Phase 2 ZENITH20 Trial Meets Primary Endpoint in NSCLC Subgroup


The study is evaluating poziotinib in patients who were previously treated for non-small cell lung cancer with HER2 exon 20 insertion mutations.

The pre-specified primary end point was met in cohort 2 of the phase 2 ZENITH20 trial, evaluating poziotinib in patients who were previously treated for non-small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations, according to Spectrum Pharmaceuticals, the developer of the agent.

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

The ZENITH20 trial is made up of 7 independent cohorts. The first 4 cohorts are each independently powered for a pre-specified hypothesis, with a primary end point of objective response rate (ORR); the remaining cohorts 5-7 are exploratory.

In December 2019, Spectrum Pharmaceuticals reported that the primary endpoint for cohort 1 was not met, though clinical activity was observed. Based on the results of cohort 1, the company has amended the protocol for ZENITH20 to explore additional twice daily dosing regimens as well as lower single daily dosage amounts. Importantly, this amendment did not impact cohorts 2 and 3, as these cohorts were already fully enrolled. Results from cohort 3 are anticipated in the second half of the year.

In cohort 2 of the ZENITH20 trial, a total of 90 patients were enrolled and received poziotinib orally once daily at a dose of 16 mg. Notably, all of the patients had failed at least 1 line of prior systemic therapy, with 60 patients (67%) having failed 2 or more prior therapies, including chemotherapy and immunotherapy.

The intent-to-treat analysis demonstrated a confirmed ORR of 27.8% (95% CI, 18.9%-38.2%). Based on the pre-specified statistical hypothesis for the primary endpoint, the observed lower bound of 18.9% exceeded the pre-specified lower bound of 17% in this heavily pre-treated population.

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

The safety profile was comparable to the type of adverse events observed with other second-generation EGFR tyrosine kinase inhibitors and similar to that seen in cohort 1. Overall, 30% of patients experienced grade 3 treatment related rash and 26% had grade 3 diarrhea. In cohort 2, no pneumonitis was reported.

“The positive results of cohort 2 are a significant milestone and we are looking forward to meeting with the FDA,” Joe Turgeon, president and CEO of Spectrum Pharmaceuticals, said in the release. “We believe that poziotinib is a significant advancement for patients with this deadly disease in an area of high unmet medical need.”

Cohort 2 was only designed to be a registrational study. Moving forward, Spectrum Pharmaceuticals is in the process of requesting a meeting with the FDA to discuss the data and its plans for a New Drug Application (NDA) submission. The company plans to present additional study results from cohort 2 at an upcoming medical meeting.


Spectrum Pharmaceuticals Announces Positive Topline Results in HER2 Exon20 Insertion Mutations from Cohort 2 of the Poziotinib ZENITH20 Trial [news release]. Henderson, Nevada. Published July 27, 2020. Accessed July 28, 2020.

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