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

Author(s): Xiuning Le 1, Robin Cornelissen 2, Marina Garassino 3, Jeffrey M Clarke 4, Nishan Tchekmedyian 5, Jonathan W Goldman 6, Szu-Yun Leu 7, Gajanan Bhat 7, Francois Lebel 7, John V Heymach 1, Mark A Socinski 8
Source: J Clin Oncol. 2022 Mar 1;40(7):710-718. doi: 10.1200/JCO.21.01323. Epub 2021 Nov 29.
Lucio Gordan MD

Dr. Gordan's Thoughts

Importance of NGS testing cannot be overemphasized. Besides poziotinib (which has very reasonable clinical benefit), anti-HER2 combination therapy may be of value in this patient population. Studies are ongoing. Poziotinib-related rash and diarrhea are manageable with proper understanding and interventions.

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.

Author Affiliations

1Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX.2Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.3Medical Thoracic Oncology, Istituto Nazionale dei Tumori di Milano-Fondazione IRCCS, Milan, Italy.4Medical Oncology, Duke University Medical Center, Durham, NC.5Medical Oncology, Pacific Shores Medical Group, Irvine, CA.6David Geffen School of Medicine at UCLA, Los Angeles, CA.7Research and Development, Spectrum Pharmaceuticals, Irvine, CA.8Thoracic Oncology, AdventHealth Cancer Institute, Orlando, FL.

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