Reference Detail

Ref Type

PMID

Authors

M.A.Socinski, R.Cornelissen, M.C.Garassino, J.Clarke, N.Tchekmedyian, J.Molina, J.W.Goldman, G.Bhat, F.Lebel, X.Le

Title

ZENITH20, a multinational, multi-cohort phase II study of poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	31	suppl_4

URL

https://www.sciencedirect.com/science/article/pii/S0923753420423750

Abstract Text

Background: Treatment of non-small cell lung cancer (NSCLC) with EGFR or HER2 exon 20 mutations is a serious unmet medical need. We are evaluating the efficacy and safety of poziotinib, a potent EGFR and HER2 exon 20 tyrosine kinase inhibitor (TKI), in a large, prospective multi-cohort study (N=603). Here, we report results from a cohort of previously treated patients with advanced NSCLC exon 20 insertion mutations (ZENITH20-2 N=90). Methods: Patients enrolled in ZENITH20-2 had HER2 exon 20 insertion mutations per a CLIA certified (or equivalent) sequencing test. Poziotinib (16 mg) was administered orally QD, allowing dose interruptions/reductions for toxicity if needed. The primary endpoint was objective response rate (ORR), evaluated centrally by an independent image review committee using RECIST 1.1 with a 95% CI pre-specified lower bound of 17%. Secondary endpoints included disease control rate, duration of response, progression-free survival, and safety. Results: In ZENITH20-2, 90 patients were enrolled with a median age of 60 years; 64% females, 66% non-smokers, 78% Caucasians, and 16% had concurrent clinically stable brain metastases at entry. Median number of prior therapies was 2 (range: 1-6), with 98% of patients having prior chemo/platinum-based therapy; 67% immunotherapy, including checkpoint inhibitors; and 28% HER2 therapy. The most common treatment-related Grade ≥3 AEs were rash (30%), diarrhea (26%), and mucosal inflammation (14%). ORR in 74 evaluable patients was 35.1% (95% CI: 24.4 – 47.1%) and 27.8% (95% CI: 18.9 – 38.2%) in all 90 patients (As-Treated Population). The 95% CI lower bound exceeded the protocol-specified threshold of 17%. Median DoR was 5.1 months (range: 1-12.3+ months) with 3 patients continuing on treatment. DCR was 70% and median PFS was 5.5 months (range: 0.03-13.1+ months). Responses were observed in most subgroups. Specifically, ORR was 38.7% in 31 patients with 3+ lines of therapy and 28.6% in 14 patients with CNS metastasis. Conclusions: ZENITH20-2 met its ORR primary efficacy endpoint with durable responses and presented a manageable safety profile, typical of 2nd generation TKIs. Additional cohorts are enrolling to explore alternative dose levels and BID dosing. Clinical trial identification: NCT03318939.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References