LBA60 - ZENITH20, a multinational, multi-cohort phase II study of poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations

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 2^nd generation TKIs. Additional cohorts are enrolling to explore alternative dose levels and BID dosing.

Clinical trial identification

NCT03318939.

Editorial acknowledgement

Legal entity responsible for the study

Spectrum Pharmaceuticals.

Funding

Spectrum Pharmaceuticals.

Disclosure

M.A. Socinski: Research grant/Funding (institution): Spectrum Pharmaceuticals. R. Cornelissen: Research grant/Funding (institution): Spectrum Pharmaceuticals. M.C. Garassino: Research grant/Funding (institution): Spectrum Pharmaceuticals. J. Clarke: Research grant/Funding (institution): Spectrum Pharmaceuticals. N. Tchekmedyian: Research grant/Funding (institution): Spectrum Pharmaceuticals. J. Molina: Research grant/Funding (institution): Spectrum Pharmaceuticals. J.W. Goldman: Research grant/Funding (institution): Spectrum Pharmaceuticals. G. Bhat: Full/Part-time employment: Spectrum Pharmaceuticals. F. Lebel: Full/Part-time employment: Spectrum Pharmaceuticals. X. Le: Research grant/Funding (institution): Spectrum Pharmaceuticals.