Dr Hafez on the Design of the FeDeriCa Trial in HER2+ Early Breast Cancer

Maria Hafez, MD, assistant professor, breast and sarcoma medical oncologist, director, Clinical Breast Cancer Research, Sidney Kimmel Medical College, Thomas Jefferson University, discusses the rationale and design of the phase 3 FeDeriCa trial (NCT03493854) in patients with HER2-positive early breast cancer, as well as key outcomes from this trial.

The randomized, multicenter, open-label, noninferiority FeDeriCa trial investigated the efficacy, safety, and pharmacokinetics of administering a fixed-dose, subcutaneous formulation of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy vs standard intravenous (IV) pertuzumab plus trastuzumab and chemotherapy in the neoadjuvant setting in patients with HER2-positive early breast cancer. The chemotherapy regimen consisted of investigator’s choice of anthracycline- or non-anthracycline–based treatments, either paclitaxel or docetaxel, Hafez says. Following neoadjuvant therapy, patients underwent surgery, after which they continued to receive pertuzumab plus trastuzumab and chemotherapy for 1 year in subcutaneous or IV formulations as they had in the neoadjuvant setting.

The primary end point of FeDeriCa was the noninferiority of pertuzumab trough serum concentration (C

) levels between the 2 arms during cycle 7, which informed the pharmacological assessment of these regimens, Hafez explains. Key secondary end points included the trastuzumab C

 levels between cycles 7 and 8, Hafez notes. Pathologic complete response (pCR) was a key clinical efficacy outcome, Hafez continues.

The primary and secondary end points were comparable between the 2 arms, and no statistically significant differences in C

 levels emerged between the 2 formulations, Hafez emphasizes. Furthermore, the pharmacokinetic steady states and pCR rates were comparable between the 2 arms, according to Hafez. Notably, the toxicity profiles between the subcutaneous and IV formulations did not significantly differ, Hafez notes, although patients in the subcutaneous arm had a shorter duration of treatment than those in the IV arm. This indicates that the subcutaneous formulation may be more convenient for patients to receive. The duration of treatment with the subcutaneous regimen was approximately 5 to 7 minutes vs approximately 2 hours with the IV regimen, Hafez concludes.

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Maria Hafez, MD, discusses the design of, and outcomes from, the phase 3 FeDeriCa trial in patients with HER2-positive early breast cancer.

Dr Hafez on the Influence of Biomarker Expression on Adjuvant T-DM1 Use in HER2+ Breast Cancer

Maria Hafez, MD, assistant professor, Sidney Kimmel Medical College, breast and sarcoma medical oncologist, director, Breast Cancer Clinical Research, Sidney Kimmel Cancer Center, Thomas Jefferson University, discusses differences in biomarker expression prior to and following neoadjuvant chemotherapy treatment seen in the phase 3 KATHERINE trial (NCT01772472) in patients with HER2-positive breast cancer.

The KATHERINE trial evaluated the use of adjuvant ado-trastuzumab emtansine (Kadcyla; T-DM1) vs standard-of-care trastuzumab (Herceptin) in patients with HER2-positive breast cancer, who had residual disease following neoadjuvant chemotherapy and surgery. As previously reported, the study met its primary end point with a 50% decrease in recurrence or death with T-DM1 vs trastuzumab.

The latest update from the KATHERINE trial has provided valuable insights into biomarkers associated with response to adjuvant therapy for patients within this population, Hafez begins. The exploratory analysis aimed to identify biomarkers of response and differences in biomarker expression before and after neoadjuvant chemotherapy. This included the relationship between invasive disease-free survival (iDFS) and HER2 protein expression or gene amplification; 

 hotspot mutations; and expression of PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, as classified by Absolute Intrinsic Molecular Subtyping, Hafez details.

Key findings from the biomarker data showed that treatment with T-DM1 improved iDFS compared with trastuzumab across most biomarkers, Hafez reports. High HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab, but iDFS with T-DM1 was independent of HER2 expression level, she states. Additionally, low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab, but not with T-DM1. 

 hotspot mutations were not found to be prognostic, and increased variability in HER2 expression was observed in post-neoadjuvant samples compared with paired pre-neoadjuvant samples, Hafez adds.

These findings have important implications for the selection of adjuvant therapy in patients with HER2-positive breast cancer and residual invasive disease after neoadjuvant therapy, Hafez emphasizes. This provide valuable insights into biomarkers that may help guide treatment decisions and improve outcomes in this high-risk subgroup of patients, she concludes.

Maria Hafez, MD, discusses differences in biomarker expression prior to and following neoadjuvant chemotherapy treatment in HER2-positive breast cancer.

Dr Hafez on Key Considerations For Treatment Selection in Early-Stage HER2+ Breast Cancer

Maria Hafez, MD, assistant professor, Sidney Kimmel Medical College, breast and sarcoma medical oncologist, director, Breast Cancer Clinical Research, Sidney Kimmel Cancer Center, Thomas Jefferson University, discusses how hormone receptor status, risk stratification, and other disease factors influence the treatment decision-making process in patients with early-stage HER2-positive breast cancer.

HER2-positive status in breast cancer is determined by immunohistochemistry, Hafez begins. Currently, patients with a score of 3+ or those with a borderline 2+ score and a positive fluorescence in situ hybridization result are categorized as having HER2-positive disease, Hafez details.

The decision to use neoadjuvant or adjuvant chemotherapy depends on various factors. Typically, neoadjuvant chemotherapy is considered for patients with T2 tumors, irrespective of N0 or N1 status, Hafez states. Exceptions may include patients with T1c tumors and N1/N0 stage, she adds. These patients may also be candidates for neoadjuvant treatment. For those with T1 and T0 tumors, the preference often falls in line with surgery followed by adjuvant treatment based on surgical findings, Hafez says.

In the adjuvant setting, the decision-making process is also based on characteristics such as nodal involvement and tumor size, Hafez continues. Regardless of hormone receptor status, patients with HER2-positive disease typically undergo surgery prior to receiving other therapies, she emphasizes. This is especially true for patients presenting with N0 disease. Following surgery, those with lymph node-negative disease and tumors smaller than 3 cms may receive adjuvant treatment with single-agent chemotherapy, Hafez continues. For patients with lymph node-positive status after treatment, the therapeutic approach may involve the addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) and chemotherapy, as per the phase 3 CLEOPATRA trial (NCT00567190), Hafez explains. This tailored strategy aims to enhance the efficacy of HER2-targeted treatments in the adjuvant setting.

Overall, the choice between a neoadjuvant or adjuvant treatment approach is nuanced and guided by the specific characteristics and staging of a patient's tumor, Hafez says. This ensures tailored treatment strategies for optimal outcomes in patients with early-stage HER2-positive breast cancer.

Maria Hafez, MD, explains how hormone receptor status, risk stratification, & other factors influence clinical decisions in early HER2+ breast cancer.

Maria Hafez, MD

Articles

Dr Hafez on the Design of the FeDeriCa Trial in HER2+ Early Breast Cancer

Dr Hafez on the Influence of Biomarker Expression on Adjuvant T-DM1 Use in HER2+ Breast Cancer

Dr Hafez on Key Considerations For Treatment Selection in Early-Stage HER2+ Breast Cancer