For NSCLC With Mutant EGFR or HER2 exon 20, Twice-Daily Poziotinib Induces Better Efficacy, Tolerability

Twice- versus once-daily dosing of investigational poziotinib for HER2 and EGFR mutations in exon 20 was more efficacious and better tolerated, according to results of the phase 2 ZENITH20 trial presented at the AACR Annual Meeting 2021.

According to data from cohort 5 of the phase 2 ZENITH20 trial (NCT03318939), twice-daily (BID) versus one-daily (QD) administration of investigational poziotinib for patients with non–small cell lung cancer (NSCLC) harboring EGFR or HER2 exon 20 mutations led to fewer grade 3 or higher treatment emergent adverse effects (TEAEs). These results were presented virtually at the American Association for Cancer Research (AACR) Annual Meeting 2021.1

When administered at 8 mg (n = 31) and 6 mg BID (n = 32), poziotinib resulted in grade 3 or higher TEAEs in 8 (26%) and 5 (16%) patients, respectively, which compared favorably with 50% of patients receiving it at 16 mg QD (n = 26), and 44% of patients receiving 12 mg QD (n = 25). Additionally, dose interruptions occurred in 72% of patients receiving the 8-mg BID dose, 82% who received the 16-mg QD dose, 50% given the 6-mg BID dose, and 87% given 12 mg QD.

In terms of efficacy, patients on the 8-mg BID dose had an overall response rate (ORR) of 31.6%. A 15.8% ORR at the 16-mg QD dose was seen compared with 15.8% with the 12-mg QD dose and a 5.3% at the 6-mg BID dose. All of these were partial responses.

Based on these findings, stage 2 of the ZENITH20-5 study is enrolling patients who will receive poziotinib at 8 mg BID.

“Poziotinib demonstrated improved tolerability in the BID dosing compared to the daily dosing, with significantly reduced rates of TEAEs and a corresponding delay of dose interruptions,” said Xiuning Le, MD, PhD, lead study author and assistant professor of thoracic/head and neck medical oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center. “Furthermore, poziotinib at 8 mg BID improved therapeutic efficacy compared to other arms.”

Poziotinib is an irreversible TKI targeting EGFR or HER2 exon 20 insertion mutations. Previously, the safety and efficacy of a 16-mg QD dose of the agent was examined and established in a large, multicentric study with blinded central image review. However, due to the 7.2-hour half-life of poziotinib, BID dosing is possible to reduce associated TEAEs and Cmax, investigators theorized.

In the open-label, multi-cohort, multi-center, phase 2 ZENITH20 trial examining the efficacy, safety, and tolerability of poziotinib in patients with previously treated and treatment-naïve NSCLC. In cohort 5 of the study, patients with locally advanced or metastatic NSCLC with EGFR- or HER2 exon 20 insertion mutations were randomized to receive either 10 mg, 12 mg, or 16 mg of poziotinib QD, or 6 mg or 8 mg of the drug BID. Dose reductions were allowed if TEAEs occurred, and patients were treated until intolerable toxicity, disease progression, or death.

To be eligible for enrollment, patients had to have locally advanced or metastatic NSCLC, with confirmed EGFR- or HER2 exon 20 insertion mutations via next-generation sequencing. Additionally, an ECOG performance status of 0 or 1 was required and patients with stable central nervous system metastases were permitted. 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 mutationsm were excluded from enrollment.

The primary end point was ORR, while secondary end points included disease control rate (DCR), duration of response (DOR), and safety and tolerability. ORR was also based on central independent imaging review. The trial was done in a Simon 2-stage design.

Patients enrolled in cohort 5 had a median age of 63.3 years (range, 23-87), the majority (n = 104) were female, and most (n = 102) had an ECOG performance status of 1. Additionally, 59% of patients had EGFR-exon 20 insertion mutations, while 41% had HER2 exon 20 insertion mutations.

As of the data cutoff date of March 5, 2021, 75 patients were still enrolled, including 68% of patients who were being treated with the 8-mg BID dose, 72% with the 6-mg BID dose, 38% with the 16-mg QD dose, and 32% with the 12-mg QD dose. The most common reason for treatment discontinuation was disease progression, noted Le.

While some patients were also randomized to a starting poziotinib dose of 10-mg QD, which was well tolerated, it showed poor antitumor activity. Moreover, higher rates of disease progression led to this dosing arm being discontinued.

In terms of safety, the most common grade 3 or higher TEAEs were diarrhea (n = 20), rash (n = 33), and stomatitis (n = 15). For patients receiving the full BID dose of poziotinib, the median number of days to first dose interruption was delayed; it was a median 16 days for the 8-mg BID dose and 28.5 days for the 6-mg BID dose, compared with 13 days for the 16-mg QD dose and 18.5 days for the 12-mg QD dose. Additionally, the median number of days to first dose reduction was 30 days for the 16-mg QD dose, 35 days for 12 mg QD, 18 days for 8 mg BID, and 45 days for the 6-mg BID dose.


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: AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT169.