Pembrolizumab Plus Trastuzumab/Pertuzumab Shows Promise in HER2-Positive Breast Cancer

Pembrolizumab plus trastuzumab and pertuzumab may be a potential chemotherapy-free regimen for patients with HER2-enriched early breast cancer, according to findings from the WSG-KEYRICHED-1 study.

The single-arm, phase 2 clinical trial, which was published in The Lancet Oncology, demonstrated that a clinically meaningful proportion of patients achieved pathologic complete response (pCR) and tolerated the triplet therapy well.

“Accumulating evidence indicates that about 30%–40% of patients with HER2-positive early breast cancer might achieve excellent outcomes without chemotherapy,” said Sherko Kuemmel, clinical director, Multidisciplinary Breast Unit, Kliniken Essen-Mitte, Germany, and colleagues.

Therefore, the researchers investigated pCR in 43 women aged 18 years and older from 15 breast cancer centers in Germany between September 2, 2020, and May 5, 2021. Patients enrolled in the study had previously untreated clinical stage T1c–T3, N0–N2, M0, primary unilateral early invasive breast cancer; locally confirmed HER2 immunohistochemistry score 2+ or 3+ status; and hormone receptor-positive or receptor-negative status. They had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

The treatment regimen consisted of four cycles of IV pembrolizumab (200 mg every 3 weeks for 12 weeks), IV trastuzumab biosimilar ABP 980 (8 mg/ kg loading dose, then 6 mg/kg every 3 weeks for 12 weeks), and IV pertuzumab (840 mg loading dose, then 420 mg every 3 weeks for 12 weeks).

At least 52.2% of patients needed to achieve pCR to support the hypothesis that the proportion of patients with pCR after trial treatment would be higher than 40% with statistical significance, the researchers said. After a median follow-up of 8.6 months, nearly half of patients (n=20) achieved pCR by central assessment, which showed that the null hypothesis could not be rejected.

In addition, the regimen of pembrolizumab plus trastuzumab and pertuzumab was tolerated well in the study population. A small number of patients (n=4) experienced grade 3-4 treatment-related adverse events (AEs). The most common were increased alanine aminotransferase (n=1), drug hypersensitivity (n=1), nephritis (n=1), and panic attack (n=1).

Serious AEs occurred in four patients: drug hypersensitivity (n=1), panic attack (n=1), pyrexia (n=1), and COVID-19 (n=1).

None of the patients died, and three patients had to stop or postpone treatment with pembrolizumab because of AEs.

“Although the null hypothesis could not be rejected, the WSG-KEYRICHED-1 trial highlights the potential of a short chemotherapy-free combination of pembrolizumab with dual anti-HER2 therapy, warranting the initiation of randomised trials investigating the immunotherapy without chemotherapy in patients with HER2-enriched breast cancer,” Kuemmel and colleagues wrote.

Reference:

Kuemmel S, et al. Lancet Oncol. 2025;26(5):629-640. doi: 10.1016/S1470-2045(25)00097-X