ZENITH20 Trial Shows Positive Results With Poziotinib in Untreated HER2 Exon 20-Mutant NSCLC

Daily poziotinib in patients with untreated HER2 exon 20-mutant non-small cell lung cancer resulted in tumor reduction.

The phase 2 ZENITH20 trial (NCT03318939) examining a daily dose of poziotinib (NOV 120101) at 16 mg showed a 35% median tumor reduction in patients with previously untreated HER2 exon 20–mutant non-small cell lung cancer, according to data that were presented at the 2021 European Society for Medical Oncology Congress.1

“Most patients, 88%, show tumor reduction and a median tumor reduction of 35%,” said lead author Robin Cornelissen, MD, PhD, a pulmonologist with Erasmus MC Cancer Institute in Rotterdam, The Netherlands. “There are 3 patients with 100% decrease of the target lesions, however, 2 of those patients also had nontarget lesions and therefore were deemed as partial response.”

At a median follow-up of 13.5 months, the objective response rate (ORR) was 43.8% (95% CI, 29.5%-58.8%) with 1 (2.1%) complete response and 20 (41.7%) partial responses. Fifteen patients (31.3%) had stable disease and 7 (14.6%) had progressive disease; 5 patients (10.4%0 were not evaluable.

The disease control rate was 75%. The ORR, including unconfirmed response, was 47.9% (95% CI, 33.3%-62.8%). The median duration of response was 5.4 months (range, 2.8 to >19.1). The 6- and 1-year response duration rates were 42% and 24%, respectively.

The median progression-free survival (PFS) was 5.6 months (range, 0 to >20.2). The 6-month PFS rate was 42%; the 1-year PFS rate as 26%.

At present, there is no approved treatment for patients with HER2 exon 20 mutations, Cornelissen said. Studies exploring efficacy with current treatments—chemotherapy with our without immune checkpoint inhibitors and tyrosine kinase inhibitors (TKIs)—show ORRs from 6.9% to 35% and median PFS outcomes of 3 to 7 months. Furthermore, none of these current options are specific to exon 20 mutations.

In March, the FDA granted a fast track designation to poziotinib for use in previously treated patients with HER2 exon 20 mutations.2

ZENITH20 is a multicohort, multicenter, open-label trial examining the efficacy, safety, and tolerability of poziotinib, an oral, irreversible TKI targeting EGFR or HER2 exon 20 insertion mutations. In cohort 4 of the study, 48 patients with untreated locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations were assigned to 16 mg of poziotinib daily or 8 mg twice daily. Dose reductions were allowed if treatment-emergent adverse events (TEAEs) occurred. Patients were treated until intolerable toxicity, disease progression, or death.

Eligible patients must have an ECOG performance status of 0 or 1. Prior adjuvant or neoadjuvant therapies were permissible if treatment ended at least 15 days prior to study entry. Those who had received previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation–selective TKI or who had EGFR exon 20 point mutations were excluded.

The primary end point was ORR; secondary end points were DCR, DOR, and safety and tolerability.

In the daily dosing cohort, most patients were White (75%), female (54%), nonsmokers (69%), and had an ECOG performance status of 1 (65%). The median age was 60.5 years (range, 34-87).

All 48 patients were evaluable for safety and all experienced treatment-related adverse events (TRAEs). Five (10%) experienced serious TRAEs. Six (13%) left the trial due to adverse events (AEs), 88% required dose interruptions, and 77% required dose reductions.

The most common grade 3 TRAEs were rash (35%), stomatitis/mucosal inflammation (21%), and diarrhea (15%). There were no grade 4/5 AEs observed.

The cohort is still recruiting patients for an 8-mg, twice-daily group (n = 23).

Xiuning Le, MD, PhD, an assistant professor of thoracic/head and neck medical oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center, presented safety and efficacy data from cohort 5 (n = 19) during the 2021 AACR Annual Meeting.3 In this cohort, patients with locally advanced or metastatic NSCLC with EGFR or HER2 exon 20 insertion mutations were randomly assigned to either 10 mg, 12 mg, or 16 mg of poziotinib daily, or 6 mg or 8 mg of the drug twice daily.

The ORRs were 31.6% at 8-mg twice-daily, 15.8% at 16-mg daily, 15.8% at 12-mg daily, and 5.3% at 6-mg twice-daily doses. All were partial responses.

Prior findings from cohort 3 of ZENITH20 presented at the 2021 ESMO TAT Virtual Congress showed that a 16-mg daily dose of poziotinib elicited clinically meaningful activity in treatment-naïve patients with metastatic NSCLC with EGFRexon 20 mutations.4


  1. Cornelissen R, Sun S, Wollner M, et al. Efficacy and safety of poziotinib in treatment-naïve NSCLC harboring HER2 exon 20 mutations: a multinational phase II study (ZENITH20-4). Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA46.
  2. FDA grants fast track designation to Spectrum Pharmaceuticals’ poziotinib. News release. Spectrum Pharmaceuticals. March 11, 2021. Accessed September 18, 2021. http://bwnews.pr/3tf1PuO
  3. Le X, Shum E, Suga J, et al. Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutant NSCLC (ZENITH20-5). Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT169.
  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. Ann Oncol. 2021;32(suppl_1):S14-S19. doi:10.1016/annonc/annonc459