A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy

Abstract

Background: Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear. Patients and methods: This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H 1 ¼ 30%) for the BM cohort and overall survival (OS) (H 1 ¼ 5 months) for the LM cohort. Results: The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progressionfree survival (PFS) was 7.6 months [95% confidence interval (CI) 5.0e16.6]; the median OS was 16.9 months [95% CI 7.9 enot reached (NR)]. In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1eNR); the median PFS was 8.0 months (95% CI 7.2eNR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n ¼ 18, P ¼ 0.39) and LM (n ¼ 17, P ¼ 0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P ¼ 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1e2. Conclusion: Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.

Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non–Small Cell Lung Cancers on the LIBRETTO-001 Trial

“…A major advance in the management of these tumors has been the development of brain-penetrant tyrosine-kinase inhibitors. 9,10 These agents not only prevent or delay intracranial treatment failure, but are also increasingly utilized as primary therapy for patients with brain metastases instead of localized interventions such as radiotherapy, an intervention potentially associated with longterm quality of life impairment. 11 Selpercatinib (LOXO-292), a highly potent and selective RET inhibitor, has marked and durable efficacy in patients with treatment-naïve or platinum chemotherapy-treated RET fusion-positive NSCLCs.…”

Leptomeningeal metastases from non-small cell lung cancer: state of the art and recent advances

“…Similar results were reported by Ahn et al [106] , retrospectively analyzing 22 patients with LM from EGFR T790M mutated NSCLC treated with osimertinib 80 mg/day: ORR was 55% (95%CI: 32-76), and median OS was 18.8 months (95%CI: 6.3-NC). Park et al [107] also reported an intracranial ORR of 55.0%, median PFS of 7.6 months (95%CI: 5.0-16.6),…”

“…Osimertinib 80 mg daily ORR 55% Median OS 18.8 months Park et al [107] , 2020 Ahn et al [109] , 2016 Prospective 29 (4 with LM) AZD3759 3/4 patients (75%) had a significant reduction of EGFR expression 1/4 patients (25%) had a CSF conversion in two consecutive samples…”

NEDD4L Regulates the Proliferation and Metastasis of Non-small-cell Lung Cancer by Mediating CPNE1 Ubiquitination

“…In the past two decades, signi cant advances have been made in the treatment of NSCLC that have improved our understanding of the biology and pathogenesis of tumor disease. The use of small molecule tyrosine kinase inhibitors and immunotherapy can increase the survival bene t in lung cancer patients, but drug resistance is a problem in some patients after treatment [3,4]. Currently, the overall cure and survival rates of NSCLC remain low.…”