Paxalisib (GDC-0084): A Brain-Penetrant PI3K/mTOR Inhibitor for CNS Malignancies

1. Introduction to Paxalisib (GDC-0084)

1.1. Overview and Chemical Identity

Paxalisib, an investigational small molecule drug, is also identified by its developmental code name GDC-0084 and synonym RG7666.[1] It is cataloged in DrugBank with the Accession Number DB15186.[1] The Chemical Abstracts Service (CAS) Number for Paxalisib is 1382979-44-3.[1]

The IUPAC name for Paxalisib is 5-(6,6-dimethyl-4-morpholin-4-yl-8,9-dihydropurino[8,9-c]\oxazin-2-yl)pyrimidin-2-amine.[1] An alternative chemical name is 5-(6,6-Dimethyl-4-morpholino-8,9-dihydro-6H-\oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine.[3] Paxalisib has a molecular formula of C18H22N8O2, corresponding to an average molecular weight of 382.428 g/mol and a monoisotopic mass of 382.18657198 Da.[1]

The presence of multiple identifiers such as GDC-0084 and RG7666, alongside the formally adopted name Paxalisib (USAN/INN), reflects the typical progression of a drug through distinct research and development phases. GDC-0084 was likely Genentech's internal research designation during its early discovery and development. As a compound advances into more formal clinical development and towards potential commercialization, it receives an official non-proprietary name like Paxalisib, which is recognized globally by regulatory authorities and in scientific literature.[1] This nomenclature evolution is a standard practice in the pharmaceutical industry, marking the transition from an early-stage research compound to a more mature clinical candidate.

Table 1: Paxalisib - Key Drug Information

Property	Value	References
Primary Name	Paxalisib	1
Synonyms	GDC-0084, RG7666, G02441729, GDC0084, Paxalisib , 5-(6,6-dimethyl-4-morpholin-4-yl-8,9-dihydropurino[8,9-c]\oxazin-2-yl)pyrimidin-2-amine, 5-(6,6-Dimethyl-4-morpholino-8,9-dihydro-6H-\oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine, CHEMBL3813842	1
DrugBank ID	DB15186	1
CAS Number	1382979-44-3	1
Molecular Formula	C18H22N8O2	1
Molecular Weight (Avg)	382.428 g/mol	1
Monoisotopic Mass	382.18657198 Da	1
Type	Small Molecule	1
InChIKey	LGWACEZVCMBSKW-UHFFFAOYSA-N	1
SMILES	CC1(C2=NC3=C(N2CCO1)N=C(N=C3N4CCOCC4)C5=CN=C(N=C5)N)C	8

1.2. Development History

Paxalisib, originally designated GDC-0084, was invented and initially developed by Genentech, Inc., a member of the Roche Group.[12] Genentech's primary focus for GDC-0084 was its potential as a novel therapeutic agent for glioblastoma, the most common and aggressive form of primary brain cancer.[14]

Between 2012 and 2015, Genentech conducted a first-in-human Phase I clinical trial (NCT01547546) involving 47 patients with advanced, recurrent high-grade gliomas. This study was crucial in establishing an adult Maximum Tolerated Dose (MTD) of 45 mg/day for GDC-0084. Furthermore, the trial demonstrated a generally favorable safety profile and provided early indications of clinical activity, with stable disease observed in 40% of the enrolled patients.[14]

In October 2016, Kazia Therapeutics Limited, an oncology-focused biotechnology company, acquired worldwide exclusive rights to Paxalisib from Genentech.[12] This transition from a large pharmaceutical entity like Genentech to a smaller, specialized company such as Kazia Therapeutics is a recognized strategic approach within the pharmaceutical industry. Large pharmaceutical companies often out-license promising assets that may not align with their core strategic priorities, require highly specialized development expertise (e.g., for rare diseases like brain cancers), or possess a market potential deemed more suitable for the focused efforts of a smaller, more agile organization. Kazia Therapeutics' subsequent development strategy for Paxalisib, emphasizing its brain-penetrant properties for various CNS malignancies, is consistent with this model of specialized drug development.[13]

2. Mechanism of Action

2.1. Targeting the PI3K/Akt/mTOR Pathway

Paxalisib is an orally bioavailable small molecule that functions as a potent dual inhibitor of Class I phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR).[1] The PI3K/Akt/mTOR pathway is a fundamental intracellular signaling cascade that governs a multitude of cellular processes, including cell growth, proliferation, survival, angiogenesis, and metabolism.[17]

Dysregulation and hyperactivation of this pathway are frequently observed in a wide array of human cancers and are particularly prevalent in glioblastoma, where estimates suggest involvement in over 85-90% of cases.[9] This high frequency of alteration makes the PI3K/Akt/mTOR pathway a compelling therapeutic target in oncology. Paxalisib exerts its therapeutic effect by inhibiting PI3K, thereby suppressing the activation of this signaling pathway. This action can lead to the inhibition of tumor cell growth and survival in susceptible cancer cell populations.[1] The inhibition of PI3K by Paxalisib consequently prevents the phosphorylation and activation of downstream signaling effectors, notably Akt (protein kinase B) and p70 S6 kinase, a key substrate of mTORC1.[29]

The dual inhibitory action of Paxalisib against both PI3K and mTOR is a significant mechanistic feature. mTOR exists in two distinct complexes, mTORC1 and mTORC2, both of which are critical downstream components of the PI3K/Akt signaling axis. By targeting both PI3K and mTOR, Paxalisib aims to achieve a more comprehensive blockade of this oncogenic pathway. This dual inhibition may offer advantages over agents that target only PI3K, potentially by mitigating compensatory signaling or feedback loops that can lead to therapeutic resistance.

2.2. Isoform Specificity and Potency

Paxalisib demonstrates inhibitory activity against all four Class I PI3K isoforms (α, β, δ, and γ) as well as mTOR.[3] The reported inhibitory constants (Ki values) for Paxalisib against these targets are as follows:

• PI3Kα: 2 nM [3]
• PI3Kβ: 46 nM [3]
• PI3Kδ: 3 nM [3]
• PI3Kγ: 10 nM [3]
• mTOR: 70 nM [3]

These Ki values indicate that Paxalisib is a potent inhibitor of multiple Class I PI3K isoforms, with particularly high potency against PI3Kα (Ki​ = 2 nM) and PI3Kδ (Ki​ = 3 nM). The PI3Kα isoform is frequently mutated and activated in various cancers, making it a prime therapeutic target. PI3Kδ and PI3Kγ isoforms are more predominantly involved in immune cell signaling. The somewhat lower potency against PI3Kβ (Ki​ = 46 nM) could be a potentially favorable characteristic, as inhibition of PI3Kβ has been associated with certain metabolic toxicities, such as hyperglycemia, due to its role in insulin signaling. Nevertheless, the inhibitory activity against mTOR (Ki​ = 70 nM), while less potent than against PI3Kα or PI3Kδ, is still within a pharmacologically relevant range, supporting its classification as a dual PI3K/mTOR inhibitor. This broad spectrum of inhibition across PI3K isoforms, combined with mTOR kinase inhibition, contributes to its overall mechanism of action and may influence both its efficacy and side effect profile.

