Research Summary
Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations have a notably increased incidence of brain metastases, compared to patients without EGFR mutations. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, has demonstrated intracranial activity, and an American Society of Clinical Oncology (ASCO)-Society for Neuro-Oncology (SNO)-American Society for Radiation Oncology (ASTRO) guideline recommended the use of osimertinib monotherapy and the delay of local therapy until intracranial progression in patients with EGFR-mutated NSCLC with asymptomatic brain metastases; however, this recommendation was reached by informal consensus, and evidence quality was low. In this retrospective cohort study, Imber et al1 assessed intracranial outcomes among patients with EGFR-mutated NSCLC with previously untreated brain lesions who received osimertinib treatment.
Patients with EGFR-mutated NSCLC treated with osimertinib monotherapy as the initial therapy after brain metastasis diagnosis between 2014 and 2022 were eligible for inclusion. Patients who received prior treatment with stereotactic radiosurgery, whole brain radiotherapy, or surgery for brain metastasis before starting osimertinib were not eligible for inclusion. Patients were also required to have a baseline magnetic resonance imaging (MRI) scan, as well as at least one MRI scan following osimertinib initiation. There was no minimum brain lesion size requirement. Complete response was defined as lesion disappearance, and partial response was defined as a 30-percent or greater decrease of the lesion. Progressive disease was defined as a 20-percent or greater increase in lesion size relative to the nadir or the development of new brain metastasis. All other scenarios were defined as stable disease.
Thirty-six patients were included for analysis. Most patients were female (72%) and had no smoking history (69%). Eighty-six percent of patients presented with extracranial metastases as well. Fifty percent of patients had neurological symptoms attributable to brain metastases. EGFR exon 19 deletion (67%) and L858R mutation (22%) were the most common mutations. Two patients had missense mutations, and one patient had exon 19 insertion. Median time to osimertinib initiation following brain metastasis diagnosis was 25 days.
A total of 136 brain lesions were treated. Thirteen patients (36%) had at least 11 brain lesions; 6 to 10 and 2 to 5 lesions were reported in eight patients (22%) each. Seven patients (19%) had only one brain lesion. The median maximum diameter at baseline was 0.66cm, with 42 lesions (30.9%) having a diameter larger than 1cm.
At first MRI reassessment following osimertinib initiation, 66 brain lesions (49%) demonstrated partial response, 64 (47%) demonstrated complete response, and six (4.4%) showed stable disease. Over the study period, complete response was reported as the best response in 105 lesions (77.2%), with partial response recorded as the best response in the remaining 31 lesions; therefore, the best overall response rate was 100 percent. Median time to best response was 95.5 days.
The median follow-up from the start of osimertinib treatment was 2.6 years, and median overall survival was not reached. Post-osimertinib therapy, the one-year survival estimate was 90.9 percent. Two- and three-year survival estimates were 79.7 and 62.4 percent, respectively.
At a median time of nine months after osimertinib initiation, disease progression was reported in 21 patients, with 12 patients experiencing their first progression outside of the central nervous system (CNS) only. Eight patients had CNS only disease progression, and mixed CNS/extra-CNS progression was observed in one patient. Twelve CNS progression events occurred, four of which were leptomeningeal. Three local parenchymal only, three distant parenchymal only, and two local/distant parenchymal CNS progression events were reported. One year following osimertinib initiation, the rate of CNS progression was 21.3 percent; this increased to 41.2 percent at three years post-osimertinib initiation.
Although there were no significant associations between clinicodemographic factors and risk of CNS progression following osimertinib initiation, a trend toward complete response in lesions with a diameter less than 1cm and partial response in lesions with a diameter of 1cm or larger within the first year of osimertinib treatment was observed.
Limitations of this study included potential referral and selection biases, as there were no consistent criteria to guide osimertinib monotherapy. Also, lesions were generally smaller among included patients, compared to excluded patients. Detection biases when tracking small lesions (<5mm) were possible. Furthermore, scan thickness varied among post-treatment scans due to the retrospective nature of the study.
This study demonstrated the efficacy of osimertinib monotherapy in the treatment of patients with EGFR-mutated NSCLC with previously untreated brain metastases. Patients with brain lesions smaller than 1cm in diameter might especially benefit with first-line osimertinib monotherapy.
Reference
- Imber BS, Sehgal R, Saganty R, et al. Intracranial outcomes of de novo brain metastases treated with osimertinib alone in patients with newly diagnosed EGFR-mutant NSCLC. JTO Clin Res Rep. 2023;4(12):100607.