Twice Daily Poziotinib Beats Safety of Single Dose in NSCLC

Adrian Sacher MD, MMSc, FRCPC

Perliminary analyses of 2 cohorts from the phase 2 multicohort ZENITH20 trial (NCT03318939) evaluating poziotinib show clinical activity and tolerability for the tyrosine kinase inhibitor in patients with non–small cell lung cancer (NSCLC) harboring EGFR and HER2 exon 20 insertions. Results were presented virtually at the European Society for Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021 by Adrian Sacher MD, MMSc, FRCPC.

The international trial is comprised of 7 cohorts. For the presentation, results from cohorts 3 and 5 were discussed. Cohort 3 evaluated poziotinib in the first-line setting in patients with NSCLC whose tumors harbor an EGFR exon 20 insertion. The primary end point of this cohort was objective response rate (ORR), and secondary end points included disease control rate, duration of response, and safety and tolerability. Cohort 5 was a dosing exploration study that evaluated previously treated patients or first-line patients with NSCLC with EGFR or HER2 exon 20 insertions across dosage settings—6 mg or 8 mg administered twice a day or 10 mg, 12 mg, or 16 mg administered once a day.

Cohort 3 enrolled 79 patients, 12 (15%) of whom are still undergoing treatment, Sacher, an assistant professor of medicine, Departments of Medicine and Immunology at the University of Toronto in Canada, said. Age and gender distribution in the cohort is consistent with expectations for the metastatic NSCLC population. The investigators reported that the ORR was 27.8% (95% CI, 18.4%-39.1%), the disease control rate was 86.1% (95% CI, 76.5%-92.8%), and the progression-free survival rate was 7.2 months (range, 0.8-19.8+).

Overall, the investigators observed that 91% of patients in cohort 3 had some tumor reduction and specifically, a median percentage tumor reduction of 25.5%.

“This is not entirely unsurprising given that we know that poziotinib is an active drug. I think the challenge for poziotinib is often maintaining the dose at a level that retains efficacy, given the potential for [adverse] effects,” Sacher said during his presentation.

Sacher said that enrollment for cohort 5 is still early, but there are between 16 to 23 patients across the dosing cohorts. The data from the 10-mg arm was not ready for this presentation but will be presented during the American Association of Cancer Research meeting, Sacher told Targeted Therapies in Oncology in an email.

Dose interruptions in the 6 mg and 8 mg twice-a-day arms are 50% and 63%, respectively, and 87% and 82% in the 12 mg and 16 mg once-daily arms, respectively.

Dose reductions in the 6 mg and 8 mg twice-a-day arms are 38% and 50%, respectively, and 57% and 59% in the 12 mg and 16 mg once-daily arms, respectively.

“We are also seeing that the frequency of treatment-related adverse effects is lower with twice-a-day dosing, particularly those with adverse effects that are common for poziotinib, including diarrhea, rash, and stomatitis,” Sacher said.

Treatment-related adverse effects (AEs) greater than grade 3 for 6 mg twice a day was 19%, 8 mg twice a day was 31%, 12 mg once daily was 39%, and 16 mg once daily was 45%. Overall, grade 3 or higher AEs of special interest were 19% (6 mg twice a day), 19% (8 mg twice a day), 35% (12 mg once daily), and 36% (16 mg once daily).

When looking at the preliminary data for twice-a-day dosing efficacy, Sacher said that the response rate in that cohort appears to be similar to the once-daily dosing cohort (cohort 1) but cautioned that the numbers are still preliminary (TABLE1).

In cohort 3, clinical meaningful activity was observed in treatment-naive patients with metastatic disease whose tumors harbor EGFR exon 20 mutations at 16 mg once-daily dosing. Preliminary data from cohort 5 demonstrate improved tolerability with twice-a-day dosing, a reduced dose interruption with once-daily compared with twice-a-day dosing by 23% in the 16-mg dose level and 43% in the 12-mg dose level, and twice-a-day dosing reduced treatment-emergent grade 3 AEs. These preliminary data suggest potentially improved antitumor activity with twice-a-day dosing, Sacher said.

“ZENITH20 data are maturing and actively enrolling to further evaluate the impact of dose variation,” Sacher concluded.

_REFERENCE:

_{Sacher A, Le X, Cornelissen R, et al. Safety, tolerability, and preliminary efficacy of poziotinib with twice daily dosing strategy in EGFR/HER2 exon 20 mutant non-small cell lung cancer. Ann Oncol. 2021;32(suppl 1):S14-S19. doi:10.1016/j.an-nonc.2021.01.051}