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Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2
Xiuning Le1, Robin Cornelissen2, Marina Garassino3
1Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX.
Purpose:
Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene (ERBB2 or HER2) exon 20 occur in 2%-5% of non-small-cell lung cancers (NSCLCs) and function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was evaluated in previously treated patients with NSCLC with HER2 exon 20 insertions.
Methods:
ZENITH20, a multicenter, multicohort, open-label phase II study, evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2, patients received poziotinib (16 mg) once daily. The primary end point was objective response rate evaluated by independent review committee (RECIST v1.1); secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability. Quality of life was assessed.
Results:
Between October 2017 and March 2021, 90 patients with a median of two prior lines of therapy (range, 1-6) were treated. With a median follow-up of 9.0 months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90 patients achieved a partial response. Disease control rate was 70.0% (95% CI, 59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%). Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was seen regardless of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations. Grade 3 or higher treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with median relative dose intensity of 71.5%. Permanent treatment discontinuation because of treatment-related adverse events occurred in 13.3% of patients.
Conclusion:
Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.
Insights
Poziotinib showed antitumor activity in patients with previously treated non-small-cell lung cancer (NSCLC) harboring HER2 exon 20 insertions. The study demonstrated clinical benefit across various patient subgroups, despite notable treatment-related adverse events.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2 exon 20 insertions are oncogenic drivers in 2%-5% of non-small-cell lung cancers (NSCLCs).
- Targeted therapies are crucial for NSCLC patients with specific genetic alterations.
- Poziotinib is a tyrosine kinase inhibitor investigated for its efficacy in NSCLC.
Purpose of the Study:
- To evaluate the efficacy and safety of poziotinib in patients with advanced or metastatic NSCLC and HER2 exon 20 insertions.
- To assess the objective response rate (ORR) as the primary endpoint.
- To explore secondary outcomes including disease control rate, duration of response, progression-free survival, and quality of life.
Main Methods:
- ZENITH20 is a multicenter, open-label, Phase II study.
- Cohort 2 included 90 previously treated patients with NSCLC and HER2 exon 20 insertions.
- Patients received poziotinib 16 mg once daily, with efficacy assessed by independent review committee (RECIST v1.1).
Main Results:
- The objective response rate was 27.8% (95% CI, 18.9 to 38.2), with 25 partial responses.
- Disease control rate was 70.0% (95% CI, 59.4 to 79.2), and 74% of patients experienced tumor reduction.
- Median progression-free survival was 5.5 months; median duration of response was 5.1 months. Common Grade 3+ adverse events included rash, diarrhea, and stomatitis.
Conclusions:
- Poziotinib demonstrates significant antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.
- Clinical benefit was observed irrespective of prior therapy, CNS metastasis, or specific HER2 mutation type.
- Adverse events were manageable, though dose reductions and discontinuations occurred, highlighting the need for careful patient monitoring.
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