Molecular Selection Raises pCR Levels in Early Breast Cancer Trial

Biosimilars used in clinical studies may reduce the costs of these studies compared to the use of brand name medicines. As clinical research tools, they can also provide answers to questions about appropriate therapy.

Regarding the treatment of breast cancer, researchers used biosimilar trastuzumab (Trazimera) to help understand whether a genetically targeted patient population would benefit from de-escalating standard treatment by omitting chemotherapy.

Improved results have been obtained with the addition of targeted human epidermal growth factor 2 (HER2) receptor therapies to conventional chemotherapy, although patients are sometimes overtreated with combination therapies or experience adverse events that could otherwise be avoided.

In KEYRICHED-1 (NCT03988036), a prospective phase 2 trial, researchers investigated whether comparable pathologic complete response (pCR) rates could be achieved in the neoadjuvant setting without a therapeutic component of chemotherapy in patients with HER2-positive early breast cancer (EBC).

For this study, the investigators recruited patients with EBC enriched with HER2 (HER2-E) because this PAM50 molecular subtype of HER2 positive breast cancer is associated with higher pCR levels after treatment with HER2-EBC. anti-HER2. In other words, this subgroup of patients were more likely to respond well to de-escalation of treatment.

In this single-arm study, researchers recruited pre- and post-menopausal patients (N = 48) with newly diagnosed stage I-III HER2-positive EBC with 2+ or 3+ immunohistochemical expression (IHC) and a HER2-E subtype by PAM50.

The treatment consisted of 4 cycles (every 21 days) of the following:

  • Pembrolizumab (200 mg)
  • Trastuzumab biosimilar (Trazimera, loading dose 8 mg / kg, maintenance dose 6 mg / kg)
  • Pertuzumab (loading dose 840 mg / kg, maintenance dose 420 mg / kg)

Pembrolizumab is an immunotherapy that blocks the programmed cell death receptor (PD-1) from binding to PD-L1 / L2 ligands, thereby preventing the tumor cell from “turning off” the immune system’s response to cancer.

Pertuzumab inhibits the signaling process of tumor cells by locking onto HER2-expressing cancer cells, thereby stopping their growth and inducing apoptosis, or cell death.

Trastuzumab is complementary in its action to pertuzumab. It attaches to HER2 receptors in breast cancer cells and prevents them from receiving growth signals.

The trial was recruited between May 2020 and March 2021. Investigators said that of 98 patients initially screened, 52 (55%) had the HER2-E subtype by PAM50, and of these, 48 have entered the treatment phase.

The median age of the patients was 57 years; 65% had tumors larger than 2 cm and 30% were positive for lymph node invasion.

Investigators stated that the centrally confirmed pCR rate was 52% in 46 evaluable patients (a minimum pCR rate of 50% was predetermined for further recruitment).

“Despite the HER2-E subtype, no pCR was observed in 4 patients with IHC HER2 2 + / fluorescence in situ hybridization (FISH) – positive in contrast to 20/39 (51.2%) pCR in HER2 3+ tumors, ”wrote the study authors.

They stated that the confirmed pCR rate for HER2-positive / hormone receptor (HR) -positive tumors was 38.5% versus 58.5% for HER2-positive / HR-negative tumors. They did not observe any new safety signs.

The researchers said the results were favorable compared to those in the WSG-ADAPT HER2 + / HR- trial, another de-escalation study, which compared trastuzumab and pertuzumab alone (double blocking) with trastuzumab, pertuzumab and paclitaxel in patients with HER2-EBC positive / HR-negative.

In the WSG-ADAPT study, researchers concluded that adding taxane treatment (paclitaxel / chemotherapy) to the 3-month HER2 double blockade “dramatically” increased pCR levels in the HER2-positive EBC / HR-negative compared to double blocking alone.

They stated that in KEYRICHED-1, “the observed pCR levels compared favorably in HR-positive as well as HR-negative / HER2-positive EBCs. In addition, KEYRICHED-1 demonstrates that with appropriate molecular selection of patients, clinically significant pCR levels in the range of those obtained with longer and more toxic regimens containing chemotherapy can be achieved.


Kuemmel S, Gluz O, Reinisch M, et al. KEYRICHED-1 – a prospective, multicenter, open-label, single-arm phase II neoadjuvant study with pembrolizumab in combination with double anti-HER2 blockade with trastuzumab and pertuzumab in patients with early breast cancer with an intrinsic molecular subtype enriched in HER2. Presented at: 2021 SABCS; December 7-10, 2021.!/10462/presentation/1034

Martin E. Berry