NSCLC with EGFR exon 20 mutations: Twice-daily poziotinib clinically active, reduces AEs

Twice daily (BID) dosing of the irreversible tyrosine kinase inhibitor (TKI) poziotinib demonstrates clinically meaningful activity in treatment-naïve metastatic squamous non-small-cell lung cancer (mNSCLC) patients with EGFR exon 20 mutations, according to results of the phase II multicohort ZENITH20 trial presented at European Society for Medical Oncology Targeted Anticancer Therapies (ESMO TAT) Virtual Congress 2021.

“Effective treatment of patients with mNSCLC harbouring EGFR or HER2 exon 20 insertion mutations represents a critical unmet need,” said lead author Dr Adrian Sacher of the Medical Oncology and Haematology Department, Princess Margaret Cancer Centre in Toronto, Canada. “The specific challenge with poziotinib, which we know to be active in these patients, is maintaining a dose level that retains efficacy, given the potential for side effects.”

Poziotinib’s half-life of 7.2 hours and pharmacokinetic modelling offer an opportunity to improve tolerability with a BID dosing schedule. Therefore, poziotinib’s efficacy and tolerability are being studied in multiple cohorts of treatment-naïve mNSCLC patients with EGFR or HER2 exon 20 insertion mutations. Patients in the ZENITH20-Cohort 3 (n=79) were treated with poziotinib at 16 mg once daily (QD), whereas patients in the ZENITH20-Cohort 5 (n=40) received poziotinib at 10 mg, 12 mg or 16 mg QD and at 6 mg or 8 mg BID. [Annals of Oncology 2021;32(Suppl_1):S14-S19]

At a median follow-up of 9.2 months, 12 patients in Cohort 3 remained on treatment. The overall response rate (ORR) was 27.8 percent (95 percent confidence interval [CI], 18.4 to 39.1 percent) and disease control rate was 86.1 percent. Tumour shrinkage was reported in 91 percent of patients, with a median tumour reduction of 25.5 percent. Median duration of response (DoR) was 6.5 months and median progression-free survival (PFS) was 7.2 months. The adverse event (AE) profile was similar to that observed with second-generation EGFR TKIs, with grade ≥3 rash occurring in 33 percent of patients and grade ≥3 diarrhoea in 23 percent of patients.

“Although enrolment is still early in Cohort 5 [16–23 patients across dosing groups], we can already see that the frequency of dose reductions and interruptions is lower with BID treatment,” said Sacher. BID dosing schedules resulted in relative reductions in dose interruptions by 38 percent (8 mg BID vs 16 mg QD) and by 52 percent (6 mg BID vs and 12 mg QD), respectively.

“Notably, the frequency of grade ≥3 treatment-related AEs of interest, namely, diarrhoea, rash and stomatitis, is also lower with BID dosing,” highlighted Sacher. The AE rates were 31 percent with 16 mg QD vs 21 percent with 8 mg BID dosing and 27 percent with 12 mg QD vs 16 percent with 6 mg BID dosing.

“The preliminary efficacy data in the BID groups appear at least similar to the efficacy observed in QD dosing groups,” said Sacher. “Although the data are still immature, there may also be an indication of poziotinib’s enhanced antitumour activity with BID dosing, which is unsurprising if the resulting reduction in side effects enables continued administration of higher daily doses.”