Among women with HER2-positive metastatic breast cancer enrolled in a phase 2 randomized trial, the pan-ErbB inhibitor pyrotinib plus capecitabine had manageable toxicity and a significantly higher overall response rate (ORR) than lapatinib plus capecitabine, investigators reported.
The pyrotinib/capecitabine combination also led to significantly longer progression-free survival (PFS) versus that of standard lapatinib/capecitabine treatment in these women, who had previously received treatment with taxanes, anthracyclines, and in some cases trastuzumab, the investigators wrote in the.
“To our knowledge, this is the first trial to demonstrate that a novel epidermal growth factor receptor/HER2–targeting tyrosine kinase inhibitor provides ORR and PFS benefits over lapatinib,” wrote Fei Ma, MD, of the National Cancer Center, State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking, and colleagues.
In the phase 2 study, a total of 128 Chinese women with histologically confirmed relapsed or metastatic breast cancer were randomized to receive the pyrotinib- or lapatinib-containing regimens given in 21-day cycles.
Overall response rates, the primary end point, were 78% (51 of 65 patients) in the pyrotinib arm and 57.1% (36 of 63 patients) in the lapatinib arm (P = .01), Dr. Yu and colleagues reported.
Median PFS was 18.1 months versus 7.0 months in the pyrotinib and lapatinib arms, respectively (P less than .001). A “potential trend” toward improved overall survival was noted in the pyrotinib arm, though the data were premature and not statistically significant at the time of data analysis, according to the investigators.
Altogether, these efficacy results tracked with those of an earlier phase 1 investigation, and currently, a randomized phase 3 study is underway to confirm the findings, reported Dr. Yu and coauthors.
Hand-foot syndrome and diarrhea were the most common grade 3 adverse events seen with pyrotinib. The rate of grade 3 hand-foot syndrome wit pyrotinib was 24.6% versus 20.6% for the lapatinib group, and the rate of grade 3 diarrhea for the two groups was 15.4% and 4.8%, respectively.
Overall, grade 3 or 4 adverse events were seen in 61% of patients receiving pyrotinib, of which 3.1% were grade 4; they were seen in 47.6% of patients receiving lapatinib, of which 3.2% were grade 4.
Diarrhea of grade 3 severity occurred mainly in the first treatment cycle for both the pyrotinib and lapatinib groups, investigators said.
While the protocol for this randomized phase 2 study did not permit diarrhea prophylaxis, the use of prophylactic loperamide is being studied in a phase 3 study of pyrotinib plus trastuzumab and docetaxel in women with HER2-positive metastatic disease and no prior systemic therapy
Investigators said patients are told to interrupt capecitabine if they experience ongoing grade 3 diarrhea or grade 1 or 2 diarrhea with complications such as dehydration, nausea, vomiting, or fever. If the diarrhea persists after 3 days, pyrotinib should then be interrupted, they said.
Similar advice was given for hand-foot syndrome.
“To date, the only method proven to effectively manage hand-foot syndrome is interruption of treatment and, if necessary, dose reduction,” said the investigators, who recommended first interrupting capecitabine and later pyrotinib.
The study was sponsored by Jiangsu Hengrui Medicine and supported by the CAMS Initiative for Innovative Medicine and the National Science and Technology Major Project of the Ministry of Science and Technology in China. The corresponding author of this study, Binghe Xu, MD, PHD, reported institutional research funding from Jiangsu Hengrui Medicine and other disclosures related to AstraZeneca, Pfizer, Roche, and Eisai. Two study coauthors reported employment with Jiangsu Hengrui Medicine.