OT Breast Cancer

PHEREXA Trial: Analyzing Overall Survival in HER2-Positive Metastatic Breast Cancer

By Catlin Nalley

CHICAGO—“Over the past 2 decades, we have made great strides towards improving outcomes for patients living with metastatic HER2-postive breast cancer,” noted Sara M. Tolaney, MD, MPH, of Dana-Farber Cancer Institute, Boston. “Since the seminal report of the benefits of adding trastuzumab to chemotherapy we have seen an improvement in overall survival (OS) from approximately 2 years to now almost 5 years.

“These improvements in outcomes can be contributed to the use of continued anti-HER2 therapy beyond progression, as well as to the introduction of several new HER2-directed therapies,” she continued. “One of the largest improvements in survival has come from the addition of pertuzumab to taxane and trastuzumab as seen in the CLEOPATRA study. This resulted in an unprecedented 16-month improvement in OS, establishing this regimen as a standard in the first-line setting.”

The following question remains, according to Tolaney: “Does adding pertuzumab to trastuzumab and chemotherapy outside the first-line setting provide benefit?” The PHEREXA trial sought to address this query.


PHEREXA Background

This phase III, randomized, two-arm study (NCT01026142) evaluated the combination of trastuzumab and capecitabine with or without pertuzumab in patients with HER2-positive metastatic breast cancer.

Patients, whose disease had progressed during or following previous trastuzumab therapy, were randomized to receive capecitabine plus trastuzumab with or without pertuzumab. Investigators found that adding pertuzumab to trastuzumab plus capecitabine did not significantly improve independent review facility-assessed progression-free survival (IRF-PFS), which was the primary endpoint, in this patient population.

Patients in both Arm A and Arm B received trastuzumab (8 mg/kg IV as loading dose and then 6 mg/kg IV q3w) and capecitabine oral twice daily for 14 days every 3 weeks (1,250 mg/m2 twice daily in Arm A and 1,000 mg/m2 twice daily in Arm B). Individuals in Arm B also received pertuzumab (840 mg IV as loading dose and then 420 mg IV) every 3 weeks.

Researchers observed an 8-month increase in median OS with the addition of pertuzumab; however, this was not statistically significant due to hierarchical testing of IRF-PFS, and subsequently of OS.


Final OS Analysis

Researchers recently presented the final OS analysis at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 1013).

Neither the 2.8-month increase in PFS nor the 9.1-month increase in OS were statistically significant, according to Tolaney, an ASCO discussant. “There were no new safety signals that were identified and adverse events were similar between both arms with the exception of a higher rate of grade 3/4 diarrhea in those patients that received pertuzumab.”

Tolaney noted that this open-label trial was underpowered for the OS analysis. “Additionally, the control arm capecitabine plus trastuzumab is not the current standard of care in the second-line and one could argue that perhaps the appropriate control could be TDM-1.”

While the study has its limitations, Tolaney also pointed out several strengths of the research. “This represents the only randomized data we have for the use of pertuzumab outside the first-line setting,” she explained.

Direct comparisons cannot be made, however, Tolaney noted that the median PFS in this trial is similar to that seen in other second-line studies with trastuzumab and pertuzumab as well as TDM-1.

During her discussion of the PHEREXA, she noted, “there is no current data for the use of pertuzumab beyond progression and this is not recommended at this time outside of a clinical trial.”



Taxane with trastuzumab and pertuzumab remains the first-line standard of care, according to Tolaney.

“Consideration of trastuzumab and pertuzumab in patients previously untreated with pertuzumab is recommended,” she said. “The preference would be to use this in combination with chemotherapy; however, if chemo were contraindicated, one could consider using trastuzumab and pertuzumab alone or in combination with endocrine therapy for those patients who have HR-positive disease.”

Catlin Nalley is associate editor.