In recent years, work in pediatric and adult craniopharyngioma has sought to inform clinical trial development using genomic features of craniopharyngioma in precision-based strategies [12,13,14]. Numerous clinical studies focused on the molecular and inflammatory components of craniopharyngioma have been developed and are currently underway (Table 1).

In the setting of ACP, both the molecular and inflammatory profile of the tumor make attractive targets of agents under investigation and/or commercially available. Apps et al. characterized a pattern of MAPK/ERK dysregulation and activation in ACP [15]. Petralia et al. similarly characterized that pediatric ACP displayed proteomic profiles with phenotypic similarity to BRAF-V600E mutated low-grade gliomas, further suggesting a potential role for MAPK driven activation in ACP [30]. Based on these characteristics, clinical trials have been developed to shutdown MAPK pathway activation through MEK inhibition, a protein involved in the MAPK pathway. Case studies have demonstrated efficacy of this approach in ACP but there remains limited prospective data on toxicity and clinical outcomes in the context of formal clinical trials [31]. Multiple studies have also characterized the inflammatory environment of ACP. Apps et al. and Hankinson et al. characterized the association of IL-6 expression within a distinct inflammatory phenotype [4, 33, 34]. While expression of this marker is prevalent in the cystic component of ACP, Donson et al. has also shown high proteomic expression of this cytokine in the solid tissue component of ACP suggesting a role for IL-6 in the development of ACP [33]. Recent case studies of tocilizumab, an IL-6 inhibitor, have provided strong rationale for its use as treatment for ACP [34,35,36]. The PD-1 pathway offers another potentially targetable therapeutic vulnerability as seen in the work of Coy et al. and Petralia et al. [30, 32]. Using the molecular, proteomic, and transcriptomic profiles of ACP, three trials are underway exploring novel targeted strategies – PNOC029 (NCT05465174), CONNECT2108 (NCT05286788), and CONNECT 1905 (NCT05233397) [37,38,39].

PNOC029 seeks to combine MAPK pathway inhibition with immune checkpoint blockade via PD-1 inhibition in ACP [14, 16, 32, 37]. The trial is open to enrollment for pediatric patients ages 1–39 years with newly diagnosed or recurrent craniopharyngioma. Investigational therapy includes tovorafenib, a type II RAF inhibitor, to target the MAPK pathway in combination with nivolumab to target the PD-1 pathway. Tovorafenib is administered orally every week, while nivolumab is administered intravenously every two weeks. The trial applies a treat-biopsy-treat approach with the goal to characterize the downstream impact of these targeted strategies and inform on mechanisms of response and resistance. The primary endpoint is a composite endpoint, wherein patients must achieve both progression-free survival and maintenance of quality of life at 12 months for this therapy to be deemed a success. To further characterize the QoL and functional outcomes of patients in response to this therapy, PNOC029 is also uniquely collecting follow-up information for three years following therapy start with a specific focus on neuroendocrine and visual outcomes. Importantly, this trial prioritizes these functional outcomes alongside tumor burden as a measure of treatment efficacy. At the same time, this study is collecting robust biospecimens from blood, cyst fluid, tumor tissue, and the microbiome to characterize molecular and immune changes at the patient level, which will inform mechanisms of drug response and guide the next phase of trials for this disease.

Similar to PNOC029, CONNECT2108 aims to target the MAPK pathway in craniopharyngioma [38]. This trial is currently enrolling pediatric patients ages 1–25 years with progressive or recurrent ACP with or without upfront radiation. Patients are treated with binimetinib, an oral, highly-selective MEK1/MEK2 inhibitor, twice a day for up to two years. The primary endpoint of this study is objective response rate, stratified by RT. This study is also exploring biospecimens from blood, cyst fluid and tumor tissue to inform on the biologic effects of this therapy.

CONNECT1905 aims to target the IL-6 pathway in ACP [39]. Building on numerous case studies showing the efficacy of IL-6 use in ACP, this trial is currently enrolling patients ages 1–25 years with progressive or recurrent ACP with or without upfront radiation. Patients are treated with tocilizumab, an IL-6 receptor antagonist, intravenously every two weeks for up to two years. Similar to CONNECT2108, the primary endpoint for this study is objective response rate, stratified by RT, and will also perform collection of blood, cyst fluid, and tumor tissue to characterize patient response to this therapy.

In the setting of PCP, studies have predominantly and successfully explored BRAF inhibitors as a targeted therapy, building on the recent identification that most PCP cases harbor BRAF-V600E mutations [40,41,42,43]. Alongside trials exploring BRAF inhibitors alone, BRAF and MEK inhibitors are being explored as combination therapy to reduce the possibility of tumor resistance commonly associated with single-agent BRAF inhibitors. Through this mechanism, trials in the PCP setting have sought to shutdown MAPK pathway activation through BRAF and MEK inhibition. Two trials have combined BRAF/MEK targeting for PCP to explore the benefit of dual inhibition. This includes the “Swecranio” (NCT05525273) and Alliance A071601 (NCT03224767) trials [44, 45]. “Swecranio” seeks to target MAPK pathway activation in BRAF-V600E mutated PCP [44]. The trial is currently enrolling adult patients with non-irradiated, newly diagnosed or recurrent PCP and a confirmed BRAF-V600E mutation. Patients are treated with dabrafenib, a BRAF-V600E inhibitor, alongside trametinib, a MEK inhibitor. Dabrafenib is administered orally twice daily, while trametinib is administered orally once daily. The primary endpoint is to measure reduction in tumor volume, while secondary endpoints include duration of response, progression-free survival and neuroendocrine, visual, and cognitive QoL outcomes. This study will also collect blood throughout treatment to measure changes in circulating BRAF-V600E.

Similar to “Swecranio,” the recently concluded phase 2 Alliance A071601 explored the combination of BRAF and MEK inhibition in PCP [45]. Patients over the age of 18 years with a histologically confirmed diagnosis of a BRAF-V600E driven papillary craniopharyngioma and no upfront radiation were eligible for this study. Enrolled patients received a combination of vemurafenib, a BRAF V600E inhibitor, and cobimetinib, a MEK inhibitor. The primary endpoint was objective response at 4 months. In this trial, investigators saw tumor regression in 94% of the cohort (n = 16) with regression proving to be durable over 24 months (24-month PFS: 58%, 24-month OS: 100%) [43]. Most patients (75%) experienced grade 3 or higher adverse events (AEs), with the most common AEs including skin rash and fever, as previously described with these agents [43]. Unfortunately, the long-term neuroendocrine and neurological outcomes patients characteristically struggle with under standard care paradigms have not yet been described in the early stages of follow-up. Longer term efficacy of this combinatorial approach in recurrent PCP also remains unknown. While BRAF-MEK inhibition is not a solution for all PCPs, this targeted therapy suggests a reliable adjuvant therapy for tumor regression that avoids the surrounding tissue damage characteristic of current treatment approaches. However, as with many targeted inhibitors, unknowns in the best use of these agents remain, such as duration of therapy, treatment schedule, development of resistance as well as a rebound after discontinuation of treatment [46].