Osimertinib in advanced EGFR-mutant lung adenocarcinoma with asymptomatic brain metastases: an open-label, 3-arm, phase II pilot study

Abstract

Background: Osimertinib is selective for both epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported.

Methods: In this nonrandomized, phase II, open-label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naive (arm A = 20) or previously treated with an EGFR-TKI and Thr790Met positive (arm B = 18) or negative (arm C = 10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression-free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513.

Results: The iORRs were 84.2%, 66.7%, and 50% and the iDCRs were 94.7%, 94.4%, and 80% in arms A, B, and C, respectively. The median iPFS was 11.8 months (95% CI 7.7 to NA), 7.6 months (95% CI 5.3 to NA), and 6.3 months (95% CI 3.9 to NA) in arms A, B, and C, respectively. Following dose escalation, pooled iORR was 54% (arm A = 5, arm B = 4, arm C = 2). Adverse events were similar to those in previously published literature.

Conclusion: Osimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and -negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.

Keywords: EGFR; LUAD; Thr790Met; brain metastases; osimertinib.

© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Figures

Figure 1.

Efficacy of osimertinib in all treatment arms. (A) Illustrates the intracranial and systemic efficacy of osimertinib in each arm of the trial. The percent of patients that reached ORR in each study arm is represented by each bar. 95% CIs for intracranial ORR and DCR are included in blocked parentheses. aAnalysis was done on 19 patients with 1 participant being excluded following molecular profiling. CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. (B) Waterfall plot of each arm demonstrates the best percentage change in intracranial target lesions from baseline. Complete response (n = 18), partial response (n = 15), stable disease (n = 10), and progressive disease (n = 4).

Figure 2.

(A) The Kaplan–Meier plot of intracranial progression-free survival (iPFS) by study arm (P = .11), the dashed line indicates 50% (median iPFS). (B) The Kaplan–Meier plot of overall survival (OS) by study arm (P = .37), the dashed line indicates 50% (median OS).

Figure 3.

Illustrates the changes in diameter of target brain lesions from the time of enrollment to the time of best intracranial response. A significant decrease in the median diameter of target brain lesions is seen throughout all arms. The number and diameter of target lesions, and their corresponding P values, at each time point, are proved in the table.

Figure 4

Spider chart illustrating the median change in diameter from baseline for each arm. Dashed vertical lines represent the median time on trial to dose escalation for arm A = 61.33 weeks (blue), arm B = 28.5 weeks (orange), and arm C = 60 weeks (green).