2.3. Blood-Brain Barrier Penetration

A critical and distinguishing characteristic of Paxalisib is its designed ability to efficiently cross the blood-brain barrier (BBB).[3] This property is of paramount importance for a drug intended to treat malignancies within the central nervous system (CNS), such as glioblastoma and brain metastases.

Preclinical studies have provided substantial evidence of Paxalisib's BBB penetration:

• In mice, the brain-to-plasma unbound concentration ratio (Kp,uu), a key measure of BBB penetration, was determined to be 0.31.[40]
• In rats, administration of a 15 mg/kg dose resulted in a total brain-to-plasma concentration ratio ranging from 1.9 to 3.3.[9]
• Furthermore, Paxalisib has been shown to be a poor substrate for key efflux transporters located at the BBB, namely P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).[9] These transporters actively pump many xenobiotics out of the brain, thereby limiting their CNS exposure. Paxalisib's ability to evade significant efflux by these transporters likely contributes to its enhanced brain penetration.

Clinical evidence from the Phase I study (NCT01547546) in patients with recurrent high-grade glioma further supports Paxalisib's BBB permeability. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans indicated metabolic changes in the brain suggestive of drug penetration and target engagement. More directly, analysis of resection specimens from two patients in this study revealed that GDC-0084 was present at similar concentrations in both tumor tissue and surrounding brain tissue. The brain tissue/tumor-to-plasma concentration ratios were reported to be >1 for total drug and >0.5 for free (unbound) drug.[18]

The capacity of Paxalisib to effectively penetrate the BBB and achieve therapeutic concentrations within brain tissue and CNS tumors is fundamental to its therapeutic rationale for brain cancers. This characteristic, combined with its potent inhibition of the PI3K/mTOR pathway, distinguishes Paxalisib from many other PI3K inhibitors that exhibit poor CNS penetration and are therefore unsuitable for treating primary or metastatic brain tumors.[13]

3. Preclinical Development and Findings

3.1. In Vitro Efficacy and Potency

Paxalisib has demonstrated significant antiproliferative activity across a range of cancer cell lines in vitro. In studies involving glioma cells, Paxalisib inhibited proliferation with EC50 values (concentration causing 50% of maximal effect) reported to be in the range of 0.3 to 1.1 μM.[3]

The activity of Paxalisib has also been evaluated in the context of breast cancer brain metastases. In vitro studies revealed a differential response based on the PIK3CA mutation status of the cells. In PIK3CA-mutant breast cancer brain metastatic cell lines, GDC-0084 (Paxalisib) led to a considerable dose-dependent decrease in cell viability and an induction of apoptosis. This was accompanied by inhibition of the phosphorylation of downstream signaling proteins Akt and p70 S6 kinase. In contrast, PIK3CA wild-type cell lines primarily exhibited growth inhibition without a similar induction of apoptosis or as pronounced signaling pathway modulation.[31] This observation suggests that the presence of activating PIK3CA mutations, which drive pathway activity, may sensitize cells to Paxalisib. Such findings are critical as they point towards PIK3CA mutation status as a potential predictive biomarker for patient selection in clinical trials, a cornerstone of targeted cancer therapy.

In cutaneous squamous cell carcinoma (cSCC) cell lines (A431, SCC-13, and SCL-1), GDC-0084 also demonstrated dose-dependent inhibition of cell survival. A431 cells were identified as the most sensitive, with a reported IC50 value (concentration causing 50% inhibition) of 186.51 ± 11.31 nM.[2]

Table 2: Summary of Paxalisib Preclinical Potency (Ki​ and IC50​/EC50​ Values)

Target/Cell Line	Potency Value	Units	Type	Reference(s)
PI3Kα	2	nM	Ki​	3
PI3Kβ	46	nM	Ki​	3
PI3Kδ	3	nM	Ki​	3
PI3Kγ	10	nM	Ki​	3
mTOR	70	nM	Ki​	3
Glioma Cell Lines (Range)	0.3 - 1.1	µM	EC50​	3
U-87MG ATCC (Glioma)	0.74	µM	EC50​	10
SF-268 (Glioma)	1.01	µM	EC50​	10
PC-3 (Prostate Cancer)	0.4	µM	EC50​	10
A431 (cSCC)	186.51	nM	IC50​	2
JIMT-1 BR-3 (PIK3CA-mutant Breast Cancer Brain Mets)	Dose-dependent decrease in viability & apoptosis induction	-	Qualitative	31
MDA-MB-361 (PIK3CA-mutant Breast Cancer Brain Mets)	Dose-dependent decrease in viability & apoptosis induction	-	Qualitative	31

3.2. In Vivo Efficacy in Animal Models

The in vivo antitumor activity of Paxalisib has been evaluated in various preclinical cancer models, particularly those relevant to CNS malignancies.

Glioma Models:

In orthotopic glioblastoma models, where human tumor cells are implanted into the brains of immunocompromised mice, GDC-0084 demonstrated significant efficacy. It achieved 70% tumor growth inhibition (TGI) in the U87 glioblastoma model and 40% TGI in the GS2 glioblastoma model.3 Studies using subcutaneous U87 xenografts also showed dose-dependent tumor growth inhibition, with significant effects observed at doses as low as 2.2 mg/kg, and tumor regressions noted at 17.9 mg/kg.11 Crucially, matrix-assisted laser desorption/ionization (MALDI) imaging confirmed that GDC-0084 distributed evenly throughout the brain and within intracranial U87 and GS2 tumors, indicating that the drug reached its target site.43 Consistent with its mechanism of action and BBB penetration, GDC-0084 markedly inhibited the PI3K pathway in the mouse brain, evidenced by up to 90% suppression of phosphorylated Akt (pAkt) levels, a key downstream signaling molecule.3

Breast Cancer Brain Metastases Models:

The efficacy of GDC-0084 was also assessed in xenograft mouse models of breast cancer brain metastases. Treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant (JIMT-1 BR-3) brain tumors. This antitumor effect was accompanied by corresponding changes in downstream signaling, including reduced pAkt and pS6 levels in the tumor tissue. In contrast, no significant therapeutic benefit was observed in models derived from PIK3CA wild-type (MDA-MB-231 BrM2) cells.2 These findings further support the notion that PIK3CA mutation status may predict sensitivity to Paxalisib.

