What is the initial treatment approach for patients with lung adenocarcinoma harboring an Epidermal Growth Factor Receptor (EGFR) exon 20 mutation?

From the Guidelines

The initial treatment approach for patients with lung adenocarcinoma harboring an EGFR exon 20 mutation should be platinum-based chemotherapy, preferably without checkpoint ICIs, as first-line therapy, with targeted agents such as amivantamab or mobocertinib considered as second-line therapy. This approach is based on the most recent and highest quality study, which recommends platinum-based chemotherapy as the first-line treatment for patients with EGFR exon 20 insertions mutant lung cancer 1. The study suggests that the disruption of the key protein structure at the a-C helix lowers the affinity for EGFR TKIs, making standard EGFR TKIs less effective.

Key Considerations

• Platinum-based chemotherapy is the recommended first-line treatment for patients with EGFR exon 20 mutations, with targeted therapy reserved for second-line treatment 1.
• Targeted agents such as amivantamab or mobocertinib should be considered as second-line therapy after platinum failure 1.
• The role of first-line single agent immunotherapy is uncertain and should not be prioritized, as both KEYNOTE 024 and KEYNOTE 042 have intentionally excluded patients with any type of EGFR mutations 1.
• A more recent study suggests that first-line treatment with amivantamab in combination with carboplatin-pemetrexed chemotherapy leads to improvements in PFS compared to chemotherapy alone for patients with EGFR exon 20 insertion alterations 1.

Treatment Options

• Platinum-based chemotherapy as first-line therapy, with targeted agents such as amivantamab or mobocertinib considered as second-line therapy 1.
• Amivantamab in combination with carboplatin-pemetrexed chemotherapy as first-line therapy for patients with EGFR exon 20 insertion alterations, with improvements in PFS compared to chemotherapy alone 1.
• Mobocertinib as a targeted therapy option for patients with EGFR exon 20 mutations, although its use as first-line therapy is not established 1.

Monitoring and Side Effects

• Patients should be monitored for specific side effects including rash, diarrhea, and infusion reactions with amivantamab, and QTc prolongation with mobocertinib.
• The safety profile of the combination of amivantamab with carboplatin-pemetrexed chemotherapy is comparable to that of each agent alone, with key AEs of interest from amivantamab including paronychia, rash, peripheral edema, and infusion reactions 1.

From the Research

Initial Treatment Approach for Lung Adenocarcinoma with EGFR Exon 20 Mutation

• The initial treatment approach for patients with lung adenocarcinoma harboring an Epidermal Growth Factor Receptor (EGFR) exon 20 mutation is a subject of ongoing research and debate 2, 3, 4, 5, 6.
• Historically, chemotherapy has been considered a standard treatment option for these patients, due to the limited efficacy of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) against EGFR exon 20 insertion mutations 2.
• However, recent studies have reported promising results with new treatment strategies, including next-generation TKIs, such as poziotinib, and bispecific antibodies, which may establish a new standard of care for these patients 3, 4.
• A systematic literature review and meta-analysis found that first-line chemotherapy resulted in a pooled overall response rate (ORR) of 25.7%, pooled progression-free survival (PFS) of 5.6 months, and pooled overall survival (OS) of 18.3 months 4.
• Another study reported a case of a patient with metastatic non-small cell lung cancer (NSCLC) harboring an EGFR exon 20 insertion mutation who achieved a complete response to poziotinib as first-line systemic therapy 3.
• Immunotherapy, including pembrolizumab, has also shown potential in treating patients with EGFR exon 20 insertion mutations, particularly in combination with chemotherapy or anti-angiogenic therapy 5, 6.
• A real-world study found that immunotherapy combined with chemotherapy (ICI+Chemo) was more effective than chemotherapy alone for patients with EGFR exon 20 insertion mutations, with a median PFS of 10.3 months vs 6.3 months (p=0.013) 6.

Treatment Options

• Chemotherapy: remains a standard treatment option for patients with lung adenocarcinoma harboring an EGFR exon 20 mutation 2, 4, 6.
• Next-generation TKIs: such as poziotinib, have shown promising results in treating patients with EGFR exon 20 insertion mutations 3, 4.
• Bispecific antibodies: may offer a new treatment option for patients with EGFR exon 20 insertion mutations 2.
• Immunotherapy: including pembrolizumab, has shown potential in treating patients with EGFR exon 20 insertion mutations, particularly in combination with chemotherapy or anti-angiogenic therapy 5, 6.