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Local treatment of lung cancer by the inhalation route is an emerging therapeutic area, particularly for early stages of the disease when the cancer is localized in the lung tissue. This article outlines manufacturing and formulation considerations for local treatment of lung cancer by dry powder inhaler and highlights three recent case studies. 10 OctOber 2022 Inhalation Local treatment of non-small- cell lung cancer (NSCLC) by dry powder inhaler Repurposing approved compounds for improved patient outcomes Kimberly B. Shepard, PhD and Maureen Kadleck, BS Lonza Small Molecules Motivations for inhaled treatment of lung cancer Lung cancer remains the leading cause of cancer- related death worldwide. Total deaths from lung cancer exceed that of breast, colon, prostate and pan- creatic cancer combined, despite its relatively low prevalence, making up only 13% of newly- diagnosed cases [1]. is is due to its low survivability; for patients diagnosed with late stage (3+, with tumors distant from the lung) non-small cell lung cancer (NSCLC), the 5-year survival rate is only 8% [2]. Approximately 83% of lung cancer cases are NSCLC, which will be the focus of this article [1]. To combat NSCLC, a wide range of new chemi- cal entities and novel combinations of therapies are under investigation in clinical trials. For example, the United States National Cancer Institute lists 530 active clinical trials for patients throughout the stages of NSCLC [3]. Chemotherapy, radiation, immuno- therapy and targeted therapies are used in combina- tion depending on specific patient needs. Targeted therapies, which rely on genetic sequencing of tumor mutations, enable specialized treatment for each individual. e active pharmaceutical ingredients (APIs) used for NSCLC range from small molecules (e.g., cisplatin, erlotinib, crizotinib) to monoclonal antibodies (e.g., bevacizumab, pembrolizumab) [4]. All currently approved drugs for NSCLC are deliv- ered systemically, whether by intravenous infusion or oral administration. Systemic administration can be advantageous when cancer has spread beyond the lung into other parts of the body. However, sys- temic administration also exposes healthy tissues to the drug, which can lead to adverse effects. For many highly potent or cytotoxic APIs, dose-limiting tox- icity can prevent a drug from realizing its full ther- apeutic potential. Chemotherapy is a well-known example in which the patient can only tolerate the drug for a short time before adverse effects outweigh treatment benefits. For some APIs, such as bevaci- zumab, systemically associated adverse effects can lead to substantial exclusion criteria for patients who might otherwise benefit from treatment [5]. When treatments are administered by intravenous (IV) infusion, repeated visits to the clinic to receive treat- ment can place a substantial burden on patients. Local treatment of lung diseases by inhalation has been common for centuries and is today's stan- dard-of-care for numerous diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. In recent years, local delivery has been investigated in clinical trials for additional lung indications includ- ing pulmonary hypertension, lung infection and lung cancer. e reduced risk of systemic adverse effects and potential for reduced dose are compelling advan- tages of local delivery. Local treatment of lung cancer by the inhalation route is an emerging therapeutic area, particularly for early stages of the disease when the cancer is localized in the lung tissue. is article focuses on local treatment of lung cancer by dry powder inhaler (DPI), though nebulizers have also been investigated as a delivery technology, par- ticularly for inhaled biotherapeutics. Advantages of dry powder inhalers include their ease of use, quick administration and excellent shelf stability. Here, we outline manufacturing and formulation consider- ations for local treatment of lung cancer by dry pow- der inhaler and highlight three recent case studies. Spray drying to facilitate local delivery to the lungs Spray drying is a scalable manufacturing technique used to produce engineered pharmaceutical pow- ders. It combines the formulation and particle engi-