Osimertinib – effective treatment of NSCLC with activating EGFR mutations after progression on EGFR tyrosine kinase inhibitors

Abstract

Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib. The objective response rates to these drugs in randomised clinical trials were in the range of 56–74%, and median time to progression 9–13 months. The most common determinant of resistance to these drugs is the clonal expansion of cancer cells with T790M mutation (Thr790Met) in exon 20 of EGFR. Osimertinib (Tagrisso™), a 3rd generation, irreversible EGFR tyrosine kinase inhibitor, constitutes a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. Resistance mutation can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common. In this article, we present three cases that were successfully treated with osimertinib after progression on 1st and 2nd generation EGFR TKIs.

The Value of Liquid Biopsies for Guiding Therapy Decisions in Non-small Cell Lung Cancer

“…In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA via digital polymerase chain reaction (PCR) declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks ( 23 ). Monitoring T790M may indicate when the cancer is developing resistance to first- and second-generation TKIs and provides a basis for changing treatment toward drugs that have specific activity on the evolved mutation ( 34 , 36 ), i.e., third-generation TKIs such as osimertinib or chemotherapy.…”

Detection of somatic mutations in ctDNA derived from adenocarcinoma patients – EGFR tyrosine kinase inhibitor monitoring preliminary study

“…The p.Thr790Met mutation can also be assessed at academic research centers and commercial laboratories in Poland using standard collection of peripheral blood into K2EDTA tubes and isolation of plasma by centrifugation within 3 hours [17]. Reference oncology centers, such as the Franciszek Lukaszczyk Oncology Centre in Bydgoszcz, in which procedures such as transportation, storage and immediate processing of biological material are standardized, follow restrictive rules and take from 2 to 12 minutes.…”

A case report of toxic epidermal necrolysis associated with AZD-9291

“… 11 EGFR is obviously overexpressed in NSCLC. NSCLC with EGFR-activated mutations makes up about 10% of NSCLC cases, 12 suggesting that EGFR is a potential target for treating NSCLC. EGFR-TKIs are a kind of small molecular inhibitor that specifically functions in the tyrosine domain of EGFR through restraining the activation of tyrosine kinases, binding EGFR and blocking its signaling pathway, and ultimately suppressing tumor cell proliferation and differentiation, and promoting tumor cell apoptosis and other biological reactions.…”