FDA Accepts NDA for Poziotinib in HER2 Exon 20–Mutated NSCLC

Feb 14, 2022

The FDA has accepted for review a new drug application for poziotinib in patients with previously treated locally advanced or metastatic non–small cell lung cancer with HER2 exon 20 insertion mutations.

The FDA has accepted for review a new drug application (NDA) for poziotinib in patients with previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations.1

The NDA is supported by data from cohort 2 of the phase 2 ZENITH20 trial (NCT03318939), which demonstrated that poziotinib, when given at a once-daily dose of 16 mg, induced an objective response rate (ORR) of 27.8% (95% CI, 18.9%-38.2%) in this population (n = 90).2 The median duration of response (DOR) was 5.1 months (95% CI, 4.2-5.5), and the median progression-free survival (PFS) was 5.5 months (95% CI, 3.9-5.8).

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the application by November 24, 2022.

“The NDA acceptance is a major step toward advancing the treatment for patients with HER2 exon 20 insertion mutations in lung cancer,” Tom Riga, president and chief executive officer of Spectrum Pharmaceuticals, stated in a 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.”

ZENITH20 is a multicenter, multicohort, open-label, phase 2 trial that is comprised of 7 cohorts of patients with NSCLC. Those with previously treated NSCLC and EGFR exon 20 insertion mutations were enrolled to cohort 1, and those with HER2 exon 20 insertion mutations were included in cohort 2. Cohort 3 was comprised of treatment-naïve patients with EGFR exon 20 insertion mutations, and cohort 4 is enrolling those with HER2 exon 20 insertion mutations who are receiving the agent in the frontline.

Cohort 5 is enrolling previously treated or treatment-naïve patients with EGFR or HER2 exon 20 insertion mutations, and cohort 6 is enrolling those with classical EGFR mutations who progressed on frontline osimertinib (Tagrisso) and developed an additional EGFR mutation. Cohort 7 is enrolling those whose tumors had several less common mutations in EGFR or HER2 exons 18 through 21 or the extracellular or transmembrane domains.

To be eligible for inclusion in cohort 2 of the trial, patients had to be at least 18 years of age, have previously received treatment for locally advanced or metastatic NSCLC, tumors that harbored HER2 exon 20 insertion mutations, and measurable disease. Although patients with brain metastases were permitted, they needed to be stable, asymptomatic, and not require high-dose or increasing doses of corticosteroids.

Oral poziotinib was administered in the outpatient setting as part of 28-day treatment cycles for up to 24 months. If patients experienced toxicities with the agent, they were permitted to reduce the dose in 2-mg increments, and dose interruption of up to 28 days was allowed.

The primary end point of ZENITH20 was ORR. Secondary end points comprised disease control rate (DCR), DOR, PFS, and safety and tolerability. Quality of life was also assessed.

Among the 90 patients enrolled to the cohort, the median age was 60 years (range, 25-86), and the majority were female (64.4%), White (77.8%), never smokers (65.6%), and had an ECOG performance status of 1 (57.8%). Most patients had adenocarcinoma vs squamous cell carcinoma, at 96.7% and 3.3%, respectively. Stable central nervous system (CNS) metastases at the time of study entry were noted in 25.6% of participants.

Patients had received a median of 2 prior lines of therapy (range, 1-6), with 30.0% having received 1 prior line, 31.1% having received 2 prior lines, and 38.9% having received 3 or more prior lines. Additionally, 96.7%, 67.8%, and 27.8%, of patients previously received platinum-based chemotherapy, a checkpoint inhibitor, or an anti-HER2 drug, respectively. Just under 70% of patients, or 65.6%, had previously received both chemotherapy and immunotherapy.

Additional findings from the trial indicated that 25 of the 90 patients experienced a partial response. No complete responses were reported. The median time to response was 32 days (range, 23-183).

Moreover, poziotinib resulted in a DCR of 70.0% (95% CI, 59.4%-79.2%) in this population. Most patients experienced tumor shrinkage with treatment, and 37.8% (95% CI, 25.5%-50.0%) were free of disease progression at 6 months.

Among those who received 3 or more prior lines of therapy, the ORR with poziotinib was 37.1% (95% CI, 21.5%-55.1%) vs 21.4% (95% CI, 8.3%-41.0%) in those who received 2 prior lines, and 22.2% (95% CI, 8.6%-42.3%) in those who received 1 prior line. Notably, 26.2% of those who previously received treatment with a checkpoint inhibitor responded to poziotinib.

Twenty-five of these patients received a prior HER2-targeted agent with 1 or more antibodies or antibody-drug conjugates; all received prior chemotherapy. A total of 3 patients received prior trastuzumab (Herceptin) and afatinib (Gilotrif), and 1 patient received trastuzumab and neratinib (Nerlynx).

Poziotinib elicited an ORR of 28.6% in the patients who had stable CNS metastases at the time of enrollment (n = 14), with a median PFS of 7.4 months. One patient who had 2 brain lesions at baseline was noted to no longer have those lesions on 2 or more MRI scans after having received poziotinib. Nine additional patients achieved CNS stable disease.

All participants experienced treatment-emergent toxicities with poziotinib, with 97.8% of adverse effects (AEs) associated with the treatment. Moreover, 78.9% of toxicities were noted to be grade 3 in severity, and 4.4% were grade 4.

Rash (91.1%), diarrhea (82.2%), and stomatitis (68.9%) were among the most common AEs reported with poziotinib. The most frequent grade 3 or higher AEs also comprised rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Serious treatment-related toxicities included rash (3.3%), asthenia (2.2%), diarrhea (2.2%), dehydration (2.2%), and stomatitis (2.2%).

Grade 4 treatment-related AEs were experienced by 4.4% of patients and included stomatitis, dyspnea, hypomagnesemia, hypocalcemia, and pancreatitis relapsing. One patient experienced grade 5 pneumonia.

Previously, in March 2021, the FDA granted a fast track designation to poziotinib for use in previously treated patients with HER2 exon 20 mutations, based on cohort 3 of the ZENITH20 trial.3 Results showed that poziotinib elicited an ORR of 27.8% (95% CI, 18.4%-39.1%) and a DCR of 86.1% in treatment-naïve patients with metastatic NSCLC who harbored EGFR exon 20 mutations.4


  1. Spectrum Pharmaceuticals announces acceptance of new drug application filing for poziotinib. News release. Spectrum Pharmaceuticals; February 11, 2022. Accessed February 14, 2022. https://bit.ly/3gGReox
  2. Le X, Cornelissen R, Garrassino 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. Published online November 29, 2021. doi:10.1200/JCO.21.01323
  3. FDA grants fast track designation to Spectrum Pharmaceuticals’ poziotinib. News release. Spectrum Pharmaceuticals; March 11, 2021. Accessed February 14, 2022. http://bwnews.pr/3tf1PuO
  4. Sacher A, Le X, Cornelissen R, et al. Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 exon 20 mutant non-small cell lung cancer. Presented at: ESMO TAT Virtual Congress; March 1-2, 2021; Virtual. Accessed February 14, 2022.
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