Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer most commonly linked to asbestos exposure. Current treatment options, including surgery, chemotherapy, and immunotherapy, offer limited survival benefits and are often palliative in nature. Despite recent advances, such as the approval of immunotherapy combinations, overall prognosis remains poor. There is a critical need for novel, more effective, and better-targeted therapies. One emerging area of interest involves repurposing existing cancer drugs and exploring innovative delivery methods to improve outcomes in MPM.
In this interview, Mural Quadros, PhD candidate, Industrial Pharmacy (St John’s University, New York, USA) discusses current treatment challenges in MPM, the rationale for investigating osimertinib in this indication, and the key findings from their preclinical study. The abstract “Inhaled Osimertinib for the Treatment of Malignant Pleural Mesothelioma” was presented at ATS 2025 International Conference, San Francisco, 16–21 May.
Q. Could you give an overview of the current treatment paradigm for MPM?
Malignant pleural mesothelioma (MPM) is an aggressive and rare cancer, primarily caused by asbestos exposure. The current standard of care involves a combination of surgery, chemotherapy, typically cisplatin with pemetrexed, and, in some cases, radiation therapy. However, these approaches are largely palliative, with limited survival benefit. Immunotherapy regimens, such as nivolumab and ipilimumab, have recently been approved for unresectable MPM and show promise in improving overall survival. Despite these advancements, treatment options remain limited, and prognosis remains poor, underscoring the urgent need for novel, more effective therapies.
Q. What was the rationale for investigating osimertinib for the treatment of MPM?
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations. Although MPM typically lacks these specific EGFR mutations, emerging evidence indicates that EGFR pathway activation via overexpression may play a role in MPM progression. In our preliminary in-vitro studies, osimertinib demonstrated significant cytotoxic effects in MPM cell lines despite their EGFR wild-type status, suggesting a possible mutation-independent or off-target mechanism of action. Coupled with osimertinib’s favourable safety profile, established pharmacokinetics, and FDA approval for other indications, these findings provided a strong rationale for repurposing osimertinib as a potential therapeutic agent for MPM.
Q. How will the inhaled formulation of osimertinib improve drug delivery and targeting?
Delivering osimertinib via the inhalation route offers several pharmacological and clinical advantages. First, it enables direct drug delivery to the pleural and pulmonary region, increasing local drug concentration at the tumour site, while minimizing systemic exposure and associated toxicities. This targeted approach enhances therapeutic efficacy, particularly in tumours confined to the thoracic cavity like MPM. Additionally, pulmonary delivery bypasses hepatic first-pass metabolism, potentially improving bioavailability and allowing for dose reduction. This method aligns with the growing interest in non-invasive, localized therapies for thoracic malignancies.
Q. What was the methodology of your study?
We selected poly(lactic-co-glycolic acid) (PLGA) as the nanoparticle matrix, due to its biodegradability, biocompatibility, and FDA approval for use in controlled-release and depot formulations, making it ideal for pulmonary drug delivery. Osimertinib-loaded PLGA nanoparticles were formulated by optimizing two critical process parameters, sonication time and polyvinyl alcohol (PVA) concentration, which influence particle morphology and, consequently, drug encapsulation efficiency, particle size, and aerodynamic deposition in the respiratory tract. The nanoparticles were thoroughly characterized for their physicochemical properties, including particle size, zeta potential, surface morphology, and encapsulation efficiency, while in-vitro drug release studies were performed to assess sustained release behaviour. To evaluate biological efficacy, we utilized both 2D monolayer cultures and 3D tumour spheroid models of MPM. Cytotoxicity assays in 2D cultures provided an initial measure of therapeutic activity, while 3D spheroids allowed assessment of nanoparticle penetration and efficacy in a more physiologically relevant tumour environment. Finally, aerosol performance was evaluated using a Next Generation Impactor (NGI) to determine aerodynamic particle size distribution and to confirm the formulation’s suitability for deep lung delivery via inhalation.
Q. What were the findings from the study, and what is the clinical significance of these findings?
Our findings demonstrated that the inhalable PLGA-osimertinib nanoparticles exhibited excellent aerodynamic properties with mass median aerodynamic diameters within the respirable range. The formulation showed significantly enhanced cytotoxicity in MPM cells compared to free drug, with improved tumour penetration in 3D models. These results indicate that osimertinib, when delivered directly to the lungs, holds promise as a localized and effective therapy for MPM. Clinically, this approach could shift the treatment paradigm by offering a non-invasive, targeted alternative with reduced systemic toxicity and enhanced patient compliance.
References
- Quadros M and Gupta V. Inhaled Osimertinib for the Treatment of Malignant Pleural Mesothelioma. Am J Respir Crit Care Med 2025;211:A6563. Available at: https://doi.org/10.1164/ajrccm.2025.211.Abstracts.A6563 (accessed 20 May 2025).
Further content in lung cancer.
Editor: Victoria Jones, Senior Content Editor.
Disclosures: This short article was prepared by touchRESPIRATORY in collaboration with Dr Mural Quadros. touchRESPIRATORY utilize AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No fees or funding were associated with its publication.
Cite: Dr Mural Quadros. Targeting a Rare and Aggressive Lung Cancer: A Study of Inhaled Osimertinib for Malignant Pleural Mesothelioma: Mural Quadros, ATS 2025. touchRESPIRATORY. 20 May 2025.
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