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Poziotinib Shows Promising Antitumour Activity in Patients with HER2 Exon 20 Mutated NSCLC

Findings from a phase II single-arm investigator-initiated study
29 Sep 2021
Anticancer agents & Biologic therapy;  Lung and other thoracic tumours;  Personalised medicine

In a phase II study conducted by the MD Anderson Cancer Center researchers, poziotinib resulted in a 27% confirmed partial response (PR) rate and a median progression-free survival (PFS) of 5 months in patients with advanced HER2 exon 20 mutated non-small cell lung cancer (NSCLC). The study team observed responses across HER2 exon 20 insertions subtypes. Furthermore, an additional 46% of patients achieved stable disease (SD), for a disease control rate (DCR) of 73%. The median overall survival (OS) reached 15 months. The findings are reported by Dr. John V. Heymach, Chair of the Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues online on 22 September 2021 in the Journal of Clinical Oncology (JCO).  

The authors wrote in the study background that HER2 mutations occur in 3% of lung cancers. In NSCLC, 48% of all HER2 mutations including variants of unknown significance are exon 20 mutations. Preclinical studies have demonstrated that HER2 exon 20 mutations are resistant to most currently approved covalent and non-covalent tyrosine kinase inhibitors (TKIs), including afatinib, neratinib, and dacomitinib.

More recently, other HER2-directed approaches have been explored. A 21% objective response rate (ORR) for patients with NSCLC was reported with the combination of anti-HER2 monoclonal antibodies trastuzumab and pertuzumab. In a study of patients with NSCLC harbouring any HER2 mutation, ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC), 6 of 11 patients (54.5%) harbouring HER2 exon 20 insertion mutations had a PR. In preliminary results for another trastuzumab-based ADC, trastuzumab deruxtecan, an ORR of 62% with median PFS of 14 months was reported in patients with NSCLC bearing any HER2 mutation.  Pyrotinib, an irreversible TKI, yielded a response rate of 30.0% with a median PFS of 6.9 months in patients with HER2 exon 20 mutated NSCLC.

Poziotinib (HMB781-36B) is an orally available, irreversible covalent TKI. Although poziotinib shares a similar quinazoline backbone with afatinib and dacomitinib, because of the smaller size, increased halogenation, and flexibility of the drug, poziotinib can circumvent the steric hindrance in drug-binding pocket induced by HER2 or EGFR exon 20 insertions.

The predicted activity of poziotinib was confirmed using in vitro and in vivo models demonstrating the potent antitumour activity of poziotinib in cells with these mutations. Based on preclinical findings, the MD Anderson Cancer Center researchers initiated an investigator-sponsored multicohort phase II study of poziotinib in patients with advanced solid tumours including NSCLC harbouring HER2 or EGFR mutations. In JCO, they reported the primary results from a cohort of patients with NSCLC with HER2 exon 20 mutations.

In this open-label, phase II study, patients with advanced HER2 exon 20 mutant NSCLC were enroled to receive poziotinib at a dose of 16 mg per day for 28-day cycles. The primary endpoint was ORR per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response.

In total, 30 patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies.

As of data cut-off on 1 March 2021, the confirmed ORR was 27% (95% confidence interval [CI] 12 to 46). Responses were observed across HER2 exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI 4.0 to not estimable).

The median PFS was 5.5 months (95% CI 4.0 to 7.0).

The median OS was 15 months (95% CI 9.0 to not estimable).

The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhoea (20%). There was one possible treatment-related death because of pneumonitis.

The authors commented that an independent multicentre phase II study of poziotinib in HER2 exon 20 mutated previously treated metastatic NSCLC (ZENITH20 study), which was initiated after their study and was based on their findings, enroled 90 patients, and preliminary reports from this study were similar.

A number of promising agents have been tested recently in clinical studies in patients with HER2 exon 20 mutated NSCLC. Unlike the study presented here, which included only patients with HER2 exon 20 insertion, DESTINY-LUNG01 enroled patients with any HER2 mutation. Moreover, unlike oral TKIs including poziotinib, trastuzumab-deruxtecan is administered intravenously, which may be less convenient for patients.  In the pyrotinib study 20% of patients had a HER2 exon 20 or 19 point mutation. Preclinical studies have shown that the majority of HER2 point mutations, with the exception of L755P, are more sensitive to HER2 TKIs than exon 20 insertion mutations.

This study has several limitations, including the small sample size, single centre enrolment, and lack of control arm and of independent blinded radiologic review. A larger multicentre study is currently enroling.

The authors concluded that poziotinib as a single agent showed promising antitumour activity in patients with HER2 exon 20 mutated NSCLC, including patients who had previously received platinum-based chemotherapy, where there are currently limited therapeutic options, and patients with heavily pretreated disease where there is no defined standard-of-care treatment.

The optimal dosing of poziotinib is investigated in a randomised study that compares twice daily dosing to once daily dosing. The daily dose of 16 mg used in the current study was associated with significant, but manageable side effects and frequently required dose reduction.

Poziotinib has been granted fast track designation for HER2 exon 20 mutated NSCLC by the US Food and Drug Administration and is undergoing further clinical development.

This work study was supported by Spectrum Pharmaceuticals, the Conquer Cancer Foundation, and the Lung Cancer Research Foundation. It was also supported in part by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. MD Anderson Cancer Center Support Grant was acknowledged.

Reference

Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for Patients With HER2 Exon 20 Mutant Non–Small-Cell Lung Cancer: Results From a Phase II Trial. JCO; Published online 22 September 2021. DOI: 10.1200/JCO.21.01113

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