Background: Transmembrane receptor tyrosine kinase protein involved in activation of various signaling pathways, including PI3K/Akt. Binding of EGFR to its ligand results in dimerization and tyrosine autophosphorylation leading to cell proliferation and maintenance. Alterations resulting in overexpression of EGFR are associated with tumorigenesis, reduced survival, lymph node metastasis and poor chemosensitivity. EGFR mutations occur predominately in exons 18-21 and are identified in approximately 10-15% of patients with NSCLC.
- Clinical Features Associated: females, minimal/no smoking history, adenocarcinoma histology, Asian ethnicity
Detection Methods: NGS, FISH, PCR, liquid biopsy (when tissue biopsy unavailable)
Most Common Alterations:
- Sensitizing (Classical) Mutations: These mutations account for approximately 90% of EGFR mutations in NSCLC. Sensitizing mutations are associated with high sensitivity to and prolonged progression-free survival (PFS) with targeted EGFR tyrosine kinase inhibitors (TKIs) compared with chemotherapy. The most common mutations include:
- Exon 19 Deletions destabilize the inactive form of EGFR, causing it to remain in the active conformation. These deletions account for around 45% of all EGFR mutations. The most common frame shift deletion is delE756-A750, followed by delL747_P753insS and delL747_A750insP.
- Exon 21 Point Mutations lock EGFR in a constitutively active conformation and account for 40% of EGFR mutations. The most common exon 21 mutation is L858R.
- Uncommon Mutations: Rare EGFR mutations account for roughly 5-10% of EGFR mutations. The location of these mutations can have significant effects on sensitivity to EGFR TKIs. The most common include exon 20 S7681 (3% EGFR mutations), exon 21 L861Q (1%) and exon 18 G719X (1%).
- Acquired Resistance Mutations: These mutations occur after treatment with TKI therapy. The most common post-first- and second-line EGFR TKI acquired resistance mutation is exon 20 T790M. The most common post-third generation EGFR TKI therapy mutation is exon 20 C797S, which accounts for 10-26% of resistance mutations following osimertinib (Tagrisso, AstraZeneca) therapy.
FDA-Approved Targeted Therapies:
*NCCN guidelines recommend osimertinib as first-line therapy for EGFR-sensitizing mutations. Additionally, targeted therapy is recommended prior to chemotherapy or immunotherapy.
Table 1. FDA Approved EGFR Tyrosine Kinase Inhibitors used in the Treatment of NSCLC
- Erlotinib (Tarceva, Roche):
- First-generation EGFR TKI granted accelerated approval by the FDA in 2004 for treatment of patients with locally advanced or metastatic NSCLC who progressed on at least one prior chemotherapy regimen. Approval was based on a single randomized trial of patients with stage IIIB or IV NSCLC who failed one or two prior chemotherapy regimens. A response rate of 8.9% and median OS of 6.7 months was found compared with 4.7 months in the placebo arm. This approval was later expanded by the FDA to include maintenance therapy for patients with locally advanced or metastatic NSCLC who had not progressed after first-line chemotherapy. In 2013, FDA expanded approval of erlotinib further into the first-line setting to include patients with metastatic NSCLC with eitherEGFR exon 19 deletions or exon 21 L858R substitution. This approval was based on a phase 3 clinical trial (EURTAC) with PFS of 10.4 months compared with 5.2 months with chemotherapy.
- Most Common Adverse Events: diarrhea, rash, nausea, vomiting, cough, shortness of breath, decreased appetite
- Gefitinib (Iressa, AstraZeneca):
- First-generation EGFR TKI granted accelerated approval by the FDA in 2003 for patients with advanced stage NSCLC who progressed on both platinum-based and docetaxel chemotherapies prior to biomarker screening for EGFR. The approval was based on two phase 2 clinical trials— IDEAL 1 and 2 — with an objective response rate (ORR) of 15%. However, gefitinib was removed from the market in 2005 due to perceived ineffectiveness at the time with exceptions granted to patients already receiving and benefiting from gefitinib or for use in clinical trials. In 2015, gefitinib returned to the U.S. market with FDA approval for first-line therapy in patients with metastatic NSCLC with confirmed EGFR mutations (EGFR exon 19 deletions or exon 21 L858R substitution) based on biomarker testing. The new approval was based on a multicenter study of treatment-naive patients with metastatic EGFR-positive NSCLC. An ORR of 50% was found, with median duration of response of 6 months.
- Most Common Adverse Events: diarrhea, rash, acne, dry and itchy skin, decreased appetite, shortness of breath
- Afatinib (Gilotrif, Boehringer Ingelheim):
- Second-generation irreversible EGFR TKI approved by the FDA in 2013 for first-line therapy of patients with commonEGFR-mutated metastatic NSCLC. The approval was based on an international, multicenter phase 3 clinical trial of patients with metastatic EGFR-mutated NSCLC. An ORR of 50.4% was found, with median PFS of 11.1 months. In 2018, the FDA broadened approval to the first-line setting for patients with metastatic NSCLC positive for other nonresistant EGFR mutations (including S768I, L861Q, and/or G719X). This indication was based on a subset of patients from LUX-LUNG 2, 3, and 6 clinical trials. An ORR of 66% was found across these three trials, with 52% of patients experiencing a duration of response of 12 months or longer.
- Most Common Adverse Events: diarrhea, rash, dry skin, decreased appetite, vomiting, fatigue, sore mouth, skin infection around the nails, itchy skin,shortness of breath
- Osimertinib (Tagrisso, AstraZeneca):
- Third-generation EGFR TKI was granted accelerated approval by the FDA in 2015 with full approval in 2017 for the treatment of patients with metastaticEGFR T790M mutation-positive NSCLC whose disease progressed after EGFR TKI therapy. In 2018, osimertinib was granted broadened approval by the FDA for first-line therapy of patients with metastatic NSCLC with common EGFR mutations. This approval was based on the international, multicenter FLAURA clinical trial of unresectable or metastatic NSCLC patients with EGFR exon 19 deletions or exon 21 L858R substitution who progressed on prior systemic therapy. At the time of approval, the median PFS was 18.9 months vs. 10.2 months with first-generation EGFR TKIs (gefitinib or erlotinib). Updated results from the phase 3 FLAURA trial showed median OS of 38.6 months compared with 31.8 months with erlotinib or gefitinib and enhanced central nervous system (CNS) penetration and efficacy (PFS of 15.2 months vs. 9.6 months, respectively).
- Most Common Adverse Events: diarrhea, nausea, rash, dry skin, nail toxicity, sores mouth, decreased appetite
- Dacomitinib (Vizimpro, Pfizer):
- Second-generation irreversible EGFR TKI approved by the FDA in 2018 for first-line therapy of patients with metastatic NSCLC withEGFR exon 19 deletions or exon 21 L858R substitution mutations. The approval was based on the multicenter ARCHER 1050 clinical trial of patients with unresectable, metastatic NSCLC with common EGFR mutations and a minimum of 12 months disease-free post-systemic therapy. No significant difference was found in ORR and OS between patients treated with dacomitinib or gefitinib; however, a significant improvement in PFS of 14.7 months vs. 9.2 months, respectively, was found.
- Most Common Adverse Events: diarrhea, interstitial lung disease, rash, skin infection around the nails, sore mouth, decreased appetite, dry skin, decreased weight, cough, itchy and dry skin, hair loss
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