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Osimertinib in advanced EGFR-mutant lung adenocarcinoma with asymptomatic brain metastases: an open-label, 3-arm,
Nir Peled1, Waleed Kian2, Edna Inbar3
1Department of Oncology, The Institute of Oncology, Shaare Zedek Medical Center, Jerusalem, Israel.
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.
Insights
Osimertinib effectively treats asymptomatic brain metastases in EGFR-mutant lung adenocarcinoma (LUAD) patients. This study shows significant intracranial response rates regardless of Thr790Met mutation status, supporting its use in brain-involved LUAD.
Area of Science:
- Oncology
- Medical Research
- Pharmacology
Background:
- Osimertinib targets epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) sensitizing and Thr790Met mutations.
- Previous trials documented osimertinib's intracranial activity, but a prospective study on asymptomatic brain metastases was lacking.
Purpose of the Study:
- To prospectively evaluate the efficacy of osimertinib in patients with asymptomatic brain metastases from EGFR-mutant lung adenocarcinoma (LUAD).
- To assess intracranial objective response rate (iORR), intracranial disease control rate (iDCR), and intracranial progression-free survival (iPFS).
Main Methods:
- A nonrandomized, phase II, open-label, 3-arm prospective study involving 48 patients with metastatic EGFR-mutant LUAD.
- Patients received osimertinib 80 mg daily, categorized by treatment history and Thr790Met mutation status (treatment-naive, previously treated TKI + Thr790Met positive, previously treated TKI + Thr790Met negative).
- Dose escalation to 160 mg was permitted for isolated intracranial progression.
Main Results:
- Intracranial objective response rates (iORRs) were 84.2% (Arm A), 66.7% (Arm B), and 50% (Arm C).
- Intracranial disease control rates (iDCRs) were 94.7% (Arm A), 94.4% (Arm B), and 80% (Arm C).
- Median intracranial progression-free survival (iPFS) ranged from 6.3 to 11.8 months across arms.
Conclusions:
- Osimertinib demonstrates high efficacy in treating asymptomatic brain metastases in EGFR-mutant LUAD.
- The drug significantly reduced the size and number of brain lesions, irrespective of Thr790Met mutation status.
- Osimertinib is a viable treatment option for EGFR-mutant LUAD patients with brain metastases, regardless of Thr790Met status.
