Clinical Activity Shown with Poziotinib in NSCLC and EGFR exon 20

In a subgroup analysis of cohort 1 of the phase 2 ZENITH20 study (NCT03318939), patients with previously treated non-small cell lung cancer (NSCLC) and EGFR exon 20 insertions demonstrated clinical activity when receiving poziotinib (NOV120101, HM781-36B), including those with central nervous system (CNS) metastatic disease, which was not impacted by prior lines of therapy.

According to a poster in the 2020 American Society of Clinical Oncology Virtual Scientific Program, the patients in the intent-to-treat (ITT) population (n = 115) had an overall response rate (ORR) of 14.8% and the evaluable population (88 of 115) had an ORR of 19.3%. The disease control rate (DCR) was 68.7% and 80.7%, respectively.

The median duration of response (DOR) was 7.4 months for both the ITT and evaluable population and the median progression-free survival (PFS) was 4.2 months for the ITT population and 4.1 the evaluable patients. The evaluable patients had tumor shrinkage of 84% with poziotinib.

ZENITH20 had 7 cohorts total of patients with NSCLC and an EGFR or HER2 exon 20 insertion, which is a patient population where there are currently no approved therapies. The primary end point was ORR and the secondary end points were DOR, DCR, exploratory PFS, and safety. For cohort 1, patients received 16 mg of poziotinib daily.

Poziotinib exhibited a sustained response with a better ORR of 22.2% in the of evaluable patients with 3 or more lines of prior therapy (31% of the evaluable population).

There were 27% of patients with 2 prior lines of treatment in the evaluable population; these patients an ORR of 16.7%, a 3.7-month median PFS, and a 6.9-month median DOR. Patients with 1 prior line, which was 42%, had an ORR of 18.9%, median PFS of 5.4 months, and median DOR of 3.7 months.

Most patients had no prior EGFR tyrosine kinase inhibitor treatment (74% of the evaluable population) and these patients had an ORR of 23.1%, a median PFS of 5.5 months, and a median DOR of 7.4 months. Patients who had treatment with prior EGFR tyrosine kinase inhibitor (26%) showed an ORR of 8.7%, a median PFS of 3.5 months, and a median DOR that was not reached. There were 9% of patients with prior osimertinib (Tagrisso) therapy, of which 12.5% had ORR, and there was a 3.5-month median PFS and 2.3-month median DOR.

The most prevalent alterations, in over 50% of patients, were EGFR exon 20 near-loop insertions. Patients with this mutation benefitted the most from treatment with poziotinib, with an ORR of 20.8% in 53 patients in the evaluable population. These patients had a DCR of 86.8%. The molecular distribution of EGFR exon 20 insertion was consistent with previously reported data.

Patients with a far loop mutation (n = 22) had an ORR of 9.1% and DCR of 68.2%; there was 1 patient with a helical insertion and they had an ORR of 0% and DCR of 100%; the 12 patients who did not have a distinguishable mutation had an ORR of 33.3% and a DCR of 75.0%.

Of the 12 patients with stable CNS metastases at baseline, 10 had no CNS progression. There were 3 of 103 patients with no baseline brain metastases that had a new brain lesion or lesions.

The safety profile for these patients showed that the most common grade 3 treatment-related adverse events were rash at 28%, diarrhea at 25%, stomatitis at 9%, and paronychia at 6%.

The first 3 cohorts in the ZENITH20 trial received 16 mg of poziotinib daily; cohort 4 received 8 mg twice daily; cohort 5 was randomized to 10 mg daily, 6 mg twice daily, or 8 mg daily; and cohort 6 and 7 were given 8 mg daily.

Cohort 2 included previously treated patients with NSCLC andHER2 exon 20 mutations, cohort 3 included treatment-naïve patients with EGFR mutations, cohort 4 included treatment-naïve patients with HER2 mutations, cohort 5 had patients with either EGFR or HER2 mutations, cohort 6 had patients with EGFR mutations who progressed on osimertinib, and cohort 7 had patients with atypical EGFR or HER2 mutations.

_Reference:

_{Le X, Goldman JW, Clarke JM, et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol. 2020;38(suppl 15):9514. doi:10.1200/JCO.2020.38.15_suppl.9514}