Over the past 2 decades, there has been an extraordinary progress in the regimens developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1) are commonly recommended anti-HER2 target agents by the U.S. Food and Drug Administration. This review summarizes the most significant and updated research on clinical scenarios related to HER2-positive breast cancer management in order to revise the guidelines of everyday clinical practices. In this article, we present the data on anti-HER2 clinical research of neoadjuvant, adjuvant, and metastatic studies from the past 2 decades. We also highlight some of the promising strategies that should be critically considered. Lastly, this review lists some of the ongoing clinical trials, findings of which may soon be available.

Targeted therapeutic options and future perspectives for HER2-positive breast cancer.

PURPOSEPyrotinib, an irreversible pan-ErbB inhibitor, showed promising antitumor activity and acceptable tolerability in a phase I trial. We assessed the efficacy and tolerability of pyrotinib vers...

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.19.00108

Pyrotinib or Lapatinib Combined With Capecitabine in HER2–Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, and/or Trastuzumab: A Randomized, Phase II Study

Purpose This phase I study assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Patients and Methods Pyrotinib was administered continuously, orally, once per day to patients who did not have prior exposure to tyrosine kinase inhibitors of HER2. Planned dose escalation was 80, 160, 240, 320, 400, and 480 mg. For pharmacokinetic analysis, timed blood samples were collected on day 1 and day 28. Next-generation sequencing was performed on circulating tumor DNA and genomic DNA from tumor samples. Results Thirty-eight patients were enrolled. The dose-limiting toxicity was grade 3 diarrhea, which occurred in two patients administered 480 mg of pyrotinib; thus, the maximum tolerated dose was 400 mg. Common pyrotinib-related adverse events included diarrhea (44.7% [17 of 38]), nausea (13.2% [five of 38]), oral ulceration (13.2% [five of 38]), asthenia (10.5% [four of 38]), and leukopenia (10.5% [four of 38]). The only grade 3 adverse event was diarrhea. Pharmacokinetic analyses indicated that pyrotinib exposure was dose dependent. The overall response rate was 50.0% (18 of 36), and the clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) was 61.1% (22 of 36). The median progression-free survival was 35.4 weeks (95% CI, 23.3 to 40.0 weeks). The overall response rate was 83.3% (10 of 12) in trastuzumab-naive patients and 33.3% (eight of 24) in trastuzumab-pretreated patients. Preliminary results suggest that PIK3CA and TP53 mutations in circulating tumor DNA ( P = .013) rather than in archival tumor tissues ( P = .474) may predict the efficacy of pyrotinib. Conclusion Continuous once-per-day pyrotinib was well tolerated and demonstrated promising antitumor activity in HER2-positive patients with metastatic breast cancer. The maximum tolerated dose was established as 400 mg. Diarrhea was the dose-limiting toxicity. The promising antitumor activity and acceptable tolerability of pyrotinib warrant its further evaluation in a phase II study.

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2016.69.6179

Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

Summary Background Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab Methods This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease The primary endpoint was progression-free survival according to masked independent central review Efficacy and safety were assessed in all patients who received at least one dose of the study drugs Results presented here are from a prespecified interim analysis This study is registered with ClinicalTrialsgov, NCT03080805 Findings Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p Interpretation Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy Funding Jiangsu Hengrui Medicine and National Key R&D Program of China Translations For the Chinese translation of the abstract see Supplementary Materials section

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30702-6.pdf

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial

Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer.

Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

e11596 Background: Pyrotinib is a novel small molecule irreversible pan-tyrosine kinase inhibitor with IC50values of 8.1 nM at HER2 and 5.6 nM at EGFR1, respectively. Methods: The Phase I study was...

A phase I study for tolerability, safety, and pharmacokinetics of pyrotinib, a novel irreversible HER2 and EGFR inhibitor, in Chinese patients with HER2+ metastatic breast cancer.

Ge Zhang

Papers

Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer.

Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

A phase I study for tolerability, safety, and pharmacokinetics of pyrotinib, a novel irreversible HER2 and EGFR inhibitor, in Chinese patients with HER2+ metastatic breast cancer.