PHOEBE Trial: Pyrotinib vs Lapatinib

PHOEBE (ClinicalTrials.gov Identifier: NCT03080805) is a phase 3 trial conducted in China. The study enrolled patients with HER2+ mBC who had received 2 or fewer prior lines of chemotherapy for metastatic disease. Patients must have received prior trastuzumab and taxanes and/or anthracyclines.

The patients were randomly assigned to receive oral pyrotinib at 400 mg or lapatinib at 1250 mg once daily. In both arms, patients received oral capecitabine at 1000 mg/m² twice daily on days 1-14 of each 21-day cycle. Patients were stratified by HR status and the number of previous lines of chemotherapy for mBC (≤1 vs 2).


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At SABCS 2021, Binghe Xu, MD of the Chinese Academy of Medical Sciences Cancer Hospital in Beijing, presented updated PFS and OS results from the trial.2

As in the interim analysis,4 pyrotinib plus capecitabine significantly improved investigator-assessed PFS compared with lapatinib plus capecitabine. In the update, the median PFS was 12.5 months and 5.6 months, respectively (HR, 0.48; 95% CI, 0.37-0.63; P <.0001).

At a median follow-up of approximately 32 months, 40.3% of patients in the pyrotinib group and 52.3% in the lapatinib group had died.  

The median OS was not reached for pyrotinib and was 26.9 months in the lapatinib group (HR, 0.69; 95% CI, 0.48-0.98; P =.02). Kaplan-Meier estimated OS at 24 months was 66.6% for pyrotinib and 58.8% for lapatinib.

For both OS and PFS, the superiority of pyrotinib-capecitabine over lapatinib-capecitabine was observed in most clinically relevant subgroups.

The investigators concluded that the OS results in the PHOEBE trial reaffirmed that pyrotinib plus capecitabine should be a treatment option for patients with HER2+ mBC after progression on trastuzumab plus a taxane.

Implications and Future Directions

In later-line settings and in regions that lack approval for antibody-drug conjugates for HER2+ mBC, pyrotinib will likely join the arsenal of available tyrosine kinase inhibitors (TKIs), based on the PFS and OS data from the PHOEBE trial. 

Approval by regulatory agencies may be hindered by the fact that the PHOEBE study enrolled patients from 29 different research centers, precluding centralized testing of HER2 status.

In addition, OS is a function of access to pre- and post-protocol therapies. Neither first-line pertuzumab nor second-line trastuzumab emtansine (T-DM1) were approved in China at the time of patient enrollment. Thus, the PHOEBE investigators were unable to assess the efficacy of the pyrotinib-capecitabine regimen in patients previously treated with those agents. 

It is unknown how pyrotinib performs in patients whose tumors become resistant to other TKIs (eg, neratinib, tucatinib, and lapatinib). Thus, the sequence in which HER2-targeted therapies should be employed will require further definition.