EGFR-Directed Therapy in Lung Cancer

The epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a clinically significant driver alteration affecting approximately one-third of lung cancer patients. Osimertinib has been the widely accepted first-line therapy, but resistance through on-target and off-target pathways eventually develop. This Element describes the structural biology and pathophysiology of EGFR-mutant NSCLC and discusses past, current, and future treatment options in the metastatic, neoadjuvant, and adjuvant settings. It also outlines the promising clinical applications of circulating tumor DNA (ctDNA).

Format: Paperback / softback
Length: 75 pages
Publication date: 26 January 2023
Publisher: Cambridge University Press

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a clinically significant driver alteration affecting approximately one-third of lung cancer patients. Over the past decade, treatments for EGFR-exon 19 deletion and exon 21 L858R NSCLC have evolved from first-generation reversible tyrosine kinase inhibitors (TKI) to third-generation irreversible TKIs, with osimertinib widely accepted as the first-line therapy. While osimertinib has demonstrated survival improvement and efficacy against acquired T790M mutation, resistance through on-target and off-target pathways eventually develops. This Element provides an overview of the structural biology and pathophysiology of EGFR-mutant NSCLC, discusses past, current, and future treatment options in the metastatic, neoadjuvant, and adjuvant settings, highlights the biology and recently approved treatment for EGFR-exon 20 insertion mutation, and outlines the promising clinical applications of circulating tumor DNA (ctDNA).

EGFR-mutant NSCLC is a complex disease characterized by the presence of genetic mutations in the EGFR protein. These mutations lead to abnormal signaling and activation of the EGFR pathway, which promotes tumor growth and progression. The most common EGFR mutations in NSCLC include exon 19 deletion (del19) and exon 21 L858R mutation (L858R).

First-generation reversible TKIs, such as gefitinib and erlotinib, were initially used to treat EGFR-mutant NSCLC. However, these drugs were limited by their ability to target only the active EGFR mutation, leading to the development of resistance. As a result, second-generation irreversible TKIs, such as osimertinib, were developed to overcome this resistance.

Osimertinib is a highly potent and selective inhibitor of EGFR tyrosine kinase activity. It has been shown to improve survival outcomes in patients with EGFR-mutant NSCLC, particularly those with the L858R mutation. Osimertinib works by blocking the activation of EGFR and preventing the formation of new tumor cells.

In addition to osimertinib, other third-generation irreversible TKIs, such as afatinib and dacomitinib, have also been approved for the treatment of EGFR-mutant NSCLC. These drugs have similar mechanisms of action to osimertinib and are also effective in treating patients with EGFR-mutant NSCLC.

However, despite the success of these treatments, resistance to EGFR-mutant NSCLC eventually develops. This resistance can occur through on-target and off-target pathways. On-target resistance occurs when the EGFR mutation prevents the drug from binding to the EGFR protein, while off-target resistance occurs when the drug targets other proteins in the body that are involved in tumor growth and progression.

One of the most common mechanisms of on-target resistance is the development of the T790M mutation. This mutation occurs in approximately 20% of patients with EGFR-mutant NSCLC and leads to the activation of EGFR signaling even in the presence of osimertinib.

To overcome on-target resistance, researchers have developed new treatment strategies. One such strategy is the use of combination therapy, which involves the use of multiple drugs to target different pathways in the tumor. For example, osimertinib can be combined with chemotherapy or immunotherapy to improve treatment outcomes.

Another strategy is the use of targeted therapy, which involves the use of drugs that specifically target the EGFR mutation or other proteins involved in tumor growth and progression. For example, afatinib is a targeted therapy that targets the EGFR mutation and has been shown to be effective in treating patients with T790M mutation-positive NSCLC.

In addition to these treatment strategies, there are also several promising clinical applications of circulating tumor DNA (ctDNA). ctDNA is a form of genetic material that is released into the bloodstream by tumor cells. It can be used to detect and monitor tumor progression, as well as to guide treatment decisions.

For example, ctDNA can be used to detect the presence of EGFR mutations in patients with NSCLC. This can help physicians identify patients who are eligible for EGFR-mutant NSCLC treatment and monitor their response to treatment. ctDNA can also be used to monitor the development of resistance to EGFR-mutant NSCLC treatment.

In conclusion, EGFR-mutant NSCLC is a clinically significant driver alteration affecting approximately one-third of lung cancer patients. Treatments for EGFR-exon 19 deletion and exon 21 L858R NSCLC have evolved over the past decade from first-generation reversible tyrosine kinase inhibitors to third-generation irreversible TKIs, with osimertinib widely accepted as the first-line therapy. While osimertinib has demonstrated survival improvement and efficacy against acquired T790M mutation, resistance through on-target and off-target pathways eventually develops. To overcome this resistance, researchers have developed new treatment strategies, such as combination therapy and targeted therapy, as well as the use of circulating tumor DNA. These strategies have the potential to improve treatment outcomes and improve patient care.

ISBN-13: 9781009342308