Updated Analysis Shows Improved OS for Pyrotinib Over Lapatinib in HER2-Positive Breast Cancer

In an updated analysis of overall survival (OS) data from the PHOEBE trial (NCT03080805), investigators reported that pyrotinib plus capecitabine exhibited longer OS in patients with HER2-positive breast cancer than those who received lapatinib (Tykerb) plus capecitabine. Specifically, median OS was not reached in the pyrotinib arm (95% CI, 34.0-not reached) compared with a median OS of 26.9 months in the lapatinib arm (95% CI, 22.4-not reached; HR, 0.69; 95% CI, 0.48-0.98; P =.019). Findings were presented by Binghe Xu, MD, PhD, a professor in the Department of Medical Oncology at Peking Union Medical College in China during the 2021 San Antonio Breast Cancer Symposium.¹

“Patients with metastatic HER2-positive breast cancer are typically treated with the HER2-targeted therapies trastuzumab (Herceptin) and pertuzumab (Perjeta) in combination with a taxane, but resistance to this regimen inevitably develops,” Xu said in a news release.

At data cutoff for the updated OS analysis, the median follow-up duration was 33.2 months (95% CI, 31.4-34.2) in the pyrotinib group (n = 134) and 31.8 months (95% CI, 31.2-34.1) in the lapatinib group (n = 132).

The estimated OS at 24 months was 66.6% for the pyrotinib group (95% CI, 57.7-74.0) and 58.8% (95% CI, 49.7-66.7) in the lapatinib group. For investigator-assessed PFS, 99 (73.9%) patients in the pyrotinib group and 121 (91.7%) patients in the lapatinib group had disease progression or had died. Pyrotinib plus capecitabine significantly improved PFS (12.5 months; 95% CI, 9.8-13.8) compared with that for lapatinib plus capecitabine (5.6 months; 95% CI 5.5-7.0). The hazard ratio was 0.48 (95% CI, 0.37-0.63; P < .0001).

In the pyrotinib group, 58.2% of patients received post-discontinuation therapy compared with 74.2% of patients in the lapatinib group. The most common therapy given was trastuzumab in 44.8% of the pyrotinib group and 49.2% in the lapatinib group. At the time of this updated analysis, 40.3% of patients in the pyrotinib group and 52.3% of the lapatinib group had died.

In the phase 3 trial, patients were randomly assigned to receive pyrotinib 400 mg plus capecitabine 1000 mg/m2 or lapatinib 1250 mg plus capecitabine 1000 mg/m². The primary end point was progression-free survival (PFS), and secondary end points were OS, objective response rate, duration of response, and safety. Treatment continued until disease progression, unacceptable toxicity, death, consent withdrawal, investigator decision, or completion.

Baseline characteristics were similar between the 2 groups. The average age was 50 years (range, 42-55) in the pyrotinib group and 49 years (range, 42-57) in the lapatinib group. Across both groups, the majority of patients were ECOG performance status 1, 64.9% in the pyrotinib group and 67.4% in the lapatinib group. Regarding previous trastuzumab use, 59.0% in the pyrotinib group received the drug for advanced disease, 56.0% received the drug in the neoadjuvant setting, and 14.9% received it for both. Similarly, in the lapatinib group, 67.4% received trastuzumab for advanced disease, 47.7% received the drug in the neoadjuvant setting, and 15.2% received the drug for both.

In the pyrotinib group, most patients (42.5%) received no lines of chemotherapy for metastatic disease, but in the lapatinib group, most patients (49.2%) received 1 previous line of chemotherapy for metastatic disease. Across the groups, patients who received 2 lines of chemotherapy for metastatic disease were nearly identical (15.7% and 15.9%, respectively).

Standard of care for patients in this setting involves HER2-targeted therapies trastuzumaband pertuzumab in combination with a taxane, but resistance inevitably develops. In the second line, treatment with the HER2-targeted tyrosine kinase inhibitor (TKI) lapatinib plus capecitabine or with alternative HER2-targeted therapies, such as trastuzumab emtansine (T-DM1; Kadcyla) is an option. In this setting, however, clinical challenges can arise because lapatinib and other TKIs are reversible and cannot sustain the inhibition of HER2 signaling. Further complicating treatment is that trastuzumab emtansine, a preferred treatment in the second-line setting after trastuzumab, is not approved for metastatic disease in many countries.

In subgroup analysis that focused on PFS and OS with or without trastuzumab resistance, the hazard ratio for OS without resistance for the pyrotinib and lapatinib groups was 0.60 (95% CI, 0.39-0.91). The hazard ratio for PFS without trastuzumab resistance was 0.44 across the groups (95% CI, 0.32-0.61). The hazard ratio for OS with trastuzumab resistance was 0.94 across the groups (95% CI, 0.48-1.85) and the hazard ratio for PFS with resistance was 0.58 across the groups (95% CI, 0.35-0.98).

In a previous interim analysis,² PFS was longer in the pyrotinib group compared with the lapatinib group at 12.5 months vs 6.8 months (HR, 0.39; 95% CI, 0.27-0.56; P < .0001). This finding for PFS met the criterion for statistical significance, but OS data were not fully mature. Based on these findings, the China National Medical Products Administration granted full approval of pyrotinib in combination with capecitabine as a second-line treatment for HER2-positive metastatic breast cancer.

_REFERENCES

_{1. Xu, B. 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. Presented at: 2021 San Antonio Breast Cancer Symposium. December 7-10, 2021. Abstract GS3-02}

_{2. Xu B, Yan M, Ma F, et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(3):351-360. doi:10.1016/S1470-2045(20)30702-6}