Oncology Overview: Poziotinib for Non-Small Cell Lung Cancer


Poziotinib is an irreversible pan HER2 inhibitor with activity against mutations of HER1, HER2, and HER4.

In December 2021, the FDA accepted a new drug application (NDA) for poziotinib­—a potent tyrosine kinase inhibitor—for the treatment of non-small cell lung cancer (NSCLC) in patients who harbor the HER2 exon 20 insertion mutations. Approximately 2% to 5% of NSCLC tumors exhibit HER2 mutations, usually involving in-frame insertions in exon 20.1

These tumors often exhibit adenocarcinoma histology, with an increased prevalence among women who are never-smokers. Currently, no FDA-approved targeted therapies are available specifically for this population.

Recently, researchers reported positive phase 2 study results in patients with previously treated locally advanced or metastatic NSCLC harboring HER2 exon 20 insertion mutations. The FDA accepted the poziotinib NDA based on phase 2 study results from the ZENITH trial.1

Clinical Trial

ZENITH20 was a phase 2, multicenter, 7 cohort, open-label study of poziotinib in patients with NSCLC having EGFR or HER2 exon 20 mutations.1 Patient enrollment criteria was based on EGFR or HER2 exon 20 mutation and prior treatment status.2

  • Cohort 1: Previously treated patients with EGFR exon 20 insertion mutant positive NSCLC.
  • Cohort 2: Previously treated patients with HER2 exon 20 insertion mutant positive NSCLC.
  • Cohort 3: Treatment naïve patients with EGFR exon 20 insertion-mutant positive NSCLC.
  • Cohort 4: Treatment naïve patients with HER2 exon 20 insertion mutant positive NSCLC.
  • Cohort 5: Patients who meet the criteria for enrollment in cohort 1 to 4, but the enrollment in the respective cohort has been closed.
  • Cohort 6: Patients with acquired EGFR mutation who progressed while on treatment with first-line osimertinib.
  • Cohort 7: Patients with EGFR or HER2 activating mutations.

Investigators enrolled adults previously treated for locally advanced or metastatic NSCLC with documented HER2 exon 20 insertion mutations into cohort 2. Trial participants (N = 90) received poziotinib at a dose of 16 mg orally once daily during a 28-day treatment cycle for up to 24 months in an outpatient setting. The study’s primary end point was objective response rate (ORR), and secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability.

Study results revealed ORR of 27.8% (95% CI, 18.9%-38.2%), with a median follow up period of 9 months. The study criteria for primary efficacy was for the lower bound of ORR to be above 17%.

The observed lower bound of the study was 18.9%, exceeding the prespecified criteria for primary efficacy. Of the 90 trial participants, 25 patients achieved a partial response.

Secondary study outcome measures were as follows: 70% disease control rate, 5.5 months of median progression-free survival, and 5.1 months of median duration of response. Approximately 74% of patients had a 22% median tumor reduction. Patients also reported an improvement in lung cancer-specific symptoms of cough, dyspnea, and chest pain during poziotinib treatment.

The data from cohort 2 of the ZENITH20 trial demonstrated the efficacy of poziotinib in patients with NSCLC harboring HER2 exon 20 insertion mutations.1

Another smaller single-arm, open-label, phase 2 trial (N = 30) assessed poziotinib’s safety and efficacy in patients with HER2 exon 20 mutations.3 Study investigators reported similar results to the ZENITH20-2 trial. The confirmed ORR was 27% (95% CI, 12 to 46), the median duration of response was 5 months, median progression-free survival was 5.5 months, and median overall survival was 15 months.3

Mechanism of Action

Poziotinib is an irreversible pan HER2 inhibitor, with activity against mutations of HER1, HER2, and HER4.1 HER2 mutations are a distinct molecular subtype in NSCLC.

Exon 20 mutations result in a conformational change in the drug binding pocket of the kinase active site. HER2 gene/protein changes cause receptor hyperactivation, with multiple downward signaling pathway activation leading to uncontrolled cell proliferation.

Poziotinib’s small size and flexible structure allows it to access the restricted binding site, overcome the stearic hindrance, and inhibit tyrosine kinase activity. Inhibition of tyrosine kinase activity impedes the downstream effects of cell proliferation leading to cell death.

Dosage and Administration

Poziotinib is supplied as 8 mg tablets and 2 mg tablets. Trial participants took the medication orally with food and a glass of water at approximately the same time each day.

