First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases

Abstract

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have shown greater activity. However, their efficacy has not been well-studied in later therapy lines in NSCLC patients with BMs (NSCLC-BM). We sought to compare outcomes of NSCLC-BM treated with either first- or third-generation EGFR-TKIs in first-line and 2nd-to-5th-line settings. Methods: A retrospective review of NSCLC-BM patients diagnosed during 2010–2019 at Cleveland Clinic, Ohio, US, a quaternary-care center, was performed and reported following ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) guidelines. Data regarding socio-demographic, histopathological, molecular characteristics, and clinical outcomes were collected. Primary outcomes were median overall survival (mOS) and progression-free survival (mPFS). Multivariable Cox proportional hazards modeling and propensity score matching were utilized to adjust for confounders. Results: 239 NSCLC-BM patients with EGFR alterations were identified, of which 107 received EGFR-TKIs after diagnosis of BMs. 77.6% (83/107) received it as first-line treatment, and 30.8% (33/107) received it in later (2nd–5th) lines of therapy, with nine patients receiving it in both settings. 64 of 107 patients received first-generation (erlotinib/gefitinib) TKIs, with 53 receiving them in the first line setting and 13 receiving it in the 2nd–5th lines of therapy. 50 patients received Osimertinib as third-generation EGFR-TKI, 30 in first-line, and 20 in the 2nd–5th lines of therapy. Univariable analysis in first-line therapy demonstrated mOS of first- and third-generation EGFR-TKIs as 18.2 and 19.4 months, respectively (p = 0.57), while unadjusted mPFS of first- and third-generation EGFR-TKIs was 9.3 and 13.8 months, respectively (p = 0.14). In 2nd–5th line therapy, for first- and third-generation EGFR-TKIs, mOS was 17.3 and 11.9 months, (p = 0.19), while mPFS was 10.4 and 6.08 months, respectively (p = 0.41). After adjusting for age, performance status, presence of extracranial metastases, whole-brain radiotherapy, and presence of leptomeningeal metastases, hazard ratio (HR) for OS was 1.25 (95% CI 0.63–2.49, p = 0.52) for first-line therapy. Adjusted HR for mOS in 2nd-to-5th line therapy was 1.60 (95% CI 0.55–4.69, p = 0.39). Conclusions: No difference in survival was detected between first- and third-generation EGFR-TKIs in either first or 2nd-to-5th lines of therapy. Larger prospective studies are warranted reporting intracranial lesion size, EGFR alteration and expression levels in primary tumor and brain metastases, and response rates.

The disappearance of gastric metastasis and liver metastasis in non-small cell lung adenocarcinoma is due to osimertinib

“…Osimertinib is a third-generation TKI. The FDA approved osimertinib as first-line treatment for NSCLC carrying EGFR exon 19 deletion or exon 21 L858R mutation in April 2018 after comparing the efficacy of osimertinib with standard treatment through the FLAURA trial (Tatineni et al 2023 ; Kim et al 2009 ). Reports in the literature show that osimertinib, a third-generation, CNS-permeable, oral EGFR TKI, has shown good efficacy in patients with brain metastases regardless of T790 M (Lee et al 2020 ).…”

“…Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR–TKI) have been approved for the treatment of advanced non-small cell lung cancer (NSCLC) carrying EGFR-activating mutations. Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that was evaluated in the FLAURA trial compared to standard EGFR–TKI, gefitinib or erlotinib, leading to FDA approval of osimertinib in April 2018 as a first-line treatment for NSCLC (Tatineni et al 2023 ).…”

Targeted therapeutic options in early and metastatic NSCLC-overview

“…First- and second-generation drugs have limited brain penetration, while osimertinib rapidly crosses the blood-brain barrier (BBB) and reaches higher concentrations. Osimertinib, which has the best efficacy and most favorable side-effect profile of all EGFR inhibitors, is currently the drug for first-line treatment of EGFR mutant NSCLC, particularly in patients with BM [ 31 ]. If not available in the first line, first or second-generation agents should be administered, and in case of progression, efforts should be made to confirm T790 resistance mutation from liquid biopsy or repeated histological sampling.…”

Potential Molecular Targets in the Treatment of Patients with CNS Tumors

“…The most common solid tumor BM arises from lung cancer [3]. Tatineni et al evaluated the efficacy of first versus third-generation EGFR TKIs in EGFR-mutated NSCLC BM in both first line and later line treatments [4]. Although no survival benefits between the first-and third-generation EGFR TKIs were found, larger prospective studies to confirm these findings are warranted.…”