiocytosis https://ashpublications.org/blood/article/138/Supplement201/3618/479771/ (Accessed 6 September 2022).
]. New therapeutic approaches are needed for three situations: high-risk disease, LCH–neurodegenerative syndrome and low-risk recurrent LCH. A possible therapeutic schema is initial treatment with MAPK pathway inhibition, then chemotherapy followed by further MAPK pathway inhibition. The optimum duration of therapy with MAPK inhibition needs to be determined. There is a need for the systematic development of treatment strategies including MAPK inhibitors rather than the current widely spread off-label use in order to assess the risks and benefits of various agents and combination strategies for front-line and salvage settings. An intercontinental trial in high-risk disease could generate knowledge. Given the current evidence, it is crucial that MAPK inhibitors move forward into front-line and studies are appropriately designed and conducted to generate data suitable to support regulatory evaluation and approval.
2.5 MAPK pathway inhibitors in leukaemia
Approximately 150 children present each year in North America and Europe with JMML, where an excessive production of the monocytes infiltrate other organs including the spleen, liver, lung and gastrointestinal tract. Currently, allogeneic haematopoietic stem cell transplant is considered the only curative treatment and is usually delivered following antecedent chemotherapy for cytoreduction and disease control. Virtually, all patients with JMML have a MAPK pathway mutation [
]), 5 of 10 patients enrolled have had an objective response (1 complete response, 4 partial responses) and 2 patients have had prolonged stable disease [
]. However, no molecular responses as evidenced by decreased RAS pathway mutational burdens have been recorded in treated patients. A subsequent trial in North America, TACL2020-004, (in planning) will risk-stratify patients with newly diagnosed JMML to therapy based on genotyping and methylation analysis. Lower-risk patients [1 mutation and low DNA methylation] will receive azacitidine and trametinib. Higher-risk patients [>1 mutation and intermediate or high methylation] will receive azacitidine and trametinib, chemotherapy and allogeneic transplant. If successful, this approach may allow for a paradigm shift in ‘definitive therapy’ for these children with high-risk disease.
In acute lymphoblastic leukaemia, the most common childhood cancer, 30–50% of children have a subclonal mutation in the MAPK pathway [
]. RAS mutations can appear or disappear from diagnosis to relapse, and their prognostic significance remains unknown. Patients with RAS mutations have a higher risk/incidence of CNS relapse, so this is an area of medical need. The ongoing SeluDex trial (NCT03705507) [
International Trial of Selumetinib in Combination with Dexamethasone for the Treatment of Acute Lymphoblastic Leukaemia (SeluDex). https://clinicaltrials.gov/ct2/show/NCT03705507. (Accessed 6 September 2022).
] is evaluating the role of MEK inhibition with selumetinib in combination with dexamethasone in relapsed or refractory acute lymphoblastic leukaemia [
International Trial of Selumetinib in Combination with Dexamethasone for the Treatment of Acute Lymphoblastic Leukaemia (SeluDex). https://clinicaltrials.gov/ct2/show/NCT03705507. (Accessed 6 September 2022).
Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial.
]. Recruitment to this trial has proven challenging in the present era of available chimeric antigen-receptor T-cell therapy, commercially or clinical trials [
Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial.
]; however, responses have been noted and the early reports show reasonable tolerability and feasibility. Finally, 43% of paediatric patients with AML have a MAPK pathway mutation at diagnosis [
]. It has been reported that RAS mutation variant allele frequency often increases at relapse, suggesting a role as a driver or disease modifier. Combination approaches of a MEK inhibitor and chemotherapy are under consideration for a clinical trial in children with RAS-mutant AML.
3. Products discussed at the Forum and Paediatric Investigation Plans and Written Requests
Seventeen medicinal products (selumetinib (Koselugo®), dabrafenib (Tafinlar®), trametinib (Mekinist®), vemurafenib (Zelboraf®), cobimetinib (Cotellic®), encorafenib (Braftovi®), binimetinib (Mektovi®), tovorafenib [DAY101], belvarafenib, pimasertib, ulixertinib, BI 1701963, BI 3011441, BI 1823911, GDP pan-KRAS inhibitor, mirdametinib and BGB-3245 were discussed at the Forum (Table 3).
Table 3MAPK inhibitor medicinal products discussed at the Paediatric Strategy Forum.