Diffuse Intrinsic Pontine Glioma (DIPG) Models:

In aggressive preclinical models of DIPG, a devastating pediatric brain tumor, Paxalisib has shown promise, particularly in combination therapies. When combined with ONC201 (an activator of the mitochondrial protease ClpP), Paxalisib synergistically extended survival in two distinct autopsy-derived animal models of DIPG, with survival increases of 37% and 19%, respectively.51 Further research explored a triple combination strategy involving Paxalisib, metformin (to mitigate Paxalisib-induced hyperglycemia), and enzastaurin (a PKC inhibitor to counteract a potential resistance mechanism). This triple combination significantly prolonged survival in DIPG models, and its efficacy was further potentiated when combined with standard-of-care radiotherapy.44

The consistent demonstration of in vivo efficacy in orthotopic brain tumor models, coupled with direct evidence of target engagement (pAkt inhibition) within brain tissue and tumors, provides a strong preclinical rationale for the clinical development of Paxalisib in various brain cancers. The synergistic effects observed with combination strategies in DIPG models are particularly noteworthy, highlighting rational approaches to tackle these challenging pediatric malignancies by addressing both direct tumor biology and potential therapy-induced metabolic alterations or resistance pathways.[3]

3.3. Preclinical Pharmacokinetics, Metabolism, and Distribution (ADME)

The preclinical ADME profile of Paxalisib has been characterized across multiple species to understand its disposition and to support human dose predictions.

Paxalisib demonstrated excellent metabolic stability in in vitro incubations with human liver microsomes and hepatocytes.[3] Plasma protein binding was found to be low, with the fraction of unbound drug (fu,plasma) ranging from 0.25 to 0.43 across mice, rats, dogs, and humans.[40] In CD-1 mice, binding to brain tissue was higher than to plasma, with a reported free fraction in brain (fu,brain) of 6.7%.[3]

Hepatic clearance predictions from hepatocyte incubations indicated low clearance in mice, rats, dogs, and humans, but high clearance in monkeys. Similarly, plasma clearance was low in mice, moderate in rats, and high in dogs and monkeys.[40] Oral bioavailability exhibited significant interspecies variability, ranging from 6% in monkeys to 76% in rats.[40]

The observed species differences in clearance and oral bioavailability underscore the complexities of extrapolating preclinical ADME data to humans. Such variability necessitates the use of sophisticated approaches, such as physiologically based pharmacokinetic (PBPK) modeling [40], to more accurately predict human pharmacokinetic profiles and inform first-in-human dose selection. The prediction of low hepatic clearance in humans is a positive indicator for achieving sustained systemic exposure.

Table 3: Summary of Paxalisib Pharmacokinetic Parameters (Preclinical & Clinical)

Parameter	Species/Population	Value	Units	Reference(s)
Fraction Unbound Plasma (fu,plasma​)	Mouse, Rat, Dog, Human	0.25 - 0.43	unitless	40
Fraction Unbound Brain (fu,brain​)	Mouse (CD-1)	0.067 (6.7%)	unitless	3
Hepatic Clearance (Predicted)	Mouse, Rat, Dog, Human	Low	-	40
	Monkey	High	-	40
Plasma Clearance	Mouse	Low	-	40
	Rat	Moderate	-	40
	Dog, Monkey	High	-	40
Oral Bioavailability	Monkey	6	%	40
	Rat	76	%	40
Kp,uu (Brain/Plasma Unbound Ratio)	Mouse	0.31	unitless	40
Brain/Plasma Ratio (Total)	Rat (15 mg/kg)	1.9 - 3.3	unitless	9
	Human (Resection)	>1 (Total), >0.5 (Free)	unitless	18
Half-life (t1/2​)	Human (Adult, Rec. Glioma)	~19	hours	18
	Human (Pediatric, DIPG/DMG)	20.6 ± 9.1	hours	35
AUC0−48h​	Human (Pediatric, 27 mg/m²)	3399 ± 1301	hr·ng/mL	35
	Human (Pediatric, 35 mg/m²)	4462 ± 2868	hr·ng/mL	35

3.4. Initial Preclinical Safety and Toxicology Insights

Detailed Good Laboratory Practice (GLP) toxicology reports for Paxalisib were not available within the provided research materials. However, insights into its early safety profile can be inferred from its progression through clinical development and some limited preclinical mentions.

The fact that Paxalisib advanced from preclinical studies into Phase I, and subsequently into Phase II and Phase III clinical trials, strongly implies the existence of a comprehensive preclinical safety data package that met the requirements of regulatory authorities like the U.S. Food and Drug Administration (FDA) for human testing.[14] Such packages typically include acute and repeat-dose toxicology studies in at least two species (one rodent, one non-rodent), safety pharmacology assessments (evaluating effects on vital functions like cardiovascular, respiratory, and central nervous systems), genotoxicity assays, and, depending on the intended duration of clinical use, carcinogenicity and reproductive toxicology studies.

While specific non-clinical safety study reports (e.g., GLP toxicology, genotoxicity, carcinogenicity, reproductive toxicology) were not found in the provided snippets [14], some information can be gleaned. For instance, a 2017 corporate overview from Kazia Therapeutics mentioned that Genentech's initial Phase I study (which would have been preceded by extensive preclinical safety evaluation) showed common adverse events like mouth ulcers and hyperglycemia, with no evidence of major organ toxicities such as liver, bone marrow, or kidney toxicity, or mood disturbances.[17] These types of adverse events are often anticipated based on the mechanism of action (PI3K/mTOR inhibition is known to affect glucose metabolism and mucosal tissues) and would have been characterized in preclinical toxicology studies.

