This study reports on the ZENITH20-2 cohort of previously treated patients with advanced NSCLC and an HER2 exon 20 insertion mutation.
ZENITH20 is a multicohort phase 2 study of poziotinib, a potent EGFR and HER2 exon 20 tyrosine kinase inhibitor (TKI) for the treatment of non–small-cell lung cancer (NSCLC). ZENITH20-2 targeted patients who had HER2 exon 20 insertion mutations as determined by a Clinical Laboratory Improvement Amendments–certified or equivalent sequencing test. Patients were given an oral dose of 16 mg of poziotinib daily, with allowances for changes or interruptions of treatment because of toxicity. A central independent image review committee (IIRC) evaluated the objective response rate (ORR) as a primary end point according to Response Evaluation Criteria in Solid Tumours 1.1 guidelines, with a 95% confidence interval (CI) prespecified lower bound of 17%. Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety were secondary end points.
ZENITH20-2 enrolled 90 patients with advanced NSCLC and an HER2 exon 20 insertion mutation. The cohort had a median age of 60 years, was 64% female, 66% nonsmokers, 78% Caucasians, and 16% had concurrent clinically stable brain metastases at entry. Patients had a median of 2 prior therapies (range, 1-6); 98% had prior chemotherapy/platinum-based therapy, 67% had immunotherapy (including checkpoint inhibitors), and 28% had HER2 therapy.
The ORR in all 90 patients was 27.8% (95% CI, 18.9%-38.2%) and was 35.1% (95% CI, 24.4%-47.1%) in 74 patients who were evaluated by the IIRC. The DCR was 70%, the median PFS was 5.5 months (range, 0.03-13.1+ months), and the median DOR was 5.1 months (range, 1-12.3+ months, with 3 patients continuing treatment). Most subgroups showed a response to poziotinib; 31 patients with ≥3 treatments had an ORR of 38.7%, and 14 patients with central nervous system metastasis had an ORR of 28.6%. Rash (30%), diarrhea (26%), and mucosal inflammation (14%) were the most common adverse events of grade ≥3.
The ZENITH20-2 phase 2 clinical trial exceeded the designated 95% CI lower bound threshold of 17% for the ORR primary end point. The authors noted that the promising responses and manageable safety profile were typical of second-generation TKIs. Further studies will focus on alternative dosing strategies.
Socinski MA, et al. ESMO 2020. Abstract LBA60.