Determining the appropriate treatment for different EGFR mutations in non-small cell lung cancer patients

ABSTRACT

Introduction

Epidermal growth factor receptor (EGFR) mutations occur in a significant fraction of non-small cell lung cancer (NSCLC) patients. Most common activating mutations are in-frame deletion in exon 19 and point mutation in exon 21. EGFR tyrosine kinase inhibitors (TKIs) represent standard of care of EGFR mutated patients bearing common mutations. Therapy for individuals carrying uncommon mutations, such as G719X, L861Q, S768I, is less defined and few options exist for individuals harboring EGFR exon 20 mutations. In all mutated patients, drug resistance remains the most critical clinical problem and new agents and strategies are under investigation.

Areas covered

We have reviewed the current status of NSCLC EGFR mutated treatment by analyzing data from preclinical studies, clinical prospective and retrospective trials in order to analyze current and future options for patients harboring different EGFR mutations.

Expert opinion

At the present time, available data demonstrated that osimertinib is the best EGFR-TKI for front-line therapy. Other agents, such as dacomitinib, and new drug combinations, such as regimens including anti-angiogenic agents or chemotherapy, demonstrated to significantly prolong progression-free survival or overall survival, representing potential alternative to osimertinib. Many questions remain opened, including best drug sequencing and needing of new therapeutic approaches extending patient survival and cure rate.

KEYWORDS:

• EGFR mutations
• EGFR TKIs
• uncommon EGFR mutations

Article highlights

• EGFR mutations occur in 10–15% of Caucasian patients with NSCLC, frequently in women, never or light smokers with adenocarcinoma. The most common activating mutations are in-frame deletion in exon 19 and point mutation in exon 21, accounting for 85–90%. The remaining 10% includes rare mutations such as G719X, L861Q, S768I, de novo T790M, and insertion of exon 20.

• Standard of care for patients with advanced NSCLC harboring classic mutations is EGFR TKIs. Third generation TKI osimertinib demonstrated superiority over EGFR TKIs of first generation and at the present time available data demonstrated that this drug is the best first-line option for EGFR mutant NSCLC.

• Dacomitinib demonstrated superiority compared to first generation TKI gefitinib, although at the moment its activity on CNS metastases remained unknown.

• Erlotinib combined to antiangiogenic antibodies (bevacizumab or ramucirumab) and gefitinib in association with chemotherapy demonstrated benefit in patients with classic mutations when compared, respectively, to single agents alone, although both the combinations showed higher toxicity rate.

• Therapeutic approaches for patients harboring uncommon mutations depend on the type of mutation and its sensitiveness to EGFR TKIs. Patients with G719X, L861Q, and S781I mutations benefit from treatment with TKIs, although OS, PFS, and RR are shorter than those reported in patients with del19 and L858R.

• Responsiveness to the EGFR-TKIs changes according to the different subtypes of exon 19 deletion. L1747-A750>P has been shown to be more sensitive to afatinib than erlotinib and osimertinib, suggesting this EGFR TKIs as the preferred choice of treatment.

• Patients harboring T790M mutation are resistant to first and second generation TKIs. Osimertinib is the standard of care for patients that presented T790M mutation of resistance developed during treatment with first and second EGFR TKIs as showed in the AURA 3 trial.

• Exon 20 insertion was not responsive to EGFR TKIs; thus, chemotherapy represented the main option in first-line setting. Two TKIs, poziotinib and TAK-788, were under investigation in pretreated patients bearing exon 20 insertion and were showing promising results.

Declaration of interest

F Cappuzzo has received fees for membership of an advisory board from Roche, AstraZeneca,Bristol-Meyer Squibb, Pfizer, Takeda,Lilly and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.