Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial

Abstract

Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2positive metastatic breast cancer (MBC).Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 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 adverse events (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% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumabpretreated patients and 90.9% (10/11) in trastuzumab-na€ ve 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 with none or one genetic alteration (median, 16.8 vs. 29.9 months, P ¼ 0.006).Conclusions: In a population largely na€ ve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.

Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer

“…A previous study indicated that patients with EGFR mutations respond to neratinib 22 . In addition, the AE profile in this study was similar to that of previous studies 23 , 24 . Consistent with previous reports, diarrhoea was the most frequent treatment-related AE.…”

<p>Pathological Complete Response from Pyrotinib Combined with Trastuzumab, Paclitaxel and Cisplatin in a Postpartum Woman with HER2-Positive Locally Advanced Breast Cancer: A Case Report</p>

“…Intriguingly, the biomarker analysis of previous trials suggested that PIK3CA and TP53 mutation status in ctDNA in tumor tissues correlated with response and even PFS. 3,[18][19][20] Interestingly, our patient had the PIK3CA H1047R mutation, but the value of the detection of biomarkers in the adjuvant setting still needs to be proven. In one study, pyrotinib had a manageable toxicity profile in patients with HER2-positive metastatic breast cancer.…”

<p>Efficacy of Pyrotinib in a Heavily Pretreated Patient with Lung Adenocarcinoma Harboring HER2 Amplification and Exon 20 Insertions: A Case Report</p>

“…Preclinical studies suggested that pyrotinib can significantly inhibit the growth of HER2 factor-driven tumor cells both in vivo and in vitro. 17 This is achieved by blocking the cell cycle in the G1 phase through inhibition of the HER2 downstream signaling pathway. In a phase II study of 15 pretreated NSCLC patients with HER2 mutations, the administration of pyrotinib 400 mg resulted in an overall response rate of 53.3% and a median PFS of 6.4 months.…”