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Adding pyrotinib to capecitabine (Xeloda) therapy improved overall survival compared with lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer, according to updated results from the Chinese PHOEBE trial.

Researchers found the new drug, phenergan dosing an irreversible pan-HER inhibitor developed by Jiangsu Hengrui Pharmaceuticals and approved in China, cut the risk of death by 31%.

“With extended follow-up, pyrotinib plus capecitabine demonstrated statistically significant overall survival improvement compared to lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy,” said lead author Binghe Xu, MD, PhD, of the Chinese Academy of Medical Sciences, Beijing, who presented the results virtually at the San Antonio Breast Cancer Symposium.

An interim analysis of the phase 3 PHOEBE trial, published earlier this year in The Lancet Oncology, found the drug significantly improved progression-free survival, but overall survival data were immature at the time of publication.

“The updated analysis of overall survival we present here reaffirms pyrotinib plus capecitabine as a viable treatment option in this patient population,” Xu said in his presentation.

Patients with HER2-positive metastatic breast cancer are typically treated with the HER2-targeted therapies trastuzumab emtansine (T-DM1) and pertuzumab in combination with a taxane, but resistance inevitably develops. “T-DMI is also not approved for use in the metastatic setting in all countries and regions worldwide,” Xu noted.

The PHOEBE trial enrolled 267 Chinese patients with HER2-positive metastatic breast cancer who had been previously treated with trastuzumab and taxanes and up to two previous lines of chemotherapy in the metastatic setting. Participants were randomly assigned to receive either oral pyrotinib 400 mg or lapatinib 1250 mg once daily, combined with oral capecitabine 1000 mg/m2 twice daily on days 1 to 14 of each 21-day cycle.

Median follow-up was 33.2 months in the pyrotinib group and 31.8 months in the lapatinib group. At data cutoff, 40.3% of patients in the pyrotinib group and 52.3% in the lapatinib group had died.

Median overall survival was not reached in the pyrotinib arm and was 26.9 months in the lapatinib arm (hazard ratio, 0.69; P = .019). Patients treated with pyrotinib also had significantly longer progression-free survival (12.5 months) than did those on lapatinib (5.6 months), representing a 52% lower risk of progression.

Patients were also stratified according to hormone-receptor status and previous lines of chemotherapy for metastatic disease (≤1 vs 2).

“The benefits of pyrotinib plus capecitabine were observed in most subgroups for the updated analysis of both overall survival and progression-free survival,” Xu noted.

The most common adverse events of grade 3 or higher were diarrhea (31% in the pyrotinib group vs 8% in the lapatinib group) and hand-foot syndrome (16% vs 15%, respectively). Serious adverse events were reported for 10% of patients in the pyrotinib group and 8% in the lapatinib group.

There were no treatment-related deaths in the pyrotinib group and one sudden death in the lapatinib group that was considered treatment-related.

“The survival difference observed in this trial is impressive and certainly makes pyrotinib plus capecitabine a valid option for treatment,” said Coral Omene, MD, PhD, a medical oncologist at Rutgers Cancer Institute of New Jersey and an assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick. “However, the study was done where current anti-HER2 options like T-DM1 and pertuzumab were not available and so patients had not been treated with these drugs.”

In addition, she told Medscape Medical News, several very effective novel anti-HER2 therapies have become available in recent years, including tucatinib (Tukysa) and trastuzumab deruxtecan (Enhertu), so it’s not clear if or when pyrotinib-capecitabine should be used.

“It may likely be used in later lines of treatment given the current options available; however, it remains a very good option to be used in earlier lines for patients that may be ineligible for the other therapies,” said Omene, who was not involved in the research. “Certainly, this data will spur further clinical trial investigations using other combinations of drugs and this may help us understand how best to use this agent in our treatment arsenal.”

Amy Tiersten, MD, a professor of medicine, hematology and medical oncology at Icahn School of Medicine at Mount Sinai, New York City, noted that it’s quite unusual to see a survival difference in trials of heavily pretreated metastatic breast cancer. 

“Unlike lapatinib, which is a reversible inhibitor of HER2 signaling that may encourage resistance, pyrotinib is an irreversible inhibitor,” she told Medscape Medical News. “Patients on the pyrotinib arm had a very impressive 31% decrease in the risk of death as compared to patients on the lapatinib arm.”

“Importantly, this improvement was not at the cost of additional toxicities,” added Tiersten, who also was not involved in the study. “Better therapies are needed for our HER2-positive metastatic breast cancer patients and this new combination represents a very attractive later-line option for treatment.” 

The study was supported by Jiangsu Hengrui Pharmaceuticals Company Ltd. Xu has received research grants from the company, advisory fees from Novartis and Roche, and fees for serving on a speakers’ bureau from AstraZeneca, Pfizer, Roche, and Eisai.

San Antonio Breast Cancer Symposium: Abstract GS3-02. Presented December 9, 2021.

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