Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Abstract

Purpose: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632).Results: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11 C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11 C]rociletinib and [ 11 C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported.Conclusions: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing.

Optimizing outcomes in EGFR Mutation-Positive Nsclc: Which Tyrosine Kinase Inhibitor and When?

“…Thus, efficacy and safety of EGFR TKIs in patients with EGFR mutation-positive NSCLC and brain metastases is of high importance. Preclinical studies suggest that osimertinib is able to cross the blood-brain barrier [64]. Moreover, in FLAURA, osimertinib significantly prolonged PFS compared with erlotinib/gefitinib in patients with asymptomatic brain metastases (HR: 0.47; 95% CI: 0.30-0.74); this difference was a similar magnitude to that in patients without brain metastases (HR: 0.46; 95% CI: 0.36-0.59).…”

EGFR inhibition in NSCLC: New findings…. and opened questions?

“…Among the 21 patients receiving osimertinib 160 mg daily, 33% had PR and 43% had SD, with a tolerable safety profile including only 14% G ≥ 3 drug-related AEs (Yang et al, 2016b). Waiting for the results in the T790M-positive cohort included in the BLOOM study, osimertinib has already shown high activity in patients with CNS disease harboring T790M mutation enrolled in two phase II studies (Goss, 2017), likely due to its greater penetration of animal models' BBB compared to other TKIs, gefitinib, rociletinib, or afatinib (Ballard et al, 2016). Furthermore the recent results of the AURA 3 trial demonstrated a significant survival benefit of osimertinib over platinum-chemotherapy in 144 T790M-positive patients with CNS metastasis at baseline, suggesting it as a very effective drug for these patients (Mok et al, 2017).…”

Dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor T790M mutation: A case report

“…Osimertinib has exhibited good penetration through the blood-brain barrier in mice, delaying the development of leptomeningeal carcinomatosis in an EGFR mutation mouse model (13,14). Furthermore, Pareek et al also reported CNS disease improvement by administration of 80 mg osimertinib for 6 weeks in a case report (15).…”