Background: The third most common type of EGFR mutations seen in patients with NSCLC are exon 20 insertions, accounting for 4-12% of EGFR and 1-2% of all NSCLC mutations. Exon 20 insertions are considered particularly difficult to treat due to their poor response to standard first-, second-, and third- generation EGFR TKIs. Efficacy of current targeted therapies is dramatically impacted by which amino acids are affected by the 3-21 base pair insertion in EGFR exon 20. Due to poor targeted therapy response rates, the presence of EGFR exon 20 insertions are associated with worse patient outcomes.
- Clinical Features Associated: females, minimal/no smoking history, Asian ethnicity, adenocarcinoma histology, aggressive tumors, bone and CNS metastasis
- Detection Methods: NGS; PCR should be considered carefully as it has been shown to miss approximately 50% of exon 20 insertions.
- Most Common Alterations:
- Insertions: Representation of EGFR exon 20 mutations are shown in figure below.
- Of note: While most insertions identified to date do not respond to EGFR TKIs, exon 20 A763_Y764insFQEA has shown sensitivity to first-generation EGFR TKI erlotinib.
Acquired Resistance Mutations: The most common acquired resistance mutation is T790M, methionine substituted for threonine, within the active site of EGFR, accounting for more than half of all acquired resistance mutations from first-generation EGFR inhibitors in patients with NSCLC.
FDA-Approved Targeted Therapies:
- Osimertinib (Tagrisso, AstraZeneca):
- Third-generation EGFR TKI granted accelerated approval from the FDA in 2015 with full approval in 2017 for the treatment of patients with metastaticEGFR T790M-positive NSCLC who progressed on or after EGFR TKI therapy. Accelerated approval was granted based on two single-arm clinical trials — AURA and AURA2 — that showed a combined ORR of 59%. Full approval was based on the multicenter AURA3 clinical trial of patients with metastatic EGFR T790M-positive NSCLC who progressed on first-line EGFR TKI therapy. PFS was significantly improved in patients treated with osimertinib (10.1 months) compared with those treated with chemotherapy (4.4 months). In addition, an ORR of 57% was found in those patients with CNS tumor.
- Most Common Adverse Events: diarrhea, rash, dry skin, nail toxicity, fatigue, low white blood cell count
- Amivantamab (Rybrevant, Janssen):
- Monoclonal antibody therapy approved by the FDA in 2021 as front-line therapy for adult patients with NSCLC with EGFR exon 20 insertion mutations. The approval was based on the CHRYSALIS study of patients with EGFR 20 insertion-mutated NSCLC whose disease progressed on or after chemotherapy. At the time of approval, an ORR of 40% was found with a median duration of response of 11.1 months; 63% of patients experienced a duration of response of 6 months or longer.
- Most Common Adverse Events: rash, infusion-related reactions, skin infections around the nails, muscle and joint pain, shortness of breath, nausea, fatigue, swelling in the extremities or face, mouth sores, cough, constipation, vomiting, altered blood tests
- Mobocertinib (Exkivity, Takeda):
- An irreversible, small-molecule TKI granted approval by the FDA in 2021 for adults with locally advanced or metastatic NSCLC withEGFR exon 20 insertion mutations. The approval was based on an international, multi-cohort clinical trial, Study 101, of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. At the time of approval, an ORR of 28% was found with a median duration of response of 17.5 months.
- Most Common Adverse Events: diarrhea, rash, nausea, vomiting, decreased appetite, fatigue, dry skin, sore mouth, skin infections around the nails, muscle pain
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