In the cohort 2 of the ZENITH20 phase 2 clinical trial, investigators studied paziotinib at 16 mg orally once daily at 28-day cycles.1 Investigators reduced the dose in 2-mg increments in the presence of toxicity. Dose interruption up to 28 days was allowed in the study.

The study protocol has the following dose modification recommendations:

For grade ≥ 3 diarrhea, stomatitis, fatigue, nausea and vomiting despite adequate management:

  • Stop treatment until adverse effect grade ≤ 1 and then continue treatment at same dose or reduce poziotinib dose by 2 mg/dose.

For grade ≥ 2 diarrhea, nausea and vomiting for ≥ 48 hours despite adequate management:

  • Stop treatment until adverse effect grade ≤1 and then continue treatment at same dose or reduce poziotinib dose by 2 mg/dose.

For grade ≥3 LVEF dysfunction:

  • Discontinue treatment

Missed dose: If patients missed a dose, that dose was administered anytime, but at least 8 hours prior to the next scheduled dose.

Adverse Events (AEs)

In the phase 2 ZENITH20-2 clinical trial, 88 patients (97.8%) reported treatment-related AEs (TRAEs), with 71 patients having grade 3 and 4 patients having grade 4 TRAEs.1 Patients experienced typical EGFR TKI reactions of rash (91.1%), diarrhea (82.2%), and stomatitis (68.9%).

Incidences of AEs at or exceeding grade 3 were rash (48.9%), diarrhea (25.6%) and stomatitis (24.4%). Patients experienced the onset of treatment-related rash, diarrhea, and stomatitis at 8, 6, and 7 days, with grade 3 events occurring later at 52.5, 13, and 10 days, respectively.

Four patients had grade 4 TRAEs (stomatitis, dyspnea, hypomagnesemia, hypocalcemia, and pancreatitis relapsing), and 1 patient had grade 5 TRAEs (pneumonia). Study investigators also observed laboratory abnormalities of hyponatremia, increased creatinine, increased alanine aminotransferase, and aspartate aminotransferase.

Among the 90 participants, serious TRAEs occurred in 14.4% of patients, with 12 patients (13.3%) permanently discontinuing treatment due to TRAEs.1

Symptom Management

In ZENITH20-2, 76.8% of patients required a dose reduction, with final dose of 14 mg (22.2%), 12 mg (30%), 10 mg (22.2%), or 8 mg (2.2% mg). According to the study protocol, patients received loperamide for diarrhea management.

Trial participants were educated on prophylactic methods to reduce or prevent stomatitis, which included avoiding spicy or irritating foods, and use of saline, nystatin solution, or magic mouthwash. For rash management, patients were educated on likely skin events prior to treatment initiation. Study protocol recommends early steroid use for on-target toxicity and oral/IV antibiotics for grade 3 and grade 4 skin toxicity.

Drug Interactions

Poziotinib is a substrate for cytochrome 450 (CYP) 3A4 and 2D6 enzymes. If patients were on medications with strong CYP3A4 or CYP2D6 inducer or substrate activity, investigators tried to substitute an alternative medication, and monitored patients closely for AEs if a switch was not possible.

Poziotinib is a moderate CY2C8 and CYP2D6 inhibitor. Patients on medications that are sensitive substrates for these enzymes should be followed closely for possible changes in medication response.

Study protocol also recommends patients avoid grapefruit juice and St John’s Wort during treatment duration. Concomitant use of warfarin or other coumadin-derived anticoagulants required regular monitoring of INR and prior authorization from the sponsor’s medical monitor.

Warnings and Precautions

Poziotinib is not recommended for use during pregnancy. Study protocol required all patients who became pregnant during treatment duration to withdraw from the study.

About the Author

Bisni Narayanan, PharmD, MS, works as a supervisor for Pharmacy Operations at the Outpatient Pharmacy Services, an integrated specialty pharmacy embedded within the Yale New Haven Health System.


1. 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. 2022;40(7):710-771

2. Phase 2 Study of Poziotinib in Patients With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation. Accessed on June 5, 2022. https://clinicaltrials.gov/ct2/show/NCT03318939

3. Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for Patients With HER2 Exon 20 Mutant Non-Small-Cell Lung Cancer: Results From a Phase II Trial. J Clin Oncol. 2022;40(7):702-709

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