Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03318939.

FIG 1.

(A) Best percentage change from baseline in target lesion size (RECIST Guidelines, v1.1 by BICR) in patients with advanced NSCLC and HER2 exon 20 insertions (evaluable population, n = 74). (B). Swimmer plot for individual responders showing the number of lines of prior therapy, prior type of therapy, and mutation. The prior therapy column indicates prior exposure (not necessarily in the sequence listed). An accidental dosing error led to one patient taking 18 mg of poziotinib for 1 day. BICR, blinded independent committee review; CPI, checkpoint inhibitor; CT, chemotherapy; HER2, human epidermal growth factor receptor 2; HER2-a, HER2 antibody-drug conjugate; HER2-m, HER2-monoclonal antibody; HER2-mat, HER2-monoclonal antibody, antibody-drug conjugate, and tyrosine kinase inhibitor; HER2-mt, HER2-monoclonal antibody or tyrosine kinase inhibitor; NSCLC, non–small-cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.

FIG 2.

Forest plot presenting ORR by subgroups. CPI, checkpoint inhibitor; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; ORR, objective response rate.