Poziotinib for HER2-Mutated NSCLC New Drug Application Submitted to FDA

The application for poziotinib is supported by the phase 2 ZENITH20 trial. The agent showed a promising safety profile and antitumor activity.

A new drug application for poziotinib for the treatment of patients with previously-treated locally advanced or metastatic non–small cell lung cancer (NSCLC) with HER2 Exon 20 insertion mutations has been submitted to the FDA, according to a press release by Spectrum Pharmaceuticals.1

Poziotinib, an irreversible pan-ErbB inhibitor, has activity against HER1 insertions or mutation. Preclinical studies have found that both EGFR and HER2 exon 20 insertion mutation cancer cells. This activity separates it from other EGFR tyrosine kinase inhibitors, which have limited anti exon 20 insertion activity.

The application is supported by results of the phase 2 ZENITH20 study (NCT03318939). The trial has an estimated enrollment of 603 participants and an estimated study completion date of December 2023. The primary end point is objective response rate. Secondary end points include disease control rate and duration of response. Other end points measured include progression-free survival.3

The study is composed of 7 cohorts. Cohort 1 is made up of patients with previously treated EGFR exon 20 insertion-positive NSCLC. Cohort 2 is made up of patients with HER2 exon 20 NSCLC. Cohort 3 is made up of treatment naïve patients with EGFR exon 20 insertion-positive NSCLC. All patients in these 3 cohorts received poziotinib 16 mg daily.

Cohort 4 is made of patients with treatment naïve patients with HER2 exon 20 insertion mutation-positive NSCLC. Patients in this cohort received poziotinib 8 mg twice a day. Cohort 5 was made up of patients who met the criteria for cohorts 1 through 4, but enrollment was closed. Patients in cohort 5 were randomized to receive 8 mg twice a day, 6 mg twice a day, or 10 mg once a day.

Cohort 6 was made up of patients who acquired an EGFR mutation that progression while on treatment with first line osimertinib (Tagrisso). Cohort 7 included patients with EGFR or HER2 activating mutations. Patients in these cohorts receive 8 mg of the study drug twice a day.

In an analysis of the HER2 exon 20 insertion cohort, in evaluable patients, the ORR was 35.1%. All responses were partial responses. Stable disease was seen in 47.3% of patients, with progressive disease in 17.6% of patients. The disease control rate was 82.4%, with the median duration of response was 5.1 months (range, 0.9-14.1). The median PFS was 5.5 months (range, 0.6-17.6).

In terms of safety, common treatment-emergent adverse events (TRAEs) included rash (91.1%), diarrhea (82.2%), and stomatitis (68.9%), and grade ≥ 3 incidences were rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Grade 4 TRAEs occurred in 4.4% of patients, with grade 1 pneumonitis occurring in 1 patient.

“The NDA submission for poziotinib marks an important step in achieving a first treatment for patients with HER2 exon 20 insertion mutations in lung cancer,” said Joe Turgeon, president and CEO of Spectrum Pharmaceuticals, in a press release.

In order to participate in the study, patients must be 18 years of age or older, meet the appropriate cohort criteria, and have a confirmed diagnosis of locally advanced or metastatic NSCLC that is no amendable to treatment with curative intent. Patients must also have adequate organ function. Patients previously treated with poziotinib, concurrently receiving chemotherapy, have had other malignancies in the past 3 years, or are pregnant or breastfeeding are not eligible to participate.

1.Spectrum Pharmaceuticals submits new drug application for poziotinib. News release. Spectrum pharmaceuticals. December 6, 2021. Accessed December 8, 2021. https://bit.ly/3y8r5GM
2.Le X, Cornelissen R, Garassino M, et al. Poziotinib in non–small-cell lung cancer harboring HER2 Exon 20 insertion mutations after prior therapies: ZENITH20-2 Trial. J Clin Oncol 2021. Published online. doi: 10.1200/JCO.21.01323 
3.Phase 2 study of Poziotinib in patients with NSCLC having EGFR or HER2 exon 20 insertion mutation. ClinicalTrials.gov. Accessed December 8, 2021. https://bit.ly/3pWejYD