New Breast Cancer Agent Shows Promise in an Early Trial

Early results for a new agent, pyrotinib (HTI-1001), are showing promise for the treatment of HER2-positive breast cancer, according to phase 1 results from China published in the Journal of Clinical Oncology, which showed that the drug was well-tolerated and showed anti-tumor activity.

Incidence of diarrhea was relatively high (44 percent), but that was the only grade 3 toxicity observed and there were no grade 4 ot higher 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 one 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 2 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 1 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 three or more previous rounds of chemotherapy for metastatic disease. Twenty-five (65.8 percent) received prior Herceptin (trastuzumab), including seven in the adjuvant setting, 12 in the metastatic setting and six 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 one patient (11.1 percent) in the 320 mg group, two (25.0 percent) in the 400 mg group and two (100 percent) in the 480 mg group. Because more than 33.3 percent 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 two 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 weeks.

Twenty-eight patients (73.7 percent) experienced treatment-related adverse events (AEs) of any grade. Besides diarrhea, AEs reported in more than 10 percent of patients included nausea (13.2 percent), oral ulceration (13.2 percent), asthenia (10.5 percent) and leukopenia (10.5 percent).

Overall, 18 patients (50 percent) had partial response, 4 (11.1 percent) had stable disease of at least 24 weeks, and seven (19.4 percent) had progressive disease. Overall response rate (ORR) was 50.0 percent for the entire cohort. ORR was 87.5 percent for the 400-mg dose cohort (eight patients). The overall clinical benefit rate was 61.1 percent, and 100.0 percent in the 400-mg group.

Median time to response was eight weeks. Median duration of response for the 18 patients who had partial response was 32.4 weeks.

The best ORR among patients previously treated with Herceptin was 33.3 percent, compared with 83.3 percent in Herceptin-naïve patients.

Overall median progression-free survival was 35.4 weeks and 59.7 weeks for the 400-mg cohort. Four patients remained on treatment at the Dec. 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 percent higher in patients who had not received other anti-HER2 therapies in the past. Diarrhea was the main side effect,” said Parvin Pedd, M.D., 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. “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.”