As of March 2022, there were 7 published Paediatric Investigation Plans (PIP) agreed for selumetinib (Koselugo®), dabrafenib (Tafinlar®) and trametinib (Mekinist®), cobimetinib (Cotellic®), encorafenib (Braftovi®) and binimetinib (Mektovi®) and tovorafenib (DAY101). Two of these PIPs are for combination therapy (dabrafenib + trametinib; encorafenib + binimetinib). The indications of the PIPs are disease-specific: melanoma with BRAF V600 mutations (n=3); thyroid cancer (n = 1); NF-1 (plexiform neurofibroma) (n = 1); glioma with BRAF V600 (n = 1); LGG with BRAF fusion (n = 1). Two indications are histology agnostic: solid tumours with BRAF V600 (1) and solid tumours with RAS/RAF/MEK pathway activation (2) (Table 4). The agreed initial PIP for vemurafenib (Zelboraf®) in adolescent patients for the treatment of melanoma was later modified into a Product Specific Waiver in all age groups in the same condition on the grounds of ‘clinical studies are not expected to be of significant therapeutic benefit to or fulfil a therapeutic need of the specified paediatric subset’ [
Malignant neoplasms (except haematologic) with Ras, Raf or MEK pathway activation
Melanoma
Melanoma
Paediatric LGG
PIP Indication
NF1 - inoperable plexiform neurofibromas Selumetinib + radioactive iodine therapy for HR differentiated thyroid cancer
Glioma with BRAF V600 mutations
Melanoma with BRAF V600 activating mutations (adolescents) Solid tumours with BRAF V600 activating mutations (children)
Melanoma with BRAF V600 activating mutations (adolescent) Solid malignant tumour with known or expected RAS, RAF or MEK pathway activation (children)
Paediatric solid malignant tumour with Ras, Raf or MEK pathway activation, R/R
Melanoma in adolescents - waiver on the grounds of “clinical studies not expected to be of significant therapeutic benefit to or fulfil a therapeutic need of the specified paediatric subset”
Encorafenib + binimetinib with unresectable or metastatic melanoma with BRAF V600 mutations (>12 y)
LGG with BRAF fusion: R/R Newly diagnosed with unresectable/sub-totally resected
Waiver
NF1: 0–1 y; Thyroid cancer: 0–12 y; Melanoma: 12–18 y
Advanced BRAF V600-mutant glioma: Open-label - safety and efficacy of dabrafenib + trametinib (1–18 y)
Melanoma & Solid tumours:
• Single agent - safety, tolerability, PK and MTD (1–18 y) in advanced BRAF V600-mutant solid tumours.
• Randomised, single dose 3-way cross-over relative bioavailability study in normal adult healthy volunteers.
Melanoma (BRAF V600-mutant): Measure (modelling and simulation) to demonstrate that PK, PD, and efficacy in adolescents (12–18 y) are similar to that in adults
Melanoma & Solid tumours:
• Open-label, single agent, dose escalation trial → safety, tolerability, PK, PD in R/R solid malignant tumours (1 mo-18 y)
• Relative bioavailability study in adults.
R/R solid tumours with Ras, Raf or MEK pathway activation: Multiple dose 2-stage trial to evaluate PK, safety and activity of cobimetinib (6 months-18 y) (GO29665/NCT02639546)
N/A
Unresectable or metastatic BRAF V600 mutant melanoma: Multicentre, open-label → PK, safety, tolerability, and preliminary evidence of activity of binimetinib + encorafenib (12–18 y)
Low-grade gliomas and other RAS/RAF/MEK/ERK pathway-activated tumours: dose finding study Relapsed or progressive low-grade gliomas harbouring BRAF fusions: open0label, single-arm trial→PK, safety, and activity of DAY101 (6m-18y) Newly diagnoses unresectable or sub-totally resected low-grade glioma harbouring BRAF fusions: randomised trial →safety and efficacy of DAY101 (6m-18y)
Patient advocates were concerned about the potential adverse developmental impact and late toxic effects of MAPK pathway inhibitors. They believed it was essential that companies, academic researchers and regulators pay particular attention to late effects on children's development as monotherapy, and especially, combination therapy trials are developed. Late effects of therapy in adults may not be considered as companies develop agents for adult malignancies, but it is essential that this risk is considered in children. Patient advocates feel a special urgency about children with brain tumours, who often already live their entire lives with neurological sequelae from disease and treatment, as their families struggle with their care both short- and long-term.
Advocates urged that researchers come together with industries and regulators, perhaps in a dedicated meeting, to create new functional outcome measures that should include neurocognitive and endocrine changes in addition to PFS. Advocates’ input in creating such measures will add considerable value.
Common challenges are emerging about how to evaluate MAPK inhibitors as research uncovers deeper biological understanding of pHGG, pLGG, LCH and leukaemia. Variability in response to MAPK inhibitors shines a spotlight on the need for biomarkers to distinguish patients whose disease will respond differently. While patient advocates understand the challenges that small patient subsets create for trial design and patient recruitment, they support novel trial designs that are more finely tuned to the biology of patients’ disease profiles, e.g. platform and tumour agnostic trials, and the proposed JMML trial in which genotyping precedes disease classification and treatment. In addition, advocates urged that no paediatric data be wasted and that clinicians analyse and make public data from off label and compassionate use that may yield fresh insights. Further, advocacy groups strongly endorsed and have helped financially support the conduct of international trials to address small patient populations, as exemplified in pLGG and LCH.
