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 EGFR-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 naïve (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 iORR’s were 84.2%, 66.7% and 50% and the iDCR’s 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-NA), 7.6 (95% CI 5.3-NA) and 6.3 months (95% CI 3.9-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.

Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance

“…Similarly, a subgroup analysis of the FLAURA study showed that compared with standard first-line EGFR-TKIs (gefitinib or erlotinib), osimertinib demonstrated a higher CNS ORR (91% versus 68%) and longer CNS PFS (not reached versus 13.9 months) in patients with CNS metastases [228]. Peled et al also reported that osimertinib displayed potent intracranial activity against EGFR-mutant lung adenocarcinoma with asymptomatic brain metastases in both previously treated and treatment-naive groups, regardless of T790M status [229]. Importantly, in addition to its effect on existing CNS metastases, osimertinib also plays a protective role in CNS progression.…”

Potential Role of Cancer Stem Cells in Glioblastoma: A Therapeutic Aspect

“…Irreversible inhibitor of EGFR, osimertinib, has shown efficiency in crossing the blood-brain barrier (BBB) and significantly Potential Role of Cancer Stem Cells in Glioblastoma: A Therapeutic Aspect DOI: http://dx.doi.org/10.5772/intechopen.106332 inhibits GBM tumorigenesis in-vivo [114]. It has also entered phase II clinical studies [115][116], however, has shown to be marginally effective, which could be due to heterogeneity of GBM [117][118]. Further, combined treatment of antibodies against EGFRvIII and CD133 showed higher effectivity in elimination of GSCs compared with the antibody against either EGFRvIII or CD133 [111].…”

Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies

“…Third-generation EGFR TKIs, such as osimertinib, are also irreversible inhibitors, but show much more efficient blood–brain barrier (BBB) penetration than those from other generations due to its lower efflux by BBB multidrug efflux pumps, suggesting its potential use for treating brain cancer [ 94 , 95 ]. Several phase II clinical studies have shown that osimertinib can be used for treating EGFR-mutant lung adenocarcinoma with brain metastasis [ 96 , 97 ]. Osimertinib shows excellent BBB penetration and significantly inhibits GBM tumorigenesis in vivo [ 98 ].…”