Responses Observed With Poziotinib in HER2-Positive Non-Small Cell Lung Cancer

"We believe that poziotinib is a significant advancement for patients with this deadly disease in an area of high unmet medical need."

The pre-specified primary end point of objective response rate (ORR) has been met in cohort 2 of the phase 2 ZENITH20 clinical trial (NCT03318939), which is evaluating poziotinib as treatment of patients with non–small cell lung cancer (NSCLC) harboring a HER2 exon 20 insertion mutation, according to the topline results announced by Spectrum Pharmaceuticals in a press release.

“We are pleased with the results of cohort 2,” said Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals, in a statement. “There are currently no approved therapies for HER2 patients with exon 20 insertion mutations in NSCLC and we are looking forward to reviewing these data with the FDA to determine the path forward.”

The trial enrolled 90 patients, who were treated with an oral once-daily dose of poziotinib at 16 mg. All patients had to have failed at least 1 prior line of systemic therapy to be included in the trial, and 60 patients (67%) failed 2 or more prior lines of therapy, which included chemotherapy and immunotherapy.

All responses were independently read and confirmed by a central imaging laboratory by RECIST criteria. In the intent-to-treat analysis, the confirmed ORR is 27.8% (95% CI, 18.9%-38.2%). The observed lower bound of 18.9% exceeded the pre-specified lower bound, which was 17%, according to a pre-specified statistical hypothesis for the primary end point.

After a median follow-up of 8.3 months, the median duration of response was 5.1 months (range, 1-12.3+ months). The disease control rate with poziotinib was 70%, and the median progression-free survival was 5.5 months.

These data demonstrated that the safety profile of poziotinib was in-line with the adverse events (AEs) seen with other second-generation EGFR TKIs, and these findings were also similar to the results observed in cohort 1. Grade 3 treatment-related rash was observed in 30% and diarrhea in 26%. No cases of pneumonitis were reported in cohort 2.

Cohort 2 was a registrational study, and the company will be requesting a meeting with the FDA to discuss the data and plans for a New Drug Application submission. Additional study results for cohort 2. are expected to be presented at an upcoming medical meeting.

ZENITH20 includes 7 independent cohorts. Cohorts 1 through 4 are all independently powered for a pre-specified statistical hypothesis, with the primary end point being ORR. Cohorts 5 through 7 are exploratory cohorts. The company reported in December 2019 that the primary end point for cohort 1 was not, but clinical activity was observed in this cohort. The company also amended the protocol for the study to explore additional twice-daily dosing regimens, in addition to lower single daily dosage amounts. Cohorts 2 and 3 were not impacted by this amendment, however, as they had been fully enrolled. The results from cohort 3 are expected to be presented during the second half of 2020.

Patients enrolled in the first 3 cohorts of the study received 16 mg of poziotinib daily; cohort 4 received 8 mg twice daily; cohort 5 was randomized to 10 mg daily, 6 mg twice daily, or 8 mg daily; and cohort 6 and 7 were given 8 mg daily.

Cohort 2 included previously treated patients with NSCLC and HER2 exon 20 mutations, while cohort 3 included treatment-naïve patients with EGFR mutations. Cohort 4 included treatment-naïve patients with HER2 mutations, cohort 5 had patients with either EGFR or HER2 mutations, cohort 6 had patients with EGFRmutations who progressed on osimertinib, and cohort 7 had patients with atypical EGFR or HER2 mutations.

At the 2020 American Society of Clinical Oncology Virtual Scientific Program, a poster demonstrated that poziotinib had clinical activity in cohort 1 of the ZENITH20 study, which included patients with central nervous systemic metastatic disease. In addition, interim findings appeared promising in a presentation at the 2020 American Association for Cancer Research Annual Meeting.

“We believe that poziotinib is a significant advancement for patients with this deadly disease in an area of high unmet medical need,” said Joe Turgeon, president, and chief executive officer of Spectrum Pharmaceuticals, in a statement.


Spectrum pharmacueticals announces positive topline results in HER2 exon20 insertion mutations from cohort 2 of the poziotinib ZENITH20 trial. News Release. Spectrum Pharamaceuticals. July 27, 2020. Accessed July 28, 2020.