Multiple therapeutic opportunities make it even more important that tumour biology determines which agents are evaluated in children. Families and patients trust investigators and regulators, in collaboration with companies, to plan paediatric trials governed not only by what agents are available but also by the latest and best scientific insights. Any commitment to evaluating one specific therapy in a small patient population can effectively eliminate other potentially more promising opportunities for these patients.
5. General themes
5.1 Biology
Understanding specific tumour biology is critical, especially as the MAPK pathway is tightly connected to other signalling pathways. There may be unforeseen consequences if biology is not well understood, such as compensatory signalling up the regulation of alterative pathways and paradoxical tumour growth [
]. It is important to understand which feedback loops will be triggered by inhibiting one pathway and which other pathways could be co-inhibited for potentially synergistic effects. Furthermore, the importance of the MAPK pathway in normal development, especially glial differentiation, must be considered. The combinations of MAPK pathway inhibitors should be developed based on the mechanism of action, cancer biology and robust preclinical evaluation. The selection of combinations with compelling biological and clinical rationale for evaluation in children is essential given the rarity of paediatric cancers and the mismatch between the immense numbers of combinations that are available for testing compared to the number of clinical trials that can be conducted.
5.2 Trial design and regulatory considerations
Front-line academic trials of new products should be designed to generate data sufficient for regulatory decision making on benefit/risk assessment and there should be early discussion between academia, industry and regulators [
]. This is especially important if evaluating a new product is challenging in a randomised clinical trial. Trials submitted to fulfil regulatory requirements (e.g. PIPs and initial Paediatric Study Plans [iPSPs]) should be aligned with those designed prospectively by academic cooperative groups to be practice changing. With the increasing alignment between regulators in Europe and the US, there should be simultaneous regulatory submissions of individual PIPs and iPSPs to the EMA and FDA, respectively, including a suggestion for discussion at cluster calls [
Accelerating the global development of pediatric cancer drugs: a call to coordinate the submissions of pediatric investigation plans and pediatric study plans to the European medicines agency and US Food and drug administration.
Common Commentary - EMA/FDA Common issues requested for discussion by the respective agency (EMA/PDCO and FDA) concerning paediatric oncology development plans (Paediatric Investigation Plans [PIPs] and initial Pediatric Study Plans [iPSPs]). https://www.fda.gov/media/147197. (Accessed 6 September 2022).
]. Clinical trials should be designed to generate data supporting scientific, regulatory and payers (e.g. health technology assessment bodies in Europe) decision making, leading to regulatory approval with access for all children to the medicinal products.
5.2.1 Toxicity
In general, MEK inhibitors have been well tolerated with most toxicities being grade 1 and 2 with rare grade 3 and higher toxicities [
Phase 1 trial of trametinib alone and in combination with dabrafenib in children and adolescents with relapsed solid tumors or neurofibromatosis type 1 (NF1) progressive plexiform neurofibromas (PN).
LGG-52Binimetinib in children with progressive or recurrent low-grade glioma not associated with neurofibromatosis type 1: initial results from a multi-institutional phase ii study.
]. Currently, there has not been detailed comparison of the toxicity of differing MEK inhibitors, similarly data on long-term toxicity are lacking. Likewise, with BRAF inhibitors, grade 3 adverse effects are also rare and tend to be maculopapular rash, arthralgia and absence of pigment in the hair with the most frequent adverse effects being fatigue13,14,15. In a randomised trial in pLGG of dabrafenib and trametinib compared to carboplatin and vincristine, there were less grade ≥3 adverse events with dabrafenib and trametinib [
]. In the future, quality of life of patients and patient-reported outcome assessment of the MAPK pathway inhibitors need to be assessed and clearly reported. Patient-reported outcomes have been used in the paediatric oncology application to the FDAs for selumetinib [
]. Furthermore, e-patient-reported outcomes hopefully can provide more accurate reporting of adverse events and the better evaluation of impact of those that are symptomatic [
MyPal-Child study protocol: an observational prospective clinical feasibility study of the MyPal ePRO-based early palliative care digital system in paediatric oncology patients.
Long-term follow-up of patients receiving any new medicinal product is important so that survivors and their families, clinicians and regulatory agencies are informed of the long-term effects of treatment, including the potential for secondary malignancies. As the optimal duration of therapy is currently unknown and because the pathway is involved in normal development processes (especially glial differentiation), long-term follow-up assumes an even greater importance. It is crucial to know late effects which occur after five years or even longer as well as more short-term events. The ACCELERATE long-term follow-up initiative proposes an international and inter-company, harmonised and sustainable data registry of early and late adverse effects of new anti-cancer products, including MAPK pathway inhibitors [
ACCELERATE Long-Term Follow-Up Working Group. A global approach to long-term follow-up of targeted and immune-based therapy in childhood and adolescence.
