Biomarker Data and Patient Preference Inform Perioperative Therapy Selection in Early HER2+ Breast Cancer

The increasing body of evidence on the use of perioperative therapy in patients with early HER2-positive breast cancer has improved the understanding of unique patient characteristics influencing treatment outcomes and emphasizes the importance of considering biomarker information, risk factors, and quality of life measures when deciding on a therapeutic approach and/or formulation for patients in this population, according to Maria Hafez, MD.

“Sometimes it is still a challenge to personalize the treatment for each patient and [know] when to use these agents and when to save them for later lines,” Hafez said following her participation in an OncLive® State of the Science Summit™ on breast cancer. “That’s why we need to [learn] about the most recent trial updates and how to personalize treatment for each patient group.”

In an interview with OncLive, Hafez discussed factors such as HER2 status, lymph node negativity, and risk stratification that influence the selection of adjuvant treatment approaches for patients with early-stage HER2-positive breast cancer; highlighted the assessment of neoadjuvant subcutaneous, fixed-dose pertuzumab (Perjeta) and trastuzumab (Herceptin) in the phase 3 FeDeriCa trial (NCT03493854); and expanded on data from the phase 2 PHranceSCa trial (NCT03674112) evaluating this regimen in the adjuvant setting.

Hafez is an assistant professor at Sidney Kimmel Medical College, and a breast & sarcoma medical oncologist, and the director of Breast Cancer Clinical Research at Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

OncLive: How does HER2 status and other biomarker information influence the treatment decision-making process for patients with early-stage HER2-positive breast cancer?

Hafez: We still consider the patients who have HER2 3+ status by immunohistochemistry [IHC], or the patients who have 2+ status by IHC and have a positive fluorescence in situ hybridization result, as [having] HER2-positive breast cancer. The question is whether these patients will be eligible to receive neoadjuvant chemotherapy before going to surgery or treatment following the surgery. Most of the patients who have T2 tumors, [regardless of] whether they have N0 or N1 disease, are eligible for neoadjuvant chemotherapy. There are some exceptions, as we can sometimes treat patients who have T1c with N1 or N0 disease in the neoadjuvant setting. We prefer that patients who have T1/N0 tumors go to surgery first and then receive an adjuvant treatment based on the surgical [pathology [results].

How do you determine the need for adjuvant therapies in this patient population, and what role does risk stratification play in tailoring treatment plans for patients?

Patients who have HER2-positive disease, [regardless of] whether they have hormone receptor [HR]–negative or HR-positive disease, usually go to surgery first, especially if they have N0 disease. If the patients still have lymph node–negative disease following surgery, and the size of the tumor is less than 3 cm, they can receive adjuvant treatment with single-agent chemotherapy, which is paclitaxel. In addition, we can add pertuzumab to trastuzumab for patients who are lymph node positive after treatment based on [findings from the phase 3] APHINITY trial [NCT01358877].

Could you briefly discuss the methodology and design of the FeDeriCa trial of subcutaneous pertuzumab and trastuzumab in patients with HER2-positive breast cancer?

The FeDeriCa trial was a randomized, open-label, multicenter noninferiority study. [The study] assessed the pharmacokinetics, efficacy, and safety of a fixed-dose subcutaneous formulation [of pertuzumab and trastuzumab plus chemotherapy] compared with the standard treatment of intravenous [IV] pertuzumab, trastuzumab, [and chemotherapy] in patients with HER2-positive early breast cancer in the neoadjuvant setting.

The [study assessed the] noninferiority of the subcutaneous [formulation] vs the IV treatment. Patients who were eligible to receive [investigator’s choice of] neoadjuvant chemotherapy, whether anthracycline or non-anthracycline, [received agents such as] docetaxel and paclitaxel. There were 2 arms; the first arm received subcutaneous pertuzumab/trastuzumab, and the other arm received IV pertuzumab/trastuzumab. Then the patients underwent surgery. After surgery, the patients who received subcutaneous therapy continued to receive [this therapy] for 1 year, and the patients who received IV [therapy] continued [on this modality as well].

The primary end point was the noninferiority of the pertuzumab trough serum concentration [Ctrough] levels during cycle 7, which is more important from a pharmacological standpoint. The secondary end points included the trastuzumab Ctrough levels after cycle 7 and before cycle 8. From a clinical standpoint, [the investigators evaluated] efficacy [in the form of] pathologic complete response [pCR], as well as safety.

How did the efficacy and safety of the subcutaneous formulation compare with the IV formulation in this trial?¹

The primary and secondary end points were comparable [between arms], and there was no statistically significant difference in Ctrough levels between the 2 formulations. The pharmacokinetic steady states were also the same, and the pCR rates were [comparable]. Also, the toxicity profile was not significantly different between the 2 groups. [Patients who were given] the subcutaneous regimen [received treatment for a shorter duration of time] compared with [those who received] the IV formulation, [indicating that the subcutaneous formulation] was more convenient for the patients. There was less chair time with the subcutaneous modality, with a duration of treatment of [approximately] 5 to 7 minutes vs [approximately] 2 hours [with the IV formulation].

How do the findings from FeDeriCa tie in with findings from the PHranceSCa trial of subcutaneous pertuzumab and trastuzumab in the adjuvant setting?²

A trial that was similar to FeDeriCa was the PHranceSCa trial. [This trial was primarily focused on] adjuvant therapy rather than neoadjuvant therapy followed by adjuvant treatment. [PHranceSCa was a] randomized, open-label study to assess patient preference [for] the fixed-dose, subcutaneously delivered combination of pertuzumab and trastuzumab in patients with HER2-positive early breast cancer. Those patients had already undergone surgery. Following surgery, they were randomly assigned to receive either subcutaneous pertuzumab and trastuzumab or the conventional IV [combination]. After 3 cycles, the patients who received subcutaneous therapy received IV therapy, and [vice versa]. [The investigators assessed which modality] the patients preferred to [use to] complete 1 year of treatment. That was the primary end point.

Interestingly, [85.0%] of patients preferred using the subcutaneous injection. The most common reasons [for subcutaneous preference] were that it requires less time in the clinic and feels more comfortable during administration. [Moreover], 13.8% of patients preferred IV infusion, citing more comfort during administration and lower injection-site pain. [FeDeriCa and PHranceSCa both] addressed whether we could use subcutaneous trastuzumab and pertuzumab, and both showed results [in favor of this mode of administration].

References

1. Tan AR, Im SA, Mattar A, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85-97. doi:10.1016/S1470-2045(20)30536-2
2. O’Shaughnessy J, Sousa S, Cruz J, et al. Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study. Eur J Cancer. 2021;152:223-232. doi:10.1016/j.ejca.2021.03.047