Poziotinib Shows Promising Efficacy in First-line NSCLC With HER2 Exon 20 Insertion Mutations


Poziotinib demonstrates positive results for treatment-naïve patients with non-small cell lung cancer harboring HER2 exon 20 insertion mutations.

Poziotinib administered at a daily dose of 16 mg showed promise in the first-line treatment of patients with non–small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations, according to data from the ongoing phase 2 ZENITH20 trial (NCT03318939), presented at the 2022 European Society for Medical Oncology Targeted Anticancer Therapies Congress 2022.

Poziotinib is an irreversible pan-ErbB inhibitor, which acts against HER1 insertions or mutation. In the multicenter, multicohort, open-label ZENITH20 trial, 70 patients with NSCLC with HER2 exon 20 insertion mutations were randomized to receive 16 mg once daily or 8 mg twice daily of oral poziotinib.

The results showed a confirmed objective response rate (ORR) of 41% (95% CI:30%-54%), as evaluated centrally by an independent image review committee using RECIST 1.1 criteria. The evaluable patient population exhibited an ORR of 50%, meeting the trial’s primary endpoint as the observed lower bound of 30% exceeded the pre-specified lower bound of 20%. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and safety.

“Cohort 4 from our ZENITH20 study demonstrated positive results for treatment-naïve lung cancer patients harboring HER2 exon 20 insertion mutations,” said Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals, in a press release. “There is currently no approved treatment for NSCLC patients with these mutations. We are encouraged by these findings and look forward to further discussions with the FDA on the regulatory path forward.”

The ZENITH20 study is comprised of 7 cohorts of patients with NSCLC. Cohorts 1 (EGFR) and 2 (HER2) include previously treated NSCLC patients with exon 20 mutations, cohort 3 (EGFR) includes first-line patients and cohort 4 (HER2) includes first-line NSCLC patients with exon 20 mutations have completed patient enrollment.

Cohorts 1-4 are each independently powered for a pre-specified statistical hypothesis with a primary endpoint of ORR. Cohort 5 includes previously treated or treatment-naïve NSCLC patients with EGFR or HER2 exon 20 insertion mutations. Cohort 6 is comprised of NSCLC patients with classical EGFR mutations who progressed during treatment with first-line osimertinib and developed an additional EGFR mutation. Cohort 7 includes NSCLC patients with several less common mutations in EGFR or HER2 exons 18-21 or the extracellular or transmembrane domains.

For cohort 4, the study enrolled treatment-naïve NSCLC patients with HER2 exon 20 insertion mutations to evaluate the efficacy of poziotinib among patients dosed either with a QD or BID dosing strategy. Poziotinib was administered at 16 mg orally once daily for the first 48 patients followed by an additional 22 patients who were administered 8 mg poziotinib twice daily.

The primary endpoint of ORR was 41% (95% CI:30-54%) in the 70 treated patients including one complete response. DCR was 73% (95% CI:61-83%), DoR was 5.7 months (range 1.2-19.1+), and median PFS was 5.6 months (range 0-20.2+).

The safety profile of poziotinib was consistent with the tyrosine kinase inhibitor drug class. In cohort 4, 90% of patients had dose interruptions and 79% had reductions from the 16 mg QD starting dose, whereas 64% had reductions from the 8 mg BID starting dose.

The most common treatment related grade ≥ 3 adverse events were rash (30%), stomatitis (19%), diarrhea (14%), and paronychia (7%). The incidence of grade ≥ 3 pneumonitis was low at 3%. Dose reductions and interruptions were less frequent with BID dosing.


Spectrum Pharmaceuticals presents positive data for poziotinib in first-line NSCLC patients with HER2 exon 20 insertion mutations. News release. Spectrum Pharmaceuticals; March 7, 2022. Accessed March 8, 2022. https://bit.ly/3Kswe1l

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