FDA Considers New Drug Application for Poziotinib in HER2 Exon 20-Mutant NSCLC


An application for FDA approval has been submitted for poziotinib as a potential treatment for patients with non–small cell lung cancer harboring HER2 exon 20 insertion mutations.

A new drug application (NDA) for poziotinib seeking approval for the treatment of previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring HER2 exon 20 insertion mutations has been accepted for review by the FDA, according to Spectrum Pharmaceuticals (NasdaqGS: SPPI).1

Poziotinib is an irreversible pan-ErbB inhibitor which acts against HER1 insertions or mutation. EGFR and HER2 exon 20 insertion mutation cancer cells have been found in previous preclinical studies.2

The phase 2 ZENITH20 trial evaluated poziotinib in previously treated patients with non-small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations. The results of the trial were the basis of the NDA acceptance.

“The NDA acceptance is a major step toward advancing the treatment for patients with HER2 exon 20 insertion mutations in lung cancer,” said Tom Riga, president and chief executive officer of Spectrum Pharmaceuticals, in the press release. “This remains an area of high unmet medical need as there are no treatments specifically approved for these patients. We are actively working with the agency to support the review process.”

The multicenter, multicohort, open-label study is made up of 7 independent cohorts.3 Cohort 1 is made up of previously treated EGFR exon 20 insertion-positive NSCLC patients. Cohort 2 included patients with HER2 exon 20 NSCLC, and cohort 3 consisted of treatment naïve patients with EGFR exon 20 insertion-positive NSCLC. All of the patients in each of these 3 cohorts received 16 mg of poziotinib a day.

Cohort 4 is made of patients with treatment naïve patients with HER2 exon 20 insertion mutation-positive NSCLC and they received poziotinib at 8 mg twice a day. Cohort 5 included the patients who met the criteria for cohorts 1 through 4 after the enrollment was already closed. Cohort 5 was randomized to receive 8 mg twice a day, 6 mg twice a day, or 10 mg once a day.

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

The primary end point is objective response rate with secondary end points consisting of disease control rate and duration of response. Other end points include progression-free survival.

An analysis of the evaluable population (n = 74) of cohort 2, which enrolled 90 patients aged 18 years and older with confirmed locally advanced or metastatic NSCLC, showed the ORR to be 35.1%. Stable disease was seen in 47.3% of patients and progressive disease was seen in 17.6% of patients. 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). All responses were partial responses.

Common treatment-emergent adverse events (TEAEs) included rash (91.1%), diarrhea (82.2%), and stomatitis (68.9%). Additionally, grade ≥ 3 incidences included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). 4.4% of patients had grade 4 TRAEs, and 1 patient had grade 1 pneumonitis.

Currently, no treatment has been specifically approved by the FDA for the treatment of patients with NSCLC harboring HER2 exon 20 insertion mutations. Fast Track designation was given to the product and the agency has set a Prescription Drug User Fee Act date of November 24, 2022.


1. Spectrum Pharmaceuticals announces acceptance of new drug application filing for poziotinib. News Release. Spectrum Pharmaceuticals; February 11, 2022. Accessed February 11, 2022. https://bit.ly/3HJH56j

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

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