The development of Paxalisib specifically as a brain-penetrant PI3K inhibitor [15] suggests that particular attention would have been paid to CNS safety pharmacology during its preclinical assessment. The successful establishment of Maximum Tolerated Doses (MTDs) in both adult and pediatric clinical populations further indicates that the dose ranges explored were supported by preclinical safety data.[18]

4. Clinical Development of Paxalisib

4.1. Pharmacokinetics and Pharmacodynamics in Humans

Pharmacokinetics (PK):

The pharmacokinetic profile of Paxalisib has been characterized in both adult and pediatric patient populations. An early Phase I study (NCT01547546) in adult patients with recurrent high-grade glioma established that GDC-0084 exhibits linear and dose-proportional pharmacokinetics. The elimination half-life was approximately 19 hours, supporting a once-daily dosing regimen.18 At the adult MTD of 45 mg/day, steady-state plasma concentrations of Paxalisib were achieved that exceeded the preclinical target concentrations associated with antitumor activity in xenograft models.18

In pediatric patients with newly diagnosed DIPG or DMG (NCT03696355), the mean GDC-0084 elimination half-life was 20.6 ± 9.1 hours, which is comparable to that observed in adults. The area under the curve from 0 to 48 hours (AUC0−48h​) following a single dose was 3399 ± 1301 hr·ng/mL at a dose of 27 mg/m² and 4462 ± 2868 hr·ng/mL at 35 mg/m².[35]

A Phase II study in newly diagnosed GBM patients (NCT03522298) confirmed that at the MTD of 60mg, the PK profile remained linear and dose-proportional. Importantly, administration with food did not significantly alter the Tmax (time to maximum concentration) or elimination half-life, suggesting that Paxalisib can be taken without strict regard to meals, which is an advantage for patient convenience.[19]

Crucially, brain penetration has been confirmed in human subjects. Data from the Genentech Phase I study, including FDG-PET imaging and analysis of resected tumor and brain tissue, indicated that GDC-0084 effectively crossed the BBB. Drug concentrations in tumor and adjacent brain tissue were similar, with brain tissue/tumor-to-plasma ratios greater than 1 for total drug and greater than 0.5 for free drug, signifying substantial CNS distribution.[18]

Pharmacodynamics (PD):

Evidence of target engagement and biological activity in humans has also been reported. In the Phase I study (NCT01547546), FDG-PET scans revealed a metabolic partial response in 26% (7 out of 27) of patients. Furthermore, a trend toward decreased median standardized uptake value (SUV) of FDG in normal brain tissue was observed at doses ≥45 mg/day, suggesting that Paxalisib was reaching the brain and modulating glucose metabolism, consistent with PI3K/mTOR pathway inhibition.17 In a separate study involving patients with HER2-positive breast cancer brain metastases (NCT04192981), the inhibition of phosphorylated 4E-BP1 (p-4EBP1), a downstream effector of mTOR, in resected brain tumor tissue is being evaluated as a pharmacodynamic marker of Paxalisib activity.58

The consistent pharmacokinetic profile observed across adult and pediatric populations, coupled with the direct demonstration of BBB penetration and target engagement in the human brain, provides a strong foundation for Paxalisib's therapeutic rationale in CNS malignancies. The lack of a significant food effect on its pharmacokinetics at the MTD further simplifies its clinical administration.

4.2. Clinical Trials in Glioblastoma (GBM)

Paxalisib has been extensively evaluated in clinical trials for glioblastoma (GBM), the most common and aggressive primary brain tumor in adults.

Newly Diagnosed GBM (Unmethylated MGMT Promoter Status):

Patients with newly diagnosed GBM whose tumors have an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter typically have a poorer prognosis with standard temozolomide-based chemotherapy. Paxalisib has been investigated in this specific patient population.

• NCT03522298 (Kazia Phase II Study): This study aimed to establish the MTD, safety, and clinical activity of Paxalisib in patients with newly diagnosed GBM and unmethylated MGMT promoter status following surgical resection and standard chemoradiotherapy (Stupp Regimen).[19]
• An MTD of 60mg once daily was established.[19]
• Safety: Paxalisib was generally well-tolerated. Dose-limiting toxicities (DLTs) at a higher dose of 75mg included hyperglycemia and stomatitis. Adverse events were consistent with those typically observed with PI3K inhibitors.[19]
• Efficacy: For the overall intent-to-treat (ITT) population (n=30), the median progression-free survival (PFS) was 8.4 months (by RANO criteria) and 8.6 months (by mRANO criteria). The median overall survival (OS) was 15.7 months. In a modified ITT (mITT) population of 22 patients treated with 60mg daily and having at least one post-baseline assessment, the median PFS was 9.6 months (mRANO).[14] These results were considered encouraging when compared to historical controls for this patient population.
• GBM AGILE (NCT03970447, Global Coalition for Adaptive Research Phase II/III Platform Trial): Paxalisib was evaluated as an investigational arm in this adaptive platform trial for both newly diagnosed unmethylated (NDU) and recurrent GBM patients.[6]
• Enrollment for the Paxalisib arm occurred from December 2020 through May 2022. The control arm for NDU patients received temozolomide.[63]
• Paxalisib did not meet the predefined Bayesian predictive power thresholds to automatically advance from Stage 1 to Stage 2 of the trial.[14]
• Final Primary Analysis (data cutoff August 2022): For the NDU GBM cohort (Paxalisib n=54 vs. cumulative standard of care n=75), the mean OS hazard ratio (HR) was 0.89, with a Bayesian probability of HR<1.00 being 0.72. The model-estimated median OS was 14.77 months for Paxalisib versus 13.84 months for SOC.[14]
• Prespecified Secondary Analysis (announced July 2024): When comparing Paxalisib (n=54) to a concurrent SOC control group (n=46, patients enrolled during the same period as the Paxalisib arm), the median OS was 15.54 months for Paxalisib versus 11.89 months for SOC. This represented a 3.8-month improvement in median OS for the Paxalisib group.[14]
• Safety: In the NDU population within GBM AGILE, Paxalisib was reported to be well-tolerated with no new safety signals observed.[52]

The difference in overall survival outcomes for NDU GBM patients in the GBM AGILE trial between the primary analysis (using a cumulative control group) and the prespecified secondary analysis (using a concurrent control group) is a notable point. Regulatory agencies often prefer comparisons against concurrent controls as they better reflect the standard of care during the actual trial period. The 3.8-month median OS improvement observed in the concurrent control analysis, despite the arm not meeting initial Bayesian criteria for advancement to Stage 2, was considered clinically meaningful by the sponsor and formed the basis for further regulatory discussions with the FDA.[24]

Recurrent GBM:

Paxalisib has also been studied in patients with recurrent GBM.