]. This will provide informative data of the long-term safety to support the best use of these therapies, inform families and clinicians of the long-term effects of treatment in order to guide their decision making and support fulfilling regulatory requirements of the marketing authorisation holders.
5.4 Paediatric formulation
In view of the age of patients who may potentially benefit from MAPK pathway inhibitors and for whom prolonged administration is required, the development of oral ‘child-friendly’ formulations (especially palatable suspensions or liquid formulations) of the medicinal product that are appropriate to be administered to young children is critical.
6. Specific themes
6.1 Better use of existing MAPK pathway inhibitors
Generally, monotherapy with a MAPK pathway inhibitor will result in a clinically relevant response rate in tumours with only one molecular driver [
Phase II study of selumetinib in children and young adults with tumors harboring activating mitogen-activated protein kinase pathway genetic alterations: arm E of the NCI-COG pediatric MATCH trial.
]. However, for LCH and leukaemias, a molecular remission will likely not be obtained and when the MAPK inhibitor is discontinued, disease can recur as with pLGG and LCH. Therefore, there is a need for ‘deeper’ molecular, as well as clinical, responses. Multi-drug approaches are also required, which may be via combination with another MAPK inhibitor or, targeted agent, with chemotherapy. In other situations, where there are multiple mutations (e.g. pHGG with BRAFV600E and other mutations), MAPK inhibitors result in a 60–70% short duration response, after which resistance occurs. Studies are being carried out of combinations with BRAF and MEK inhibitors, and the results of these are awaited. In the absence of adult data, the design of such trials would be optimised if there were a randomised comparison between monotherapy and combination therapy rather than a retrospective comparison of response rates (e.g. the ROAR trial of dabrafenib plus trametinib in adult patients with BRAFV600E-mutant low-grade and high-grade glioma; NCT0203411 [
Dabrafenib plus trametinib in patients with BRAF V600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial.
]). To accelerate drug development cross-company, cross-product combined analyses of toxicity would be invaluable.
Generally, MAPK inhibitors with higher CNS penetration are preferred for diseases affecting the brain, e.g. CNS tumours or metastatic disease to the brain from other cancers, and this is an important attribute of any inhibitor. Better brain penetration should reduce peripheral toxicity, as less systematic exposure is required to deliver sufficient drug to the brain/target tissue. The theoretical concern that higher CNS penetrance will lead to a greater incidence of CNS adverse events must be monitored. The width of the therapeutic window will depend on the magnitude of oncogene addiction of the tumour cells to aberrant MAPK signalling versus normal cells. However, MAPK inhibitors which have a higher CNS penetrance need to be studied to determine if they are more effective than agents currently being used. As it is not possible to define the optimal biological dose in CNS tumours due to the inability to biopsy tumour tissue for pharmacodynamic assessment, dose escalation strategies should ideally target the pharmacokinetically defined exposure obtained in adults or, if that is not feasible, the maximum tolerated dose. Furthermore, it is conceivable that therapeutic plasma levels may vary according to tumour types, particularly between extra- and intra-cranial tumours. Pharmacodynamic and pharmacokinetic studies should be undertaken with the objective of relating these parameters to both efficacy and toxicity.
The optimal duration of therapy is currently unknown, may differ in different disease types and clinical evidence demonstrates that some patients relapse whilst others do not after discontinuation of therapy. It is proposed that patients are treated for an empirical duration from the best response or start of treatment and then treatment is discontinued. Ancillary biological studies must be integrated into trials to understand the heterogeneity in biology, monitor development of mutations and to inform rational duration of treatment and potential for development of resistance. Alternative approaches could be intermittent dosing or integrating other therapeutic modalities.
6.2 Best endpoints for MAPK pathway inhibitor trials for different diseases
In the tumour entities where MAPK inhibitors are being currently evaluated, there is a need to include additional end-points to overall survival and PFS. The number of patients in whom the cancer recurs after the discontinuation of therapy and the patterns of recurrence should also be captured. With CNS tumours, especially pLGG, visual function, quality of life, patient reported outcomes, motor function and neuropsychological functioning are invaluable and important endpoints in the evaluation of innovative therapies. For these end-points to be considered by regulators, early discussions with regulatory agencies are required, involving academia, industry and patient advocates. A further challenge is defining appropriate end-points in LCH, particularly LCH-neurodegenerative syndrome.
6.2.1 Identifying the optimal MAPK inhibitors and combinations
There are a range of inhibitors of the MAPK pathway, including: type 1 RAFV600, type 2 pan-RAF, MEK1, MEK1/2, ERK1/2, SOS1, KRASG12C0 and pan-KRAS. Clinical trials need to be designed very carefully to ensure robust data are obtained regarding the optimal agents to take forward. For example, the benefits and role of ERK1/2 inhibitors require clarification. New generation BRAF inhibitors are very promising but clinical data are very early and in small numbers of patients. The theoretical benefits of type 2 pan-RAF inhibitors compared to type 1 monomeric inhibitors have been postulated and demonstrated non-clinically, but they have not yet been confirmed in clinical trials. Peer-reviewed articles are eagerly awaited describing efficacy and toxicity.
