Chemotherapy-free neoadjuvant pembrolizumab combined with trastuzumab and pertuzumab in HER2-enriched early breast cancer (WSG-KEYRICHED-1): a single-arm, phase 2 trial.

Background: Accumulating evidence indicates that about 30-40% of patients with HER2-positive early breast cancer might achieve excellent outcomes without chemotherapy. Therefore, we aimed to