The phase 2 ZENITH20 trial evaluating poziotinib in previously treated patients with non–small cell lung cancer and HER2 exon 20 insertion mutations met its prespecified primary end point.
Francois Lebel, MD
The phase 2 ZENITH20 trial (NCT03318939) evaluating poziotinib in previously treated patients with non–small cell lung cancer (NSCLC) and HER2 exon 20 insertion mutations (cohort 2) met its prespecified primary end point, according to Spectrum Pharmaceuticals, the co-developer of the agent.1
“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, stated in a recent press release. “We believe that poziotinib is a significant advancement for patients with this deadly disease in an area of high unmet medical need.”
Ninety patients were enrolled to cohort 2 and received oral poziotinib at 16 mg once daily. All patients had progressed on at least 1 line of prior systemic therapy, and notably, 67% (n = 60) progressed on 2 previous treatments, including chemotherapy and immunotherapy.
Results from the intent-to-treat analysis showed that treatment with poziotinib resulted in a confirmed objective response rate (ORR) of 27.8% (95% CI, 18.9%-38.2%), and all responses were confirmed via a central imaging laboratory per RECIST criteria. The observed lower bound of 18.9% was found to exceed the prespecified lower bound of 17% in this patient population.
Moreover, at a median follow-up of 8.3 months, the median duration of response (DOR) reported with poziotinib in this cohort was 5.1 months, and the disease control rate (DCR) was 70%. The median progression-free survival (PFS) with the agent was 5.5 months.
“We are pleased with the results of cohort 2,” Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals, said in the press release. “There are currently no approved therapies for [patients with] HER2 exon 20 insertion mutations in NSCLC and we are looking forward to reviewing [these] data with the FDA to determine the path forward.”
ZENITH20 has 7 independent cohorts of patients; cohorts 1 to 4 are independently powered for a prespecified statistical hypothesis with a primary end point of ORR, while cohorts 5 through 7 are exploratory.
Previously, interim data from cohort 1 of the trial presented during the 2020 AACR Annual Meeting I showed that patients with pretreated NSCLC and EGFR exon 20 insertions experienced a 68.7% DCR with poziotinib.2 Moreover, the ORR in this patient subgroup was 14.8% (95% CI, 8.9%-22.6%). Seventy-nine of 115 patients enrolled to the intent-to-treat population achieved stable disease or better with the agent, with a median DOR of 7.4 months (95% CI, 3.7-9.7). Additionally, treatment with poziotinib led to a median PFS of 4.2 months (95% CI, 3.7-6.6).
However, the primary end point of ORR was not met, as only 17 of 115 patientsachieved a complete or partial response. However, 65% (n = 75) experienced tumor shrinkage with the agent. Notably, a previous single-center trial conducted at The University of Texas MD Anderson Cancer Center demonstrated that poziotinib elicited a higher rate of confirmed responses, of 43% and 44%, respectively, in heavily pretreated patients with EGFR or HER2 exon 20–mutant disease.3
The average dose of poziotinib was 11.5 mg, using the median relative dose intensity of 72% and a 16-mg dose as the denominator. Many of the patients given the full dose of poziotinib, at 16 mg, had dose interruptions or reductions; however, responses were still maintained at a lower dose level. Sixty-eight percent of patients experienced dose reductions, and 88% of patients had dose interruptions. The median duration of first dose interruption was 16 days.
With regard to safety, permanent treatment discontinuation because of treatment-related adverse effects (TRAEs) occurred at a rate of 10%. Any-grade TRAEs were reported in 99% (n = 114) of patients and the most common toxicities included diarrhea (79%), rash (60%), stomatitis (52%), and paronychia (45%). Grade 3 TRAEs that were reported in more than 10% of participants consisted of diarrhea (25%) and rash (28%). Two grade 4 effects were reported: diarrhea (n = 1) and dermatitis acneiform (n = 1). No grade 5 effects were observed.
Notably, based on results from cohort 1, Spectrum Pharmaceuticals amended the study protocol to examine additional twice daily dosing regimens and lower single daily dosage amounts; however, this amendment did not impact cohorts 2 and 3 as they had been fully enrolled.
Spectrum Pharmaceuticals is requesting a meeting with the FDA to examine data from cohort 2 and highlight plans for the submission of a new drug application for poziotinib. Additional results from cohort 2 are projected to be reported at an upcoming medical meeting. Results from cohort 3 of the trial are anticipated to read out during the second half of 2020.