6.3 Coordination of evaluation of products in development
With an increasing number of MAPK pathway inhibitors under or entering clinical evaluation with the intention of regulatory submissions, but a relatively small potential paediatric population with RAS/MAPK pathway-mutant diseases, international coordination is required to develop a strategy to identify the most effective drugs for children. The general proposed regulatory strategy, where there are multiple products of the same class, is that there is a consolidated agreement by industry and academia regarding which product or products, based on current evidence, is considered to have the highest potential to address unmet medical needs and minimises toxicity. This product(s) should then be advanced into paediatric development and submitted for regulatory approval, usually as part of PIP or iPSP, without delay (i.e. without a deferral). Part of this prioritisation discussion, however, also includes the need to decide on the sequence based on scientific arguments in which (any) other available (or emerging) products should be developed in reference to the one decided to move forward into development. The development of these products should be foreseen in sequence and in dependency so that as soon as a development is completed (either due to futility or efficacy); others are already prepared for evaluation. Regulatory tools like deferrals are in place to facilitate this within PIPs. Such consolidated prioritisation strategies allow fulfilment of the respective regulatory requirements, improves efficiency and is of benefit to children with malignancy. In the case of MAPK inhibitors, the development of some products is too advanced to employ this strategy now.
6.4 Patient access to MAPK inhibitors
MAPK inhibitors have the potential to make a substantial difference in several childhood malignancies and fulfil current unmet needs. Patients need access to new drugs which require both regulatory and payer (health technology assessment bodies) approval. One very important issue is that these new drugs are more costly than conventional therapy. The cost effectiveness of these innovative approaches needs to be robustly demonstrated to payers (e.g. health technology assessment bodies). Frequently, robust data about the effectiveness of established/standard therapies are not available for regulatory and health technology assessment bodies purposes, creating a need to generate robust real-world evidence in this domain.
6.5 Evaluation of MAPK inhibitors in pLGG
MAPK inhibitors have the potential to fulfil unmet needs in pLGG and their development should be accelerated. The results of ongoing trials of single agents, and especially combinations in newly diagnosed patients are awaited and these will inform the field. Going forward, international coordination of trials in pLGG will be crucial to ensure progress is made rapidly and repetition is minimised. Defining the benefit of MAPK inhibitors compared to current standard of care, including economic evaluation, will establish how MAPK inhibitors could be practice changing treatments. Evaluating MAPK inhibitors with the greatest CNS penetration is of critical importance, although other characteristics of agents may also be important in defining the therapeutic window for MAPK inhibitors for LGG. Investigating the optimal MAPK inhibitors in a platform trial could be advantageous in identifying which to take forward to future front-line trials. Understanding biology in greater depth, including the role of promoting senescence versus blocking proliferation in the treatment of pLGG tumours, will allow predictive biomarkers to be identified to dissect the heterogeneous nature of the tumours, enabling therapy to be tailored. Similarly, biological studies will increase the understanding of rebound, resistance, optimal duration of therapy and late toxic effects. Validating new endpoints (e.g. visual acuity, quality-of-life, motor function, neuro-psychological function) and agreeing upon them prospectively with regulators for clinical trials are additional important goals.
6.6 Evaluation of MAPK inhibitors in pHGG with BRAF V600E mutations
Combination approaches are required, utilising inhibitors with the highest CNS penetration when feasible and safe. MAPK inhibitors are being incorporated in front-line therapy of pHGG with BRAF V600E mutations, with radiation therapy [
A high priority is to carry out intercontinental prospective trials evaluating the role of MAPK inhibitors in relapsed high-risk LCH (e.g. inclusion in a modified stratum III of the LCH IV trial: second-line therapy for high-risk). The substantial toxicity of current chemotherapeutic approaches further highlights the need for these approaches. Knowledge of the efficacy of MAPK inhibitors is not being systematically gained with the current substantial off-label use. There is a clear unmet need for companies to work in partnership with established histiocyte-focused cooperative groups to generate scientific knowledge that could be used for regulatory purposes. The second high priority in LCH is a trial that systematically investigates the value of MAPK inhibitors in LCH-neurodegenerative, especially since this devastating condition is not curable with the currently available chemotherapy and/or immunomodulation.
6.8 Evaluation of MAPK in RASopathies and other solid tumours
MAPK inhibitors will highly likely have a major role in other RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins in addition to NF1, including malignant peripheral nerve sheath tumours, Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome [
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.
