Pyrotinib Promising in Phase I Metastatic HER2-Positive Breast Cancer Trial

A novel ErbB inhibitor called pyrotinib was well tolerated and showed promising activity in patients with metastatic HER2-positive breast cancer, according to results of a phase I trial.

The treatment of HER2-positive breast cancer has been dramatically improved in recent years with agents included trastuzumab, lapatinib, and others. “However, these agents have limitations with respect to cardiac or gastrointestinal adverse effects, which may hamper continuous administration,” wrote study authors led by Binghe Xu, MD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing. Patients also can acquire resistance to HER2-directed therapies, suggesting there remains a need to develop new options for this malignancy.

Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor (TKI) with activity against HER1, HER2, and HER4. The researchers tested this agent in a phase I dose-escalation trial including 38 patients with HER2-positive metastatic breast cancer. The results were published online ahead of print earlier this year in the Journal of Clinical Oncology.

The study determined the maximum tolerated dose to be 400 mg once per day, based on dose-limiting toxicities that included grade 3 diarrhea. Both patients administered a dose of 480 mg experienced that adverse effect, compared with two of eight given the 400 mg dose. There were no grade 4 or 5 adverse effects related to the study drug; pyrotinib-related adverse effects of any grade were seen in 73.7% of patients.

Of 36 patients evaluable for response, 18 (50%) achieved a partial response and four (11.1%) had stable disease for at least 24 weeks. Seven patients (19.4%) had progressive disease. The overall response rate was 87.5% for the 400 mg dose cohort, and the median time to response was 8 weeks, with a median duration of response of 32.4 weeks.

The median progression-free survival in the study was 35.4 weeks. Of 12 trastuzumab-naive patients, the response rate was 83.3%, compared with 33.3% in trastuzumab-treated patients.

The investigators conducted a biomarker analysis of 18 patients who had circulating tumor DNA (ctDNA) available. Patients with wild-type PIK3CA and TP53 had a higher response rate than other patients, at 60% (P = .013). This appeared to be a better biomarker predictor than the same genes analyzed from archival tumor tissue, with which there was no such difference in response (P = .474).

They concluded that the agent is worthy of further study in a phase II trial. In an accompanying editorial published this month, Amy Jo Chien, MD, and Hope S. Rugo, MD, both of the University of California, San Francisco Comprehensive Cancer Center, highlighted the “quite modest” toxicity at the maximum tolerated dose in the pyrotinib trial.

They pointed out that this was a less heavily pretreated population than would usually be found in the United States and Europe, which may affect pyrotinib’s efficacy. “Nevertheless, the lower rate of diarrhea and overall favorable adverse-effect profile with pyrotinib is promising, given that toxicity has limited the use of TKIs in multiple studies,” they wrote.