Poziotinib shows potential for advanced NSCLC with HER2 exon 20 insertions
medwireNews: The tyrosine kinase inhibitor poziotinib has antitumor activity in heavily pretreated patients with advanced or metastatic non-small-cell lung cancer (NSCLC) harboring HER2 exon 20 insertions, show data from the phase 2 ZENITH20 trial.
The findings are in line with those from another ZENITH20 cohort, previously reported by medwireNews, which showed poziotinib activity in people with previously treated NSCLC and EGFR exon 20 insertions, despite not meeting the trial’s primary endpoint.
In the current cohort, 90 participants (median age 60 years, 64% women) with HER2 exon 20 insertions who had received a median of two prior lines of treatment were given poziotinib 16 mg once daily for up to 24 months.
During a median 9.0 months of follow-up of, 25 participants achieved a partial response, giving an objective response rate of 27.8%. The median response duration was 5.1 months.
Mark Socinski (AdventHealth Cancer Institute, Orlando, Florida, USA) and co-investigators say that poziotinib met the prespecified efficacy criteria and has “a clinically meaningful benefit” in this group of patients, for whom there are currently no approved targeted therapies.
An additional 38 (42.2%) participants had stable disease during follow-up, giving a disease control rate of 70.0%.
The researchers also report in the Journal of Clinical Oncology that the majority (74%) of patients experienced a degree of tumor reduction, with a median reduction of 22%.
In addition, median progression-free survival was 5.5 months and 37.8% (of participants were alive and progression-free at 6 months.
Furthermore, subgroup analyses showed similar results regardless of the number of lines and types of previous therapy, presence of central nervous system (CNS) metastases, and types of HER2 insertion mutations.
In terms of safety, Socinski et al say that treatment-related adverse events [TRAEs] were typical of those seen with other tyrosine kinase inhibitors and generally occurred during the first 2 weeks of treatment.
Overall, 78.9% experienced at least one grade 3 TRAE, most commonly rash (48.9%), diarrhea (25.6%), and stomatitis (23.3%). Four patients experienced five grade 4 TRAEs, with one case each of stomatitis, hypomagnesemia, dyspnea, hypocalcemia, and relapsing pancreatitis. One participant died due to treatment-related pneumonia.
The majority (76.7%) of patients needed at least one poziotinib dose reduction, resulting in a median relative dose intensity of 71.5%, and 14.4% permanently discontinued treatment due to adverse events.
Socinski et al note, however, that the study protocol has now been amended to encourage proactive use of antidiarrheal agents and oral steroids for rash management, which they hope will mitigate toxicity and allow patients to remain on poziotinib for maximum clinical benefit.
They also report that twice-daily dosing of poziotinib in being evaluated in another ZENITH20 cohort, with preliminary analyses indicating significantly reduced side effects but similar efficacy relative to once-daily dosing.
The researchers conclude that their “findings validate HER2 exon 20 insertions as an actionable therapeutic target in lung cancer, including in patients with CNS metastasis, and present poziotinib as a potentially meaningful therapeutic option.”
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