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A Primer on EGFR TKIs and Their Resistance Mechanisms and Treatments

*November 2021*

Note: The article below, In Depth Overview of Tyrosine Kinase Inhibitor Treatment of EGFR+ Lung Cancer, is taken from CancerConnect and lists and explains the different generations of TKIs, their modes of action and  resistance mechanisms that develop as well as their treatments.

EGFR-targeted drugs that have been shown to benefit select patients with NSCLC belong to a class of drugs known as tyrosine kinase inhibitors (TKIs). The drugs enter the cell and interfere with EGFR from within.

Tagrisso (Osimertinib) is the standard of care for patients with EGFR-mutated NSCLC, but the need for novel agents is underscored as disease progression on Tagrisso is inevitable. Bispecific antibodies, antibody-drug conjugates (ADCs), EGF vaccines, and fourth-generation EGFR TKIs are all under development to enrich the treatment paradigm.

First-generation EGFR TKIs

The working mechanism of first-generation EGFR-TKIs is to block the activation of downstream signaling induced by EGFR through binding to the ATP-binding sites.

  • Tarceva® (erlotinib)
  • Iressa® (gefitinib) is approved for patients whose tumors express the most common types of EGFR mutations in NSCLC (exon 19 deletions or exon 21 L858R substitution gene mutations). The therascreen EGFR RGQ PCR Kit was approved as a companion diagnostic test to identify patients with tumors having the EGFR gene mutations in order to determine which patients would be appropriate for treatment.
  • Icotininib (only available in China)

Second-generation EGFR TKIs

The development of second-generation EGFR TKIs was necessary to overcome the acquired resistance which comes from the failure of first-generation EGFR TKIs. So the working mechanisms of second-generation EGFR TKIs are not exactly similar to first-generation EGFR TKIs and these drugs can provide benefit when first generation drugs no longer work.

Third generation EGFR TKIs

Most patients treated with 1st or 2nd generation TKI’s will eventually develop resistance to treatment.2 Third generation TKI’s offer new hopes for patients with progressive NSCLC.

The most important mechanism of acquired resistance to these drugs is the EGFR T790M mutation. Occurrence of the T790M mutation is reported to be greater than 50%.3 To overcome this resistance third-generation EGFR-mutant selective TKIs were developed.4,5 These drugs are specifically designed to inhibit EGFR T790M.6,7

Third generation EGFR TKIs provide benefit in patients who progressed after treated with other EGFR TKIs especially in the T790M mutation-positive patients. Unfortunately there are resistance mechanisms to third-generation EGFR TKIs as well and the C797S mutation is considered the most challenging for Tagrisso.8,9

In Development:

  • Tarlox (tarloxitinib), for EGFR and Exon 20 insertion mutations.
  • TAK-788 is a third-generation oral inhibitor of EGFR exon 20 insertion mutations that was specifically designed to target the exon 20 insertion mutation. Overall response rates of ~ 45% are reported and the EXCLAIM extension cohort clinical trial is ongoing to determine effectiveness. Exon 20 mutations occur are associated with primary resistance to TKIs.29
  • Rybrevant (Amivantamb – JNJ-6372) is a fully human EGFR and mesenchymal epithelial transition (MET) bispecific antibody with immune cell-directing activity. Amivantamab targets the Exon 20 mutation – the third most prevalent EGFR mutation in NSCLC. Rybrevant is the first bispecific antibody to target both EGFR and MET and received FDA approval for use in adult patients with NSCLC who harbor EGFR exon 20 insertion mutations.
  • Lazertinib has activity in patients with NSCLC who have activating EGFR mutations, T790M, and central nervous system (CNS) disease. The phase 1 CHRYSALIS trial enrolled patients with metastatic/unresectable NSCLC who had measurable disease and EGFR exon 19 deletion or exon 21 (L858R) mutation. In an expansion cohort of 45 patients who had relapsed on osimertinib the combination of amivantamab plus Lazertinib demonstrated an overall response rate of 36% with a median duration of response of 9.6 months.38-40

Fourth-generation EGFR TKIs

In order to overcome the resistance to the C797S mutation which occurs in 32% of patients fourth-generation EGFR-TKIs are being developed.

  • BLU-945 is a TKI that was designed to suppress activating EGFR mutations and spare wild type EGFR.37
  • EAI045 EAI045 targets both the T790M and C797S EGFR mutants. Interestingly, it is only when combined with cetuximab that EAI045 is working.15

Read more.