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Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents

Authors
Fabien Maldonado, MD
Andrew H Limper, MD
James R Jett, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editors
Diane MF Savarese, MD
Helen Hollingsworth, MD

INTRODUCTION

Adverse drug reactions (ADRs) due to antineoplastic agents are a common form of iatrogenic injury, and the lungs are a frequent target [1-3]. While some antineoplastic agent-induced ADRs are potentially preventable (particularly those that are related to cumulative dosing), many are idiosyncratic and unpredictable.

Increasingly, cancer treatment is selected based upon an individual tumor's molecular features, a practice termed molecularly targeted therapy. Examples include use of the monoclonal antibody trastuzumab for breast cancers that over-express HER2; imatinib, a tyrosine kinase (TK) inhibitor, for gastrointestinal stromal tumors with mutations in the KIT receptor TK, as well as chronic myelogenous leukemia (where the target is the Bcr-Abl fusion protein); and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab for metastatic colorectal tumors lacking mutations in the K ras oncogene. Many of these agents are associated with lung toxicity.

This topic review will provide an overview of the incidence and specific patterns of lung toxicity seen with molecularly targeted agents used for cancer therapy. A general discussion of the clinical presentation, pathogenesis, diagnosis, differential diagnosis, and treatment of pulmonary toxicity associated with the use of antineoplastic agents is covered separately, as is lung toxicity associated with conventional cytotoxic chemotherapy agents. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents".)

SMALL MOLECULE KINASE INHIBITORS

Anti-EGFR agents — Gefitinib (Iressa), erlotinib (Tarceva), and osimertinib (Tagrisso) are orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). They are primarily used in the treatment of advanced non-small cell lung cancer (NSCLC).

Approximately 1 percent of patients treated with gefitinib or erlotinib and 3 percent of patients treated with osimertinib develop lung toxicity, usually within the first two to three months of therapy. The risk is higher in patients with preexisting lung disease and in smokers. Approximately one-third of patients who develop interstitial lung disease (ILD) while being treated with gefitinib die of this complication. The mortality rate among patients receiving osimertinib appears to be lower; in one review of 813 cases, 27 developed ILD/pneumonitis, and 4 cases (15 percent of the total) were fatal [4]. The mortality rate in patients who develop ILD while receiving erlotinib is not well characterized but is likely similar to gefitinib, based on available information.

                            

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