Promising activity of poziotinib in previously treated NSCLC patients with EGFR or HER2 exon 20 mutations
Updated results of the phase II ZENITH20 study demonstrate substantial clinical activity of the novel tyrosine kinase inhibitor (TKI) poziotinib in previously treated advanced NSCLC patients harboring EGFR or HER2 exon 20 mutations, a patient population for whom a high medical need exists. High response rates were also seen in heavily pretreated patients, with marked CNS activity in HER2 exon 20 patients presenting with stable brain metastases at baseline.
Introduction
EGFR and HER2 exon 20 mutations are intrinsically resistant to available EGFR TKIs and anti-HER2 agents in metastatic NSCLC. Therefore, novel drugs that overcome the steric resistance induced by these mutations are urgently needed. Poziotinib a novel irreversible inhibitor of EGFR and HER2 exon 20 mutations that is currently being studied in the multi-cohort, multicenter, Phase 2 ZENITH20 study. In this trial, treatment naïve or experienced advanced NSCLC patients with EGFR or HER2 exon 20 mutations are included into one of 5 cohorts. Cohorts 6 and 7 of this trial enrolled patients with osimertinib-resistant EGFR mutations, or atypical EGFR or HER2 mutations, respectively. During WCLC 2020, updated results of cohorts 1 and 2 were presented evaluating poziotinib at a dose of 16mg QD in previously treated EGFR and HER2 exon 20 patients, respectively.
Encouraging response rates in 2nd line
Among the 115 patients enrolled in cohort 1 (previously treated EGFR exon 20), an overall response rate (ORR) of 14.8% was reported with disease control in 68.7%. Responses were durable with a median duration of response (DoR) of 7.4 months. In this cohort, the median progression-free survival (PFS) was reported at 4.2 months. In cohort 2, 90 previously treated patients with a HER2 exon 20 mutation were enrolled. In these patients, poziotinib induced an ORR of 27.8% with a disease control rate of 70.0%. The median DoR and PFS in cohort 2 reached 5.1 and .5 months, respectively.
In the EGFR exon 20 patients, the ORR was similar among patients treated with poziotinib in 2nd line (14.3%), 3rd line (13.8%) or beyond (16.8%). Among cohort 1 patients who previously received an immune checkpoint inhibitor, the ORR was 21.1%. In total, 8 patients in cohort 1 had stable brain metastases at baseline and one of them obtained a partial response (8.3%).
For HER2 exon 20 patients, a higher ORR was seen among patients receiving the study drug beyond third line (38.7% vs 23.3% and 290.7% for 2nd and 3rd line). Interestingly, clinical activity was seen in all 14 HER2 exon 20 patients with stable brain metastases at baseline. In four of them (28.6%), a response was noted and none of the patients in this cohort had progression of the brain lesion (CNS disease control rate 100%).
The most common treatment-related Grade ≥3 AEs were rash (29%), diarrhea (26%), and mucosal inflammation (10%). The onset of most related AEs occurred in Cycle 1 resulting in 87% dose interruptions and 72% dose reductions. 14% had permanent drug discontinuation for related AEs.
Conclusion
Substantial clinical activity was observed in previously treated patients in both NSCLC EGFR or HER2 exon 20 mutations regardless of specific mutations and prior therapy with consistent responses seen in more heavily pre-treated patients. The safety data shows a manageable toxicity profile that is typical of 2nd generation TKIs. Additional cohorts are enrolling with alternative dose levels and BID dosing.
Reference
R. Cornelissen, et al. Updated efficacy, safety, and dosing management of poziotinib in previously treated EGFR and HER2 exon 20 NSCLC patients. Presented at WCLC 2020; Abstract MA11.04.