• Genentech Phase I Study (NCT01547546): This study included 47 patients with recurrent high-grade gliomas. At the MTD of 45 mg/day, 19 patients (40%) achieved stable disease.[14]
• GBM AGILE (NCT03970447): In the recurrent disease (RD) cohort (Paxalisib n=100 vs. SOC [lomustine] n=188), Paxalisib did not demonstrate an OS benefit. The mean OS HR was 1.25 (Bayesian probability of HR<1.00 = 0.076). The model-estimated median OS was 8.58 months for Paxalisib versus 10.06 months for SOC.[52]

The lack of demonstrated benefit in the recurrent GBM setting within the larger GBM AGILE trial, contrasting with the stable disease observed in a proportion of patients in the earlier Genentech Phase I study, suggests that Paxalisib's primary therapeutic potential in GBM may reside in the newly diagnosed setting. The aggressive nature of recurrent GBM, often characterized by increased resistance to therapies, might limit the efficacy of Paxalisib as a monotherapy or when compared against an active control like lomustine in this patient population.

4.3. Clinical Trials in Pediatric Gliomas (DIPG/DMG)

Diffuse Intrinsic Pontine Glioma (DIPG) and Diffuse Midline Glioma (DMG), particularly those harboring the H3 K27M mutation, are highly aggressive pediatric brain tumors with extremely poor prognoses. Paxalisib's ability to penetrate the BBB makes it an attractive candidate for these challenging diseases.

• NCT03696355 (St. Jude Children's Research Hospital - First-in-Pediatrics Phase I Study): This trial was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of Paxalisib and to establish the pediatric MTD in children with newly diagnosed DIPG or other H3 K27M-mutant DMG, administered after focal radiotherapy.[7]
• The study employed a rolling-6 dose-escalation design.[35]
• The pediatric MTD for Paxalisib was established at 27 mg/m² once daily, which is approximately equivalent to 80% of the adult MTD.[35]
• Safety: At the MTD, Paxalisib was well-tolerated. The most frequent Grade 3 or 4 adverse events attributed to GDC-0084 were rash (5 patients), neutropenia (4 patients), and hyperglycemia (2 patients). DLTs observed at a higher dose level (35 mg/m²) were Grade 3 mucositis and Grade 3 rash. The only DLT at the MTD of 27 mg/m² was Grade 3 hyperglycemia.[35]
• PK: The mean elimination half-life of GDC-0084 was 20.6 ± 9.1 hours, comparable to that observed in adult patients. Systemic exposure (AUC0−48h​) at 27 mg/m² was 3399 ± 1301 hr·ng/mL.[35]
• Status: The first stage of the study successfully completed, and the study advanced into an expansion cohort to explore preliminary signals of efficacy.[56] Final data was anticipated for publication by the end of CY2022, according to a 2022 press release.[51]
• PNOC022 (NCT05009992 - DMG-ACT, Phase II Adaptive Platform Trial): This ongoing trial, sponsored by the Pacific Pediatric Neuro-Oncology Consortium (PNOC), is evaluating Paxalisib in combination with ONC201 for children and young adults with H3K27-altered DMG, including DIPG. The trial design allows for evaluation at initial diagnosis, post-radiation, and at the time of progression.[46]
• The scientific rationale for this combination is based on preclinical findings suggesting synergy between ONC201 (which activates the mitochondrial protease ClpP, targeting oxidative phosphorylation) and Paxalisib (which inhibits PI3K/mTOR, thereby impacting glycolysis) to induce metabolic distress in tumor cells.[46]
• Interim data presented in November 2023 reported a median OS from diagnosis of 16.5 months for patients in one cohort.[51] Other abstracts related to this study have mentioned median OS figures of 13.2 months (Cohort 1), 15.8 months (Cohort 2), and 8.8 months (Cohort 3) for the Paxalisib plus ONC201 combination, though specific cohort details and patient numbers for these figures require further clarification from full publications.[51]

The successful establishment of a tolerable pediatric MTD for Paxalisib, achieving exposures comparable to adults, represents a critical milestone in its development for these devastating childhood brain cancers. The combination strategy employed in the PNOC022 trial, which targets distinct metabolic vulnerabilities of DIPG/DMG cells, is a scientifically driven approach to address the aggressive nature of these tumors and overcome potential resistance mechanisms.

4.4. Clinical Trials in Other CNS Malignancies

Beyond GBM and pediatric gliomas, Paxalisib's brain-penetrant properties and mechanism of action have prompted its investigation in other CNS malignancies.

• Primary CNS Lymphoma (PCNSL):
• NCT04906096 (Phase II, Dana-Farber Cancer Institute): This ongoing trial is evaluating Paxalisib monotherapy in adult patients (≥18 years) with relapsed/refractory (R/R) primary diffuse large B-cell CNS lymphoma (DLBCL-CNSL) who have a Karnofsky Performance Status (KPS) ≥ 70.[65]
• The initial dosing regimen was 60 mg daily, but this was subsequently optimized to 15 mg twice daily (BID) or 30 mg once daily (QD) due to treatment-related adverse events (TRAEs), aiming to improve tolerability and durability of clinical benefit.[30]
• The primary endpoint is objective response rate (ORR) according to International PCNSL Collaborative Group (IPCG) criteria. Secondary endpoints include duration of response (DOR), PFS, OS, and safety.[68]
• A preliminary update in November 2023 indicated early clinical activity, with some patients achieving partial responses or stable disease. The TRAEs observed were consistent with Paxalisib's known safety profile, though they necessitated dose reductions or led to discontinuation for some participants.[68]
• Brain Metastases:
• NCT04192981 (Phase I): This trial is investigating Paxalisib in combination with whole-brain radiotherapy (WBRT) for the treatment of solid tumor brain metastases in adult patients whose tumors harbor PI3K pathway mutations (including PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PTEN, AKT1/2/3, MTOR, etc.) or leptomeningeal metastases.[58]
• Primary objectives include determining safety, tolerability, and the MTD of the combination. A key secondary endpoint is the local recurrence rate.[72]
• Interim data reported in August 2022 from the first stage of the trial (12 patients, 9 evaluable for efficacy) showed a promising ORR of 100%, with all evaluable patients exhibiting either a complete or partial response. The MTD of Paxalisib in combination with radiotherapy was confirmed as 45 mg daily. The safety profile was consistent with Paxalisib monotherapy experience.[72] Recruitment for an expansion stage was initiated.
• Advanced Breast Cancer (ABC-Pax trial, Phase Ib):
• Launched in January 2025 in Australia, this trial is evaluating Paxalisib in combination with either the immune checkpoint inhibitor pembrolizumab or the PARP inhibitor olaparib in women with advanced or triple-negative breast cancer (TNBC).[21]
• The rationale for this trial stems from preclinical data presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2024, which suggested synergistic activity between Paxalisib and these agents.[21]

The exploration of Paxalisib across this diverse range of CNS tumor types, including primary brain tumors of different histologies and metastatic disease, reflects a strategy to maximize its therapeutic potential. This strategy leverages its fundamental ability to cross the BBB and its targeted mechanism of action against the frequently dysregulated PI3K/mTOR pathway. The early positive signals observed in PCNSL and in combination with radiotherapy for brain metastases are particularly encouraging for these challenging clinical scenarios. The expansion into breast cancer, especially for patients with brain involvement or tumors with relevant PI3K pathway alterations, further broadens its potential applicability.

