Findings Are Reported From De-escalation Therapy in Early Breast Cancer

In a study of early breast cancer (EBC) involving treatment with a trastuzumab biosimilar (Trazimera), pertuzumab, and pembrolizumab, investigators observed that molecularly selecting for a certain patient type helped improve pathologic complete response (pCR).

In findings for KEYRICHED-1, presented at the 2021 San Antonio Breast Cancer Symposium, investigators said selecting for patients with human epidermal growth factor receptor 2 (HER2)–enriched subtype by PAM50 led to “clinically meaningful” pCR rates compared with more toxic chemotherapy regimens.

The trial was an effort to de-escalate breast cancer treatment for which the standard includes chemotherapy. Multiple agents can result in overtreatment with unnecessary adverse events, hence the desire to restrict treatment selection.

In this study, investigators enrolled patients with HER2-enriched (HER2-E) EBC, a PAM50 molecular subtype of HER2-positive breast cancer that tends to be associated with higher pCR rates following anti-HER2–based treatment.

Investigators enrolled patients with pre- and postmenopausal status (N = 48) with newly diagnosed HER2-positive stage I to III EBC with immunohistochemical (IHC) expression (2+ or 3+) and HER2-E subtype.

The regimen included 4 cycles (every 21 days) of pembrolizumab 200 mg; trastuzumab biosimilar, loading dose 8 mg/kg and maintenance dose 6 mg/kg; and pertuzumab, loading dose 840 mg/kg and maintenance dose 420 mg/kg.

Trastuzumab attaches to HER2-expressing cancer cells and blocks the signaling that promotes their growth. Pertuzumab also blocks cell signaling and induces apoptosis, or cell death; and pembrolizumab prevents cancer cells from shutting down the immune system via the programmed death 1 pathway.

Study dates were May 2020 to March 2021 and investigators enrolled 52 patients (median age, 57 years) with the HER2-E subtype, among whom 48 initiated treatment. They said 65% had tumors greater than 2 cm and 30% were positive for lymph node metastasis.

The centrally confirmed pCR rate was 52% in 46 evaluable patients. Investigators said pCR was observed in 20 patients of 39 (51.2%) with HER2-positive tumors with 3+ IHC expression.

The confirmed pCR rate for HER2-positive/hormone receptor (HR)-positive tumors was 38.5% compared with 58.5% for patients with HER2-positive/HR-negative tumors.

The findings compare favorably with results from the WSG-ADAPT trial, which were reported in 2017. This was a study of patients with HER2-positive/HR-negative EBC. In this study, patients were randomized to trastuzumab and pertuzumab or trastuzumab, pertuzumab, and paclitaxel.

The WSG-ADAPT trial did not molecularly select patients, and in that study investigators sought to evaluate the pCR benefit of adding taxane therapy, not de-escalating therapy. In this case, the taxane (paclitaxel) “substantially increased” pCR in patients with HER2-positive/HR-negative EBC over the 12-week trial span.

“KEYRICHED-1 demonstrates that with appropriate molecular patient selection, clinically meaningful pCR rates in the range of those obtained with longer, more toxic chemotherapy-containing regimens can be achieved,” authors of the more recent trial concluded.

Reference

Kuemmel S, Gluz O, Reinisch M, et al. KEYRICHED-1 – a prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype. Presented at: 2021 SABCS; December 7-10, 2021. Poster P2-13-03.