What is the first-line treatment for metastatic adenocarcinoma with Epidermal Growth Factor Receptor (EGFR) exon 21 mutations?

From the Guidelines

The first-line treatment for metastatic adenocarcinoma with EGFR exon 21 mutations is osimertinib, specifically at a dose of 80 mg orally once daily, due to its superior efficacy and better side effect profile compared to earlier generation EGFR TKIs. This recommendation is based on the most recent and highest quality evidence from the NCCN clinical practice guidelines in oncology, version 4.2024 1. The guidelines recommend single-agent osimertinib as a preferred treatment option for patients with advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R mutations. Key points to consider in the management of these patients include:

• Osimertinib's ability to penetrate the central nervous system, making it a preferred option for patients with brain metastases
• The importance of monitoring for side effects such as rash, diarrhea, and paronychia, which are generally manageable with supportive care
• Regular imaging, typically every 2-3 months, to assess treatment response
• The consideration of local consolidative therapy, such as SABR or surgery, for patients with a limited number of initial sites of metastasis Additionally, other studies, such as the ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer 1, and the Pan-Asian adapted clinical practice guidelines for the management of patients with metastatic non-small-cell lung cancer 1, also support the use of osimertinib as a first-line treatment option for patients with EGFR exon 21 mutations. However, the most recent and highest quality evidence from the NCCN guidelines 1 takes precedence in guiding clinical decision-making. Some key considerations in the use of osimertinib include:
• Its superior efficacy compared to earlier generation EGFR TKIs, with response rates of 60-80% and progression-free survival of approximately 18-24 months
• Its better side effect profile, particularly regarding central nervous system penetration
• The importance of monitoring for side effects and adjusting treatment as needed
• The consideration of local consolidative therapy for patients with a limited number of initial sites of metastasis.

From the FDA Drug Label

1.3 First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC TAGRISSO is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)].

The first-line treatment for metastatic adenocarcinoma with Epidermal Growth Factor Receptor (EGFR) exon 21 L858R mutations is osimertinib (TAGRISSO). However, the provided drug labels do not specifically mention exon 21 mutations other than L858R.

• Key points:
  • Osimertinib (TAGRISSO) is indicated for the first-line treatment of metastatic NSCLC with EGFR exon 21 L858R mutations.
  • The labels do not provide information on the treatment of metastatic adenocarcinoma with other exon 21 mutations. 2

From the Research

First-Line Treatment for Metastatic Adenocarcinoma with EGFR Exon 21 Mutations

• The first-line treatment for metastatic adenocarcinoma with Epidermal Growth Factor Receptor (EGFR) exon 21 mutations typically involves EGFR tyrosine kinase inhibitors (EGFR-TKIs) 3.
• EGFR-TKIs are the standard of care in the first-line setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations, including exon 21 mutations 3.
• However, patients with exon 21 L858R mutations may exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations 3.

Combination Therapies

• Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the first-line setting for patients with metastatic adenocarcinoma and EGFR exon 21 mutations 3, 4.
• A meta-analysis found that erlotinib plus bevacizumab or ramucirumab yielded remarkable progression-free survival (PFS) benefits in patients with EGFR-mutated non-small cell lung cancer, including those with exon 21 mutations 4.

Resistance Mechanisms

• Resistance to EGFR-TKIs inevitably develops in all cases, supporting the importance of overall treatment planning 3.
• The introduction of third-generation (3G) EGFR-TKIs, such as osimertinib, provides an opportunity to overcome T790M-mediated resistance to first-generation (1G) and second-generation (2G) EGFR-TKIs 3.

Clinical Efficacy and Survival

• A study found that patients with EGFR exon 20 insertions, which are rare genetic alterations, had a poor response to EGFR-TKIs and a trend towards shorter overall survival compared to patients with classic EGFR mutations, including exon 21 mutations 5.
• Another study reported a case of a patient with advanced non-small cell lung cancer and concurrent exon 19 and 21 EGFR mutations who had a poor response to the first-line EGFR-TKI erlotinib 6.