PURPOSE: This phase I study assessed the safety, tolerability, maximum-tolerated dose, pharmacokinetics, antitumor activity and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2-positive metastatic breast cancer(MBC).METHODS: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1000mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on day 1 and day 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers.RESULTS: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17(60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose limited toxicity was observed. Grade 3 treatment-related AE occurred in 12(42.9%) patients; anemia(14.3%) and diarrhea(10.7%) were the most common grade 3 AEs. The overall response rate(ORR) was 78.6%(95% CI: 59.0% to 91.7%), and the clinical benefit rate was 85.7%(95% CI:67.3% to 96.0%). The median progression-free survival(PFS) was 22.1 months(95% CI: 9.0 to 26.2 months). ORR was 70.6%(12/17) in trastuzumab-pretreated patients and 90.9%(10/11) in trastuzumab-naive patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared to none or one genetic alteration (median, 16.8 vs. 29.9 months, P=0.006). CONCLUSION: In a population largely naive to HER2-targeted therapy, pyrotinib in combination with capecitabine are well-tolerated and demonstrate promising antitumor activity in HER2-positive MBC patients.
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