4.5. Overall Safety and Tolerability Profile in Clinical Settings

Across multiple clinical trials, Paxalisib has demonstrated a generally manageable safety profile at the established MTDs, which are typically 45 mg or 60 mg once daily in adult populations and 27 mg/m² once daily in pediatric patients.[17]

The adverse events (AEs) most commonly reported are consistent with the known class effects of PI3K/mTOR inhibitors, reflecting the pathway's role in normal physiological processes.[17] The most frequent AEs include:

• Hyperglycemia (elevated blood sugar)
• Mucositis or stomatitis (inflammation of the mucous membranes in the mouth)
• Rash
• Fatigue
• Nausea
• Neutropenia (in pediatric studies) [17]

Dose-limiting toxicities (DLTs) observed in adult dose-escalation studies at a 75 mg dose (higher than the MTD) included hyperglycemia and stomatitis.[19] In pediatric patients (NCT03696355), DLTs at 35 mg/m² were Grade 3 mucositis and Grade 3 rash, while Grade 3 hyperglycemia was the DLT at the pediatric MTD of 27 mg/m².[35]

No new or unexpected safety signals were reported in the newly diagnosed unmethylated GBM population within the GBM AGILE study.[52] However, in the Phase II trial for R/R PCNSL (NCT04906096), treatment-related adverse events led to dose optimization, with the starting dose being reduced from 60 mg daily to 15 mg BID or 30 mg QD to improve long-term tolerability.[68]

The safety profile of Paxalisib, while generally manageable with appropriate monitoring and supportive care, underscores the importance of its on-target effects on the PI3K/mTOR pathway, which is involved in glucose metabolism and tissue homeostasis. The need for dose adjustments or optimization in certain patient populations or for prolonged treatment durations, as seen in the PCNSL trial, highlights the ongoing process of refining the therapeutic window to balance efficacy with tolerability. The consistency of the AE profile across different studies and patient populations is generally reassuring from a drug development perspective.

Table 4: Overview of Key Clinical Trials for Paxalisib (GDC-0084)

NCT ID	Phase	Indication(s)	Key Objectives	Paxalisib Dosage/Regimen	Comparator(s)	Key Reported Outcomes	Status (as of latest info)	Sponsor/Collaborator(s)	Reference(s)
NCT01547546	I	Recurrent High-Grade Glioma	Safety, Tolerability, PK, MTD, Early Activity	2-65 mg QD	N/A	MTD: 45 mg/day; Linear PK; t1/2​ ~19h; SD: 40%; Metabolic PR (FDG-PET): 26%	Completed	Genentech	14
NCT03522298	II	Newly Diagnosed GBM (unmethylated MGMT)	MTD, Safety, PK, Clinical Activity	Dose Escalation (Stage 1), MTD (60mg QD) Fed vs. Fasted (Stage 2)	N/A (Stage 1), Internal randomization (Stage 2)	MTD: 60mg QD; Safety consistent with class; PK linear, no food effect; mPFS: 8.4-8.6mo; mOS: 15.7mo (ITT)	Completed	Kazia Therapeutics	19
NCT03970447	II/III (Adaptive Platform)	Glioblastoma (Newly Diagnosed Unmethylated & Recurrent)	OS	60 mg QD	Temozolomide (NDU), Lomustine (RD)	NDU: mOS 14.77mo (Pax) vs 13.84mo (SOC control, primary); mOS 15.54mo (Pax) vs 11.89mo (concurrent SOC, secondary). RD: mOS 8.58mo (Pax) vs 10.06mo (SOC). Did not proceed to Stage 2.	Accrual Complete for Paxalisib arm; Ongoing for other arms	Global Coalition for Adaptive Research	6
NCT03696355	I	Newly Diagnosed Pediatric DIPG/DMG (H3 K27M+)	Safety, PK, Pediatric MTD	Dose Escalation (Rolling-6) after focal RT	N/A	Pediatric MTD: 27 mg/m² QD; Tolerable; PK comparable to adults (t1/2​ ~20.6h)	Completed Stage 1, Expansion ongoing (as per older updates)	St. Jude Children's Research Hospital	1
NCT05009992	II (Adaptive Platform)	Pediatric DIPG/DMG (Initial Dx, Post-RT, Progression)	Efficacy, Safety	Paxalisib + ONC201	Other arms in platform	Interim mOS from Dx: 16.5mo (one cohort); Other cohorts: mOS 8.8-15.8mo.	Recruiting	PNOC	46
NCT04906096	II	Relapsed/Refractory Primary CNS Lymphoma (DLBCL type)	ORR (IPCG)	Paxalisib monotherapy (initially 60mg QD, optimized to 15mg BID or 30mg QD)	N/A	Preliminary activity: PRs and SD observed. TRAEs consistent with profile.	Recruiting	Dana-Farber Cancer Institute	65
NCT04192981	I	Solid Tumor Brain Metastases or Leptomeningeal Metastases (PI3K pathway mutated)	Safety, MTD (Paxalisib + WBRT)	Paxalisib + WBRT	N/A	Interim ORR: 100% (9 pts); MTD: 45mg QD Paxalisib with RT; Safety consistent.	Recruiting (expansion stage)	Multiple sites (e.g., Miami Cancer Institute)	58
ABC-Pax (Not yet on CT.gov in snippets)	Ib	Advanced/Triple-Negative Breast Cancer	Safety, Efficacy	Paxalisib + Pembrolizumab or Paxalisib + Olaparib	N/A	Preclinical synergy reported.	Recruiting (Australia)	Kazia Therapeutics / QIMR Berghofer	21

5. Regulatory Landscape and Future Directions

5.1. FDA Designations

Paxalisib has received multiple special designations from the U.S. Food and Drug Administration (FDA), acknowledging its potential to address unmet medical needs in serious and rare oncological conditions. These designations are intended to facilitate and expedite the development and review process.

