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Pyrotinib Tops Lapatinib in Metastatic HER2-Positive Breast Cancer

— Updated PHOEBE trial results now show an overall survival benefit as well

MedpageToday

SAN ANTONIO -- Treatment with pyrotinib, an irreversible tyrosine kinase inhibitor (TKI) approved in China, appears to hold a survival advantage over lapatinib (Tykerb) in metastatic HER2-positive breast cancer, mature results of a phase III study found.

In an updated analysis of the PHOEBE trial, 66.6% of patients treated with pyrotinib plus capecitabine were alive after 2 years compared with 58.8% of those on lapatinib-capecitabine (HR 0.69, 95% CI 0.48-0.98, P=0.02), reported Binghe Xu, MD, PhD, of the Chinese Academy of Medical Sciences in Beijing.

A of the study had shown improved progression-free survival for the pyrotinib-treated group, but overall survival data were immature at the time.

"Pyrotinib plus capecitabine had a manageable safety profile and led to a statistically and clinically significant improvement in progression-free and overall survival compared with that for lapatinib," Xu said during his oral presentation at the San Antonio Breast Cancer Symposium.

The TKI would fit into the treatment algorithm as a second-line therapy for patients with metastatic HER2-positive breast cancer, Xu said, adding that the pyrotinib could be helpful in areas of the world where newer antibody-drug conjugates and other newer drugs are not readily available.

"Clearly, pyrotinib is active in metastatic breast cancer," said Steven Isakoff, MD, PhD, of Mass General Cancer Center in Boston. He noted, however, that the trial occurred during a period of rapid development in HER2-positive disease.

"It will be challenging to see where pyrotinib will fit in a rapidly changing medical landscape," Isakoff told ֱ.

PHOEBE randomized 266 patients previously treated for HER2-positive metastatic breast cancer to capecitabine plus either pyrotinib or lapatinib at 29 hospitals in China. Median follow-up was 33.2 months and 31.8 months for the two arms, respectively.

Average patient age was about 50 years and nearly two-thirds had received two previous lines of chemotherapy in the metastatic setting. More than 79% of patients in each arm showed evidence of resistance to trastuzumab (Herceptin). At data cutoff, 40.3% of patients in the pyrotinib arm and 52.3% in the lapatinib arm had died.

Xu explained that while patients with metastatic HER2-positive disease are typically treated with trastuzumab plus pertuzumab (Perjeta), in combination with a taxane, resistance inevitably develops. Patients may then be treated with lapatinib-capecitabine or with alternative HER2-targeted therapies, such as the antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla).

However, lapatinib and many other available HER2-targeted TKIs are reversible and do not sustain the inhibition of HER2 signaling. This may facilitate the development of treatment resistance, Xu noted. In addition, T-DM1, which is the preferred regimen for second-line therapy after trastuzumab in many international guidelines, is not approved for metastatic disease in many countries.

"There is an urgent unmet need for additional HER2-targeted therapies for patients who progress on standard therapies in countries and regions where access to HER2-directed agents is scarce," said Xu. Along with targeting HER2, pyrotinib also targets HER4 and the epidermal growth factor receptor, also known as HER1.

Xu pointed out that the results of PHOEBE led to approval of pyrotinib-capecitabine as the second-line standard of care for HER2-positive metastatic breast cancer in China. "The updated analysis of overall survival we present here reaffirms pyrotinib plus capecitabine as a viable treatment option in this patient population."

A limitation of the study, Xu said, was there was no centralized testing of HER2 status, which was instead assessed separately by pathologists at each site using American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. An additional limitation was that neither pertuzumab nor T-DM1 were approved in China at the time of patient enrollment. Thus, the study was unable to assess the efficacy of pyrotinib plus capecitabine in patients previously treated with either of these therapies.

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    Ed Susman is a freelance medical writer based in Fort Pierce, Florida, USA.

Disclosures

The study was supported by Jiangsu Hengrui Pharmaceuticals Company.

Xu disclosed relevant relationships with Jiangsu Hengrui, Novartis, Roche, AstraZeneca, Pfizer, and Eisai.

Isakoff disclosed relevant relationships with Novartis, Puma, Seattle Genetics, and Genentech.

Primary Source

San Antonio Breast Cancer Symposium

Xu B, et al "Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer" SABCS 2021.