]) is more complicated, in view of the complex genomic landscape and long pipeline of agents already under investigation. This is exemplified in the paediatric MATCH phase 2 trial Arm E which evaluated selumetinib in tumours harbouring activating MAPK pathway genetic alterations, but excluded LGG. Selumetinib demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib [
Phase II study of selumetinib in children and young adults with tumors harboring activating mitogen-activated protein kinase pathway genetic alterations: arm E of the NCI-COG pediatric MATCH trial.
In view of the MAPK signalling cascade being frequently activated across paediatric cancers, the development of successful therapeutic approaches to inhibit the pathway and monitoring validated functional endpoints in treated children with MAPK-pathway driven diseases are critical goals. Understanding specific tumour biology is crucial to develop the optimal combinations, to avoid paradoxical growth and to prevent unintended consequences including severe acute and late toxicity. The development of MAPK pathway inhibitors to date has been predominantly driven by adult indications. However, these inhibitors can address unmet paediatric needs in pLGG, pHGG, LCH, plexiform neurofibroma, JMML and potentially other paediatric tumours Box 1.
Text box of key conclusions of the Paediatric Strategy Forum
•
The mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers
•
It is an important therapeutic target
•
MAPK also signals through many other cascades and their feedback loops, and perturbing the MAPK pathway may have substantial influence on other pathways
•
Development of MAPK pathway inhibitors to date has been predominantly driven by adult indications (e.g. malignant melanoma)
•
MAPK inhibitors can address many unmet needs in paediatric low-grade gliomas, paediatric high-grade gliomas, Langerhans cell histiocytosis, plexiform neurofibroma and juvenile myelomonocytic leukaemia
•
Although MAPK inhibitors have demonstrated activity, breadth and depth of responses need to be improved
•
Better inhibitors with higher central nervous system penetration for cancers located in the brain need to be studied to determine if they are more effective than agents currently being used
•
Rapid development and evaluation of combination approaches is required to optimise responses
•
Understanding specific tumour biology is crucial to develop the optimal combinations, to avoid paradoxical growth and to prevent unintended consequences including severe toxicity
•
Optimum duration of therapy with MAPK inhibition needs to be determined, by rationally designed studies
•
Systematic and coordinated development of treatment strategies with MAPK inhibitors, rather than off-label use is needed to assess the risks and benefits of these agents and combination strategies in front-line and salvage settings.
•
Platform trials could have an important role
•
There is a major need for the international coordination of evaluation of products in development, in view of their number and a relatively small potential paediatric population, with RAS/MAPK pathway-driven diseases
•
Accelerating the introduction of MAPK inhibitors into front-line studies is a priority, as is ensuring that these studies generate data appropriate for regulatory purposes
•
Early discussions with regulators are crucial, in designing trials
•
Additional functional end-points e.g. visual acuity, quality-of-life, motor function and neuro-psychological function are important so that these agents benefit children with paediatric low-grade gliomas and should be included in initial designs and agreed upon prospectively with regulators
•
Long-term follow-up of patients receiving these inhibitors is crucial in view of their prolonged administration and the involvement of the pathway in normal development
The rapid development and evaluation of combination approaches (ideally combining agents which each) show single agent activity and non-overlapping toxicity is required to optimise responses and to achieve more profound molecular and clinical responses. Furthermore, determining the optimal duration of therapy is important; treatment for an empirical, but well defined duration with integrated ancillary biological studies should facilitate establishing the rational duration of treatment. Accelerating the introduction of MAPK inhibitors into front-line studies is a priority, as is ensuring that these studies generate data appropriate for regulatory purposes. Early discussion with regulators is crucial, particularly if randomised control trials are challenging to perform.
Additional end-points of function and quality of life (as these outcomes are often more reflective of benefit for lower grade tumours such as paediatric low-grade glioma and plexiform neurofibroma) should be included in initial study designs for pLGG and agreed upon prospectively with regulators.
Long-term follow-up of patients receiving MAPK pathway inhibitors is particularly crucial in view of the prolonged administration that is currently required and the involvement of the MAPK pathway in normal development. Currently, late sequelae of therapy are unknown and determining these are critically important especially in good prognosis tumours. The ACCELERATE long-term follow-up initiative should provide an appropriate infrastructure to accomplish this important task.
