Dataset Information

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.

SUBMITTER: Peled N

PROVIDER: S-EPMC8826702 | biostudies-literature | 2022 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

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

Peled Nir N Kian Waleed W Inbar Edna E Goldstein Iris M IM Zemel Melanie M Rotem Ofer O Rozenblum Anna B AB Nechushtan Hovav H Dudnik Elizabeth E Levin Daniel D Zer Alona A Keren-Rosenberg Shoshana S Yust-Katz Shlomit S Fuchs Vered V Remilah Areen A AA Shelef Ilan I Roisman Laila C LC

Neuro-oncology advances 20211227 1

<h4>Background</h4>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.<h4>Methods</h4>In this nonrandomized, phase II, open-label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung ...[more]

PMID: 35156036

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Project description:ImportanceThe combination of erlotinib and bevacizumab as initial treatment of epidermal growth factor receptor (EGFR [OMIM 131550])-mutant lung cancers improves progression-free survival (PFS) compared with erlotinib alone. Because osimertinib prolongs PFS compared with erlotinib, this trial was designed to study the combination of osimertinib and bevacizumab as first-line treatment.ObjectivesTo determine the safety and tolerability of osimertinib and bevacizumab combination treatment and assess the 12-month PFS of the combination in patients with metastatic EGFR-mutant lung cancers.Design, setting, and particiantsFrom August 15, 2016, to May 15, 2018, 49 patients with metastatic EGFR-mutant lung cancers were enrolled in this interventional clinical trial, conducted at a single academic cancer center. In the phase 1 portion of the study, a standard 3 + 3 dose de-escalation design was used to determine the maximum tolerated dose of osimertinib and bevacizumab. In the phase 2 portion of the study, patients were treated at the maximum tolerated dose defined in the phase 1 portion. Statistical analysis was performed from August 1 to October 1, 2019.InterventionsAll patients received osimertinib, 80 mg daily, and bevacizumab, 15 mg/kg once every 3 weeks.Main outcomes and measuresThe primary objective of the phase 2 portion of the study was to determine the number of patients receiving the combination of osimertinib and bevacizumab who were progression free at 12 months. Secondary end points included overall response rate, median PFS, overall survival, and definition of the toxic effects of the combination treatment.ResultsAmong the 49 patients in the study (34 women; median age, 60 years [range, 36-83 years]), PFS at 12 months was 76% (95% CI, 65%-90%). The overall response rate was 80% (95% CI, 67%-91%), and median PFS was 19 months (95% CI, 15-24 months). Of the 6 patients with measurable central nervous system disease, all had a partial or complete central nervous system response. Persistent detection of EGFR-mutant circulating tumor (ct)DNA at 6 weeks was associated with shorter median PFS (clearance at 6 weeks, 16.2 months [95% CI, 13 months to not reached]; and no clearance at 6 weeks, 9.8 months [95% CI, 4 months to not reached]; P = .04) and median overall survival (clearance at 6 weeks, not reached; and no clearance at 6 weeks, 10.1 months [95% CI, 6 months to not reached]; P = .002). Identified mechanisms of resistance included squamous cell transformation (n = 2) pleomorphic transformation (n = 1), and acquired EGFR L718Q (n = 1) and C797S (n = 1) mutations.Conclusions and relevanceThe combination of osimertinib and bevacizumab met the study's prespecified effectiveness end point. Persistent EGFR-mutant circulating tumor DNA at 6 weeks was associated with early progression and shorter survival. A randomized phase 3 study comparing osimertinib and bevacizumab with osimertinib alone is planned.Trial registrationClinicalTrials.gov Identifier: NCT02803203.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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