Pyrotinib plus chemotherapy may benefit patients with pretreated HER2-positive breast cancer
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Pyrotinib plus capecitabine prolonged OS and PFS compared with lapatinib-capecitabine among patients with pretreated HER2-positive metastatic breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
The combination also exhibited a manageable safety profile, researchers involved with the randomized phase 3 PHOEBE trial reported.
“Phase 1 studies preliminarily demonstrated the safety and anti-tumor activity of pyrotinib as a pan-HER-receptor [tyrosine kinase inhibitor] in heavily pretreated HER2-positive metastatic breast cancer,” Binghe Xu, MD, PhD, professor of medical oncology at Chinese Academy of Medical Sciences, told Healio. “An open-label, multicenter, randomized, phase 2 study had demonstrated pyrotinib plus capecitabine significantly improved objective response rate and PFS compared with lapatinib plus capecitabine in HER2-positive metastatic breast cancer. Based on the previous pyrotinib data and a desire to seek an anti-HER2 agent that could overcome resistance to trastuzumab, we tested this agent in this phase 3 trial.”
As Healio previously reported, the open-label, multicenter PHOEBE trial included 267 patients in China with pathologically confirmed HER2-positive metastatic breast cancer. All patients had received prior treatment with trastuzumab (Herceptin, Genentech), as well as taxanes and/or anthracyclines.
Researchers randomly assigned 134 patients to pyrotinib (Hengrui Therapeutics) dosed at 400 mg daily on days 1 to 14 of 21-day cycles plus capecitabine. The other 132 patients received lapatinib (Tykerb, Novartis) dosed at 1,250 mg daily plus capecitabine.
Median follow-up was 33.2 months (95% CI, 31.4-34.2) in the pyrotinib group and 31.8 months (95% CI, 31.2-34.1) in the lapatinib group.
At the time of data cutoff of March 31, 54 deaths had occurred in the pyrotinib group and 69 deaths had occurred in the lapatinib group, and fewer patients assigned pyrotinib than lapatinib had experienced disease progression or died (73.9% vs. 91.7%).
Results showed longer median OS in the pyrotinib group (not reached vs. 26.9 months; HR = 0.69; 95% CI, 0.48-0.98).
Researchers reported a higher estimated 2-year OS rate in the pyrotinib group (66.6% vs. 58.8%), as well as longer median investigator-assessed PFS (12.5 months vs. 5.6 months; HR = 0.48; 95% CI, 0.37-0.63).
Investigators acknowledged study limitations. For example, inclusion of patients from 29 research centers precluded centralized testing of HER2 status.
Also, neither pertuzumab (Perjeta, Genentech) nor ado-trastuzumab emtansine (Kadcyla, Genentech) were approved in China at the time of patient enrollment. Consequently, the efficacy of the pyrotinib-capecitabine regimen among patients previously treated with either of those therapies could not be assessed.
“To the best of our knowledge, it is not easy for anti-HER2 TKIs to obtain OS benefit in the metastatic breast cancer population. Treatment decisions on anti-HER2 agents and their sequence of use need to be based on comprehensive assessment of PFS and OS benefit, patient status, prior anti-HER2 treatments and benefit/toxicities from prior anti-HER2 agents,” Xu said. “We have also conducted a randomized phase 3 trial to look at the efficacy and safety of pyrotinib in combination with trastuzumab and docetaxel vs. placebo plus trastuzumab and docetaxel for patients with metastatic breast cancer who have not received any systemic therapy in the metastatic setting. Results are eagerly awaited.”
Perspective
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Amy D. Tiersten, MD
The phase 3 PHOEBE trial demonstrated that patients with pretreated metastatic HER2-positive breast cancer achieved longer OS when treated with pyrotinib plus capecitabine compared with lapatinib plus capecitabine. It is quite unusual to actually see a survival difference in trials of heavily pretreated metastatic breast cancer. Unlike lapatinib — a reversible inhibitor of HER2 signaling, which may encourage resistance — pyrotinib is an irreversible inhibitor. Patients in the pyrotinib group demonstrated a very impressive 31% reduced risk for death compared with patients in the lapatinib group. Importantly, this improvement was not at the cost of additional toxicities. Better therapies are needed for patients with metastatic HER2-positive breast cancer, and this new combination represents a very attractive later-line treatment option.
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Xu B, et al. Abstract GS3-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2021; San Antonio.
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