8. Participants
Tabled
1
Brian Abbott
BioMed Valley Discoveries, Kansas City, Missouri, USA
Isabelle Aerts
Institute Curie, France
Sama Ahsan
Merck & Co., Inc., Rahway, NJ, USA
Russo Alexandra
University Medicine, Mainz
Carl Allen
Texas Children Hospital, Houston, Texas, USA
Lise Alter
Haute Autorité de Santé, Saint-Denis, France
Evangelia Antoniou
Paediatric Clinic III, University Hospital of Essen, Germany
John Apps
University of Birmingham,UK
Sebastian Asaftei
Città della salute e della scienza Turin, Paediatric Onco-Haematology, Turin, Italy
Shifra Ash
Rambam Health Care Campus, Haifa, Israel
Itziar Astigarraga
Hospital Universitario Cruces, Barakaldo, Spain
Pratiti (Mimi) Bandopadhayay
Harvard Medical School, Dana-Farber, Bostonston Children's Cancer and Blood Disorders Centre, Boston, USA
Amy Barone
US Food and Drug Administration, USA
Elly Barry
Day One Biopharmaceuticals, USA
Immanuel Barth
Paediatric Committee of the European Medicines Agency, Netherlands
Sylvie Benchetrit
Agence Nationale de Sécurité du Médicament et des Produits (ANSM), France
Carly Bergstein
The Andrew McDonough B + Foundation, USA
Hana Bernatikova
University Hospital Brno, Department of Paediatric Oncology, Czech Republic
Michael Berntgen
European Medicines Agency, Netherlands
Nicholas Bird
Solving Kids' Cancer, UK
Samuel Blackman
Day One Biopharmaceuticals, USA
Patricia Blanc
Imagine for Margo, France
Eric Bouffet
The Hospital for Sick Children, Toronto, Canada
Liora Brunel
Agence Nationale de Sécurité du Médicament et des Produits (ANSM), France
Vickie Buenger
Coalition Against Childhood Cancer (CAC2), USA
Gilbert Burckart
US Food and Drug Administration, USA
Quentin Campbell Hewson
Great North Children's Hospital, Newcastle Upon Tyne, UK
Giordano Caponigro
Novartis, USA
Jorge Caravia
Day One Biopharmaceuticals, USA
Hubert Caron
F. Hoffmann-La Roche, Switzerland
Michela Casavova
Fondazione IRCCS Isituto Nazionale dei Tumori, Milano, Italy
Monica Cellini
Azienda Ospedaliero-Universitaria di Modena, Italy
Carla Centeno
McGill Institute, Montreal, Canada
Antony Ceraulo
Institut d'Hématologie et d'Oncologie Pédiatrique (IHOPe), Lyon, France.
Jordane Chaix
Institut Gustave Roussy, Paris, France
Guillermo Chantada
International Society of Paediatric Oncology
Katharine Cheng
Conect4children (c4c)
Alexander Chesi
Novartis, USA
Eric Chetaille
Pierre-Fabre, Paris, France
Davy Chiodin
Day One Biopharmaceuticals,USA
Devalck Christine
European Paediatric Soft tissue sarcoma Study Group (EpSSG)
Celine Chu
Agence Nationale de Sécurité du Médicament et des Produits (ANSM), France
Pierre Cochat
Haute Autorité de Santé, Saint-Denis, France
Nadège Corradini
Institut d'Hématologie et d'Oncologie Pédiatrique (IHOPe), Lyon, France.
Marta Cortes
Hospital Materno Infantil Malaga, Spain
Mireille Costantzer
F. Hoffmann-La Roche, Switzerland
Michael Cox
Day One Biopharmaceuticals, USA
Monika Csóka
Semmelweis University, 2nd Department of Pediatrics, Budapest
Randolph de la Rosa Rodriguez
AstraZeneca
Teresa de Rojas
ACCELERATE
Boris Decarolis
University Hospital of Cologne, Germany
Andrea Demadonna
ACCELERATE
Monique den Boer
Princess Máxima Centre, Utrecht, the Netherlands
Clare Devlin
F. Hoffmann-La Roche, Switzerland
Rebecca Deyell
BC Children's Hospital, Vancover, Canada
Daniela Di Carlo
Gustave Roussy Cancer Centre, Paris, France
Maria do Céu Diniz Borborema
Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Pernaambuco, Brazil
Michael Dolton
F. Hoffmann-La Roche, Switzerland
Martha Donoghue
US Food and Drug Administration, USA
Aizpea Echebarria
Hospital Universitario Cruces
Carrie Emery
BioMed Valley Discoveries, USA
Natacha Entz-Werle
University Hospital of Strasbourg, Strasbourg, France
Craig Erker
IWK Health Centre, Halifax, Canada
Samira Essiaf
ACCELERATE
Jason Fangusaro
Children's Healthcare of Atlanta and Emory, Atlanta, USA
Roula Farah
Lau Medical Centre Rizk Hospital, Beirut, Lebanon
Ana Fernandez-Teijeiro
Spanish Society of Paediatric Haematology and Oncology
Michael Fisher
Children's Hospital of Philadelphia, Philadelphia, USA
Christian Flotho
Division of Paediatric Haematology and Oncology, University Medical Centre, Freiburg, Germany
Deanna Fournier
Histiocytosis Association, USA
Elizabeth Fox
St Jude Children's Research Hospital, Tennessee, USA
Barry Frankel
BioMed Valley Discoveries, USA
Marion Gambart
CHU Toulouse, Toulose, France
Julia Glade Bender
Memorial Sloan Kettering Cancer Centre, New York, USA
Lia Gore
Children's Hospital Colorado/University of Colorado, Colorado, USA
Marcus Guardian
European Network for Health Technology Assessment (EUNETHTA)
Daphne Haas-Kogan
Dana-Farber/Brigham and Women's Cancer Centre, Boston, USA
Todd Hankinson
Children's Hospital Colorado/University of Colorado, Colorado, USA
Jordan Hansford
Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG) Brain Group
Darren Hargrave
UCL Great Ormond Street Institute of Child Health, London, UK
Doug Hawkins
Seattle Children's Hospital, Seattle USA
Niklas Hedberg
Dental and Pharmaceutical Benefits Agency, TLV, Sweden
Lars Hjorth
Skane University Hospital, Malmö, Sweden
Laura Huggins
Novartis, USA
Caroline Hutter
St. Anna Children's Hospital, Children's Cancer Research Institute, Vienna, Austria
Uri Ilan
Princess Máxima Centre, Utrecht, the Netherlands
Vesna Ilic
Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
Uche Iloeje
SpringWorks Therapeutics, USA
Sae Ishimaru
Princess Máxima Centre, Utrecht, the Netherlands
Shai izraeli
Schneider Children's Medical Centre, Petah Tikva, Israel Matej Jelic University Hospital Centre Zagreb
David Jones
German Cancer Research Centre (DKFZ)
Dominik Karres
European Medicines Agency
Rejin Kebudi
Istanbul University Oncology Institute, Istanbul, Turkey
Sophie Kelley
Haute Autorité de Santé, Saint-Denis, France
Olga Kholmanskikh
Federal Agency for Medicines and Health Products, Belgium
Mark Kieran
Day One Biopharmaceuticals, USA
Maria Kirby
Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG)
Andrew McDonough B + Foundation for financial support of ACCELERATE.
Disclaimer
The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of, or reflecting the position of, the agencies or organisations with which the authors are affiliated. As well, this publication reflects the views of the author and should not be construed to represent Food and Drug Administration views or policies.
Conflict of interest statement
SA is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder of Merck & Co., Inc., Rahway, NJ, USA. EB is an employee of Day One Biopharmaceuticals PB receives grant funding from Novartis Institute of Biomedical Research and has received grant funding from Deerfield Therapeutics and has been a member of an advisory board for QED Therapeutics. JF has served as an advisor for Astra-Zeneca and has been a member of a Paediatric Advisory Board. BK is an employee of BioMed Valley Discoveries. AJL is an employee and stockholder of SpringWorks Therapeutics. MM is an employee of Boehringer Ingelheim. KNa is an employee of Pierre-Fabre. GR is an employee of Hoffmann-La Roche AG. MR is an employee and stockholder of Novartis. RV is an employee of Alexion Pharmaceuticals ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest.
Acknowledgements
The authors very gratefully acknowledge Andrea Demadonna for his dedication, efficiency, enthusiasm and very substantial work in preparation of the Forum and Samira Essiaf for her pivotal role in organising the Forum. The authors thank Eric Smith for his assistance in generating the Figure, Gynette Cook for preparation of the manuscript and Sarah K. Tasian for her critical review of the summary.
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Phase II study of selumetinib in children and young adults with tumors harboring activating mitogen-activated protein kinase pathway genetic alterations: arm E of the NCI-COG pediatric MATCH trial.
Dabrafenib plus trametinib in patients with BRAF V600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial.
A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients with Neurofibromatosis and Low-Grade Glioma - https://clinicaltrials.gov/ct2/show/NCT03871257. (Accessed 6 September 2022).
A Study to Evaluate DAY101 in Pediatric and Young Adult Patients with Relapsed or Progressive Low-Grade Glioma (FIREFLY-1). https://clinicaltrials.gov/ct2/show/NCT04775485. (Accessed 6 September 2022).
A Study to Compare Treatment with the Drug Selumetinib Alone Versus Selumetinib and Vinblastine in Patients With Recurrent or Progressive Low-Grade Glioma - https://clinicaltrials.gov/ct2/show/NCT04576117. (Accessed 6 September 2022).
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial) - https://clinicaltrials.gov/ct2/show/NCT03155620. (Accessed 6 September 2022).
Trametinib and Everolimus for the Treatment of Pediatric and Young Adult Patients with Recurrent Low Grade Gliomas (PNOC021) - https://clinicaltrials.gov/ct2/show/NCT04485559. (Accessed 6 September 2022).
Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects with Cancer or Plexiform Neurofibromas and Trametinib in Combination with Dabrafenib in Subjects with Cancers Harboring V600 Mutations. https://clinicaltrials.gov/ct2/show/NCT02124772. (Accessed 6 September 2022).
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