Abstract
BackgroundThere is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations.MethodsIn this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored.ResultsSeventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2–60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2–30.0), with median PFS of 5.6 months (95% CI, 2.8–8.4), and median OS of 10.5 months (95% CI, 8.7–12.3). The median duration of response was 9.9 months (95% CI, 6.2–13.6). All treatment-related adverse events (TRAEs) were grade 1–3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression.ConclusionsPyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation.Trial registrationChinese Clinical Trial Registry Identifier: ChiCTR1800020262
Highlights
There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring Human epidermal growth factor receptor 2 (HER2) mutations
Adotrastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan-nxki (T-DXd) are recommended as treatment options for advanced HER2-mutant NSCLC patients by the National Comprehensive Cancer Network (NCCN) guidelines based on objective response rate (ORR) of 44% (N = 18) and 72.7% (N = 11), respectively in advanced HER2-mutant lung adenocarcinomas, these two drugs have not been approved yet for treating this subset of patients [4, 5]
Two patients were excluded for withdrawing informed consents before study treatment; a total of 78 patients were enrolled in this study and were included in the efficacy and safety analyses (Fig. 1)
Summary
There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. HER2-mutated non-small cell lung cancer (NSCLC) can only obtain limited clinical benefit from targeted therapies such as pan-HER tyrosine kinase inhibitors (TKIs) or TKIs targeting EGFR/HER1 or HER2 [1,2,3]. In a phase II study (N = 60) conducted by Zhou C et al, chemotherapy-treated NSCLC patients with HER2 mutations within exon 20 and 19 achieved an ORR of 30% upon pyrotinib, with mPFS of 6.9 months and median overall survival (mOS) of 14.4 months [11]. The underlying mechanism of resistance to pyrotinib and its efficacy in patients who had brain metastases and prior exposure to anti-HER2 therapy has not been well elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
