In phase I results from China published in the Journal of Clinical Oncology,
oral pyrotinib (HTI-1001) was well-tolerated and showed antitumor activity in women with HER2-positive breast cancer.
Incidence of diarrhea was relatively high (44%), but that was the only grade 3 toxicity observed and there were no grade ≥4 toxicities reported. Maximum-tolerated dose was 400 mg daily.
“All pyrotinib-related diarrhea events were effectively controlled by use of antidiarrheal agents, and only 1 patient experienced dose interruption for 1 day because of diarrhea,” wrote the researchers, who were all from the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
“Pyrotinib is well-tolerated at a dose of 400 mg once per day, and its encouraging antitumor activity in patients with HER2-positive breast cancer warrants further evaluation in HER2-positive metastatic breast cancer phase II trials with a dose of 400 mg once per day.”
Pyrotinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor with activity against EGFR/HER1, HER2, and HER4. Data from preclinical trials suggested that pyrotinib can irreversibly inhibit multiple ErbB receptors and effectively inhibit the proliferation of HER2-overexpressing cells both in vivo and in vitro.
Thirty-eight women enrolled in this single-center, open-label, phase I ascending multiple oral dose study from August 2013 to August 2015. Eligibility criteria included a confirmed diagnosis of HER2-positive metastatic breast cancer and ECOG performance status of 0 to 1.
Half of patients had undergone ≥3 previous rounds of chemotherapy for metastatic disease. Twenty-five (65.8%) received prior trastuzumab, including 7 in the adjuvant setting, 12 in the metastatic setting, and 6 in both.
Planned dose escalation was 80 mg, 160 mg, 240 mg, 320 mg, 400 mg, and 480 mg.
The only dose-limiting toxicity reported was grade 3 diarrhea reported by 1 patient (11.1%) in the 320 mg group, 2 (25.0%) in the 400 mg group, and 2 (100%) in the 480 mg group. Because more than 33.3% of patients in the 480-mg dose group experienced a dose-limiting toxicity, the maximum-tolerated dose was determined to be 400 mg once-daily.
The 2 patients assigned to 480 mg discontinued on the study. The remaining patients in the 80-mg to 400-mg groups completed the 28-day continual daily dose period. Median duration of treatment was 32.0 weeks.
Twenty-eight patients (73.7%) experienced treatment-related adverse events (AEs) of any grade. Besides diarrhea, AEs reported in more than 10% of patients included nausea (13.2%), oral ulceration (13.2%), asthenia (10.5%), and leukopenia (10.5%).
Overall, 18 patients (50%) had partial response, 4 (11.1%) had stable disease ≥24 weeks, and 7 (19.4%) had progressive disease. Overall response rate (ORR) was 50.0% (95% CI, 32.9 -67.1) for the entire cohort. ORR was 87.5% (95% CI, 47.3-99.7) for the 400-mg dose cohort (n = 8). The overall clinical benefit rate was 61.1% (95% CI, 43.5-76.9), and 100.0% (95% CI, 63.1% to 100.0%) in the 400-mg group.
Median time to response was 8.0 weeks. Median duration of response for the 18 patients who had partial response was 32.4 weeks (95% CI, 27.7-52.1).
The best ORR among patients previously treated with trastuzumab was 33.3%, compared with 83.3% in trastuzumab-naïve patients (P
Overall median progression-free survival was 35.4 weeks (95% CI, 23.3-40.0) and 59.7 weeks (95% CI, 35.4-71.9) for the 400-mg cohort. Four patients remained on treatment at the December 31, 2015, data cutoff.
“This study evaluates a new drug that is oral and inhibits HER2 and other proteins (EGFR and HER4). Overall response rate was 50% higher in patients who had not received other anti-HER2 therapies in the past. Diarrhea was the main side effect,” said Parvin Pedd, MD, assistant clinical professor of hematology and oncology at UCLA’s David Geffen School of Medicine and member of the Jonsson Comprehensive Cancer Center. She reviewed the data for OncLive.
“We need additional studies to evaluate this new compound and questions need to be answered on what chemotherapy regimen it will be combined with and whether it is less toxic or more efficacious than our current anti-HER2 medications.”
Ma F, Li Q, Chen S, et al. 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 [published online May 12, 2017]. J Clin Oncol. doi: 10.1200/JCO.2016.69.6179.