• Orphan Drug Designation (ODD):
• Glioblastoma: Granted in February 2018.[6]
• Diffuse Intrinsic Pontine Glioma (DIPG): Granted in August 2020.[6]
• Atypical Teratoid / Rhabdoid Tumours (AT/RT): Granted in July 2022.[6]
• Fast Track Designation (FTD):
• Glioblastoma (for patients with unmethylated MGMT promoter status, following radiation plus temozolomide therapy): Granted in August 2020.[6]
• Solid tumor brain metastases harboring PI3K pathway mutations (in combination with radiation therapy): Granted in July 2023.[6]
• Rare Pediatric Disease Designation (RPDD):
• Diffuse Intrinsic Pontine Glioma (DIPG): Granted in August 2020.[6]
• Atypical Teratoid / Rhabdoid Tumours (AT/RT): Granted in June 2022.[6]

The accumulation of these FDA designations across several distinct brain cancer indications highlights the significant unmet medical need in these conditions. It also reflects the FDA's acknowledgment of Paxalisib's potential to offer a meaningful therapeutic advancement. Such designations provide valuable incentives, including potential market exclusivity, tax credits, and enhanced regulatory interaction, which can be particularly beneficial for smaller biotechnology companies like Kazia Therapeutics.

Table 5: FDA Regulatory Designations for Paxalisib

Designation Type	Indication	Date Granted	Reference(s)
Orphan Drug Designation (ODD)	Glioblastoma	February 2018	6
Fast Track Designation (FTD)	Glioblastoma (unmethylated MGMT, post-RT/TMZ)	August 2020	6
Rare Pediatric Disease Designation (RPDD)	Diffuse Intrinsic Pontine Glioma (DIPG)	August 2020	6
Orphan Drug Designation (ODD)	Diffuse Intrinsic Pontine Glioma (DIPG)	August 2020	6
Rare Pediatric Disease Designation (RPDD)	Atypical Teratoid / Rhabdoid Tumours (AT/RT)	June 2022	6
Orphan Drug Designation (ODD)	Atypical Teratoid / Rhabdoid Tumours (AT/RT)	July 2022	6
Fast Track Designation (FTD)	Solid tumor brain metastases (PI3K pathway mutations, with radiation therapy)	July 2023	6

5.2. Current Regulatory Standing and Discussions

Following the completion of Stage 1 of the Paxalisib arm in the GBM AGILE trial, Kazia Therapeutics engaged with the FDA to discuss the regulatory path forward for newly diagnosed unmethylated (NDU) glioblastoma. A Type C meeting was held in December 2024.[6]

The FDA's feedback indicated that while the overall survival (OS) data from the prespecified secondary analysis of GBM AGILE (which showed a 3.8-month median OS improvement for Paxalisib compared to a concurrent standard of care arm) would generally not be sufficient for an accelerated approval, it could potentially support a traditional or standard approval pathway.[24] This distinction is important: accelerated approval often relies on surrogate endpoints or particularly strong early data in areas of high unmet need, while standard approval typically requires more definitive evidence from well-controlled pivotal trials, often with OS as a primary endpoint.

Crucially, Kazia and the FDA reached alignment on key design aspects for a proposed new pivotal Phase 3 registration study for Paxalisib in NDU GBM. This includes agreement on the target patient population, the primary endpoint (likely OS), and the appropriate comparator arm.[24] The planned pivotal Phase 3 study is expected to enroll approximately 366 patients, randomized 1:1 to receive either Paxalisib or the standard of care (temozolomide). The study is planned to be conducted at approximately 50 clinical sites globally, including North America, the UK, Europe, and the Asia-Pacific region.[25]

Information regarding specific submissions or approval status with the European Medicines Agency (EMA) or the Australian Therapeutic Goods Administration (TGA) was not detailed in the provided materials.[14] However, the GBM AGILE trial was intended to include sites in Europe [62], and the 5G study involves UK and Australian institutions [21], indicating some level of international clinical development activity. Kazia also has a commercial licensee for Paxalisib in China.[14]

The FDA's willingness to consider the existing OS data from the GBM AGILE concurrent control analysis as supportive for a standard approval, despite Paxalisib not meeting the platform trial's internal criteria for advancement to Stage 2, represents a pragmatic regulatory approach. It acknowledges the clinical meaningfulness of the observed survival signal in a notoriously difficult-to-treat cancer and provides a defined path forward through a dedicated pivotal trial.

5.3. Patent Information

The intellectual property (IP) landscape for Paxalisib is multi-faceted, aiming to provide robust and extended market protection.

• Composition of Matter Patents: The original patents covering the chemical structure of Paxalisib (GDC-0084) generally expire around 2031. However, these may be eligible for patent term extension (PTE) in key territories, potentially extending protection for up to five additional years.[62] Such extensions are common for pharmaceutical products to compensate for regulatory review periods.
• Manufacturing Process Patents: Kazia Therapeutics has secured a new suite of patents covering the manufacturing process for Paxalisib. These have been granted in the United States and India, with a similar patent accepted in Australia and applications pending in the European Union, China, Canada, and other strategic regions. These manufacturing patents are set to expire in 2036.[62] This additional layer of IP protection is significant because it would require any potential generic competitor to develop an alternative, non-infringing method of chemical synthesis, which can be technically challenging and economically prohibitive.
• WIPO PATENTSCOPE: The PubChem database entry for Paxalisib (Chemical Identifier: LGWACEZVCMBSKW-UHFFFAOYSA-N) provides a link to WIPO's PATENTSCOPE database, which can be used to search for international patent applications related to this chemical structure.[8]
• Broader PI3K Inhibitor Patents: Genentech, the originator of Paxalisib, holds various patents related to PI3K inhibitors for cancer, including brain cancer (e.g., WO2023196899A2).[49] While these may not be exclusively for Paxalisib, they contribute to the broader IP environment for this class of compounds.

This multi-layered patent strategy, encompassing both composition of matter and manufacturing processes, is a standard industry practice designed to maximize the duration and strength of IP protection for a drug candidate. For a company like Kazia Therapeutics, robust IP is critical for securing investment, enabling further development, and ensuring commercial viability upon potential market approval.

5.4. Ongoing and Future Research

The clinical development of Paxalisib continues across a range of indications and in novel combinations, reflecting a strategy to fully explore its therapeutic potential.

• Ongoing Brain Cancer Trials: Paxalisib is still under active investigation in several ongoing clinical trials for various brain cancers, including:
• Pediatric brain cancer (DIPG/DMG): The St. Jude Phase I study (NCT03696355) has completed its initial stage, and the PNOC022 adaptive platform trial (NCT05009992) is evaluating Paxalisib in combination with ONC201.[1]
• Brain metastases from solid tumors (with PI3K pathway mutations): The Phase I trial NCT04192981 is assessing Paxalisib in combination with radiation therapy.[6]
• Primary CNS Lymphoma (R/R): The Phase II trial NCT04906096 is evaluating Paxalisib monotherapy.[6]
• Expansion into Other Cancers and Diseases:
• Advanced Breast Cancer: The ABC-Pax Phase Ib trial, launched in Australia in January 2025, is studying Paxalisib in combination with either pembrolizumab (immunotherapy) or olaparib (PARP inhibitor) for women with advanced or triple-negative breast cancer. This is based on preclinical data suggesting synergistic activity.[21]
• Parkinson's Disease: Kazia Therapeutics received a research grant from The Michael J. Fox Foundation in February 2025 to fund collaborative preclinical research with The Hebrew University of Jerusalem. This research will explore the therapeutic potential of Paxalisib in Parkinson's disease, investigating its impact on neuronal degeneration pathways, potentially linked to the inhibition of AKT phosphorylation of α-Synuclein A53T.[21]
• Genomically Guided Glioma Platform (5G Study): In February 2025, Kazia executed an agreement to evaluate Paxalisib in the 5G study, an academic trial in the UK and Australia. This platform study will enroll patients with PI3K/mTOR pathway mutations, whose tumors will be genomically sequenced to guide treatment with greater precision.[21]

This broad research program demonstrates a clear strategy to leverage Paxalisib's unique brain-penetrant properties and its established mechanism of action against the PI3K/mTOR pathway. The exploration of indications beyond primary brain tumors, such as brain metastases from other solid cancers, advanced breast cancer (particularly with CNS involvement or PI3K pathway alterations), and even neurodegenerative conditions like Parkinson's disease, aims to maximize its therapeutic potential. The investigation of combination therapies, especially with immunotherapy and PARP inhibitors, aligns with current trends in oncology seeking to overcome resistance and enhance efficacy by targeting multiple oncogenic pathways or modulating the tumor microenvironment.

6. Conclusion and Expert Summary

Paxalisib (GDC-0084) has emerged as a significant investigational agent in neuro-oncology, primarily due to its dual inhibition of the PI3K and mTOR pathways and, critically, its engineered ability to penetrate the blood-brain barrier. Originally developed by Genentech and now under the stewardship of Kazia Therapeutics, Paxalisib's journey reflects a focused effort to address the profound challenges in treating CNS malignancies.

Preclinical studies have robustly supported its mechanism of action, demonstrating potent inhibition of PI3K isoforms and mTOR, leading to antiproliferative effects and apoptosis in various cancer cell lines, particularly those with PI3K pathway alterations. The consistent demonstration of BBB penetration in multiple animal models, and subsequently in human studies, has been a cornerstone of its development rationale, differentiating it from many other PI3K inhibitors. In vivo efficacy in orthotopic brain tumor models, including glioblastoma and DIPG, along with evidence of target engagement within brain tissue, further solidified its therapeutic premise.

The clinical development of Paxalisib has been extensive, encompassing trials in newly diagnosed and recurrent glioblastoma, pediatric diffuse midline gliomas including DIPG, primary CNS lymphoma, and brain metastases. Key findings include the establishment of tolerable MTDs in both adult and pediatric populations, a generally manageable safety profile consistent with its drug class (with hyperglycemia and mucositis being notable AEs), and confirmation of human brain penetration and target engagement.

In glioblastoma, while the GBM AGILE platform trial did not meet its primary criteria for Paxalisib to advance to Stage 2 in the NDU cohort, a prespecified secondary analysis comparing Paxalisib to a concurrent standard-of-care arm revealed a clinically meaningful improvement in overall survival for patients with unmethylated MGMT promoter status. This finding has paved the way for discussions with the FDA regarding a new pivotal Phase 3 trial for this specific patient population. However, Paxalisib did not show a benefit in recurrent GBM in the same platform study.

For pediatric brain tumors, particularly DIPG/DMG, Paxalisib has shown promise in early-phase studies, with an established pediatric MTD and ongoing evaluation in combination therapies, such as with ONC201 in the PNOC022 trial, targeting distinct metabolic vulnerabilities. Early signals of activity have also been observed in trials for R/R primary CNS lymphoma and for brain metastases when combined with radiotherapy.

The regulatory landscape for Paxalisib is supported by multiple FDA designations, including Orphan Drug, Fast Track, and Rare Pediatric Disease designations across various brain cancer indications, underscoring the high unmet need and the drug's potential. The intellectual property portfolio, combining composition of matter and manufacturing patents, aims to provide extended market exclusivity.

Looking forward, the success of Paxalisib will likely depend on several factors:

1. Pivotal Trial Outcomes: The planned Phase 3 trial in NDU glioblastoma will be critical in confirming the OS benefit observed in the GBM AGILE secondary analysis.
2. Biomarker-Driven Strategies: Further elucidation and validation of predictive biomarkers (e.g., PIK3CA mutation status, MGMT promoter status, specific PI3K pathway alterations) will be essential for identifying patient populations most likely to benefit.
3. Rational Combination Therapies: Continued exploration of synergistic combinations, such as those being tested in pediatric gliomas (with ONC201) and advanced breast cancer (with immunotherapy or PARP inhibitors), may broaden its applicability and overcome resistance mechanisms.
4. Management of Tolerability: Ongoing efforts to optimize dosing regimens and manage class-effect toxicities will be crucial for long-term treatment and patient quality of life.

In summary, Paxalisib represents a rationally designed, brain-penetrant PI3K/mTOR inhibitor that has demonstrated encouraging signals of activity in several challenging CNS malignancies. While its development path has encountered hurdles typical of oncology drug development, particularly in the heterogeneous landscape of glioblastoma, the compelling preclinical data, confirmed human BBB penetration, and positive clinical signals in specific contexts provide a solid foundation for its continued investigation. Its potential to address critical unmet needs, especially in unmethylated GBM and aggressive pediatric brain tumors, remains a significant driving force for its ongoing and future clinical evaluation.

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