KEY TAKEAWAYS
- The Phase 2 study evaluated the safety and efficacy of poziotinib in NSCLC pts with HER2 exon 20 mutations who had received at least two previous systemic therapies, including platinum-based regimens.
- Poziotinib showed significant efficacy and safety in NSCLC pts who had received and progressed on two or more prior lines of therapy, irrespective of the treatment types and sequence.
The HER2 mutation has recently been identified as a treatable target in non-small cell lung cancer (NSCLC), with trastuzumab-deruxtecan (T-DXd) serving as the sole approved second-line targeted therapy. Despite this, there remains a medical gap for patients (pts) who have undergone platinum-based chemotherapy followed by T-DXd treatment. Poziotinib is an irreversible tyrosine kinase inhibitor (TKI) effective against EGFR and HER2 exon 20 mutations.
It is currently undergoing investigation in a multi-cohort, multicenter Phase 2 clinical trial known as ZENITH20. This study reported the effectiveness and safety outcomes of poziotinib in NSCLC pts with HER2 exon 20 mutations who have had at least two prior systemic therapies, including platinum-based treatments.
NSCLC pts exhibiting HER2 exon 20 insertions and who have received a minimum of two systemic therapies were enrolled in two ZENITH20 cohorts. Poziotinib was given at a daily oral dose of 16 mg, with allowances for dosage adjustments and interruptions in case of toxicity. Key endpoints evaluated included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR), as assessed by an independent, central image review committee (IRC) according to RECIST 1.1 standards.
A total of 69 pts were administered 16 mg of poziotinib daily as a third or subsequent line of systemic treatment. The study group had a median age of 61 years; it comprised 65% females and 62% non-smokers. Additionally, 14% of the pts had stable brain metastases at enrollment. Every participant had received at least two previous therapies, ranging from 2 to 9 rounds; 49% had two prior lines of treatment, while 51% had three or more. All had been treated with platinum-based therapies, and other treatments included 78% with immunotherapy, 36% with HER2 antibody or antibody-drug conjugates, 17% with TKIs, and 16% with other systemic therapies such as VEGF inhibitors.
Grade 3 or higher adverse events primarily included rash (46%), diarrhea (28%), and mucositis (23%). The median relative dose intensity was 74% (ranging from 21-100%), and treatment adjustments were common: 83% of pts experienced dose interruptions, 72% underwent dose reductions, and 13% discontinued the drug due to adverse events. In this patient population with extensive prior treatment, the objective response rate (ORR) stood at 30% (21 out of 69), with a 95% confidence interval ranging from 19.9 to 42.7, surpassing the clinically meaningful benchmark of 17% set for the overall study.
The median duration of response (DOR) was 5.5 months, and the median progression-free survival (PFS) was 5.6 months. Effectiveness was consistent across varying types and sequences of prior treatments. Various ORRs were observed, ranging from 31.3% with platinum+any systemic therapy to 54.5% with platinum+TKI. The results were consistent between the two independent ZENITH20 cohorts.
Poziotinib showed significant clinical efficacy in pts who had undergone at least two prior lines of treatment, irrespective of the type or sequence. The ZENITH20 study furnishes extensive data for third or subsequent-line treatment settings in NSCLC pts with HER2 exon 20 mutations, who otherwise have very limited therapeutic options. No new safety concerns were noted in this group of pts.
Source: https://cattendee.abstractsonline.com/meeting/10925/presentation/1008
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT03318939
Le, X., Prelaj, A., Baik, C., Tchekmedyian, N., Leu, S., Bhat, G., Heymach, J.V., Cornelissen, R. Efficacy and Safety of Poziotinib in HER2 Exon 20 Insertion NSCLC Patients who Received at Least 2 Previous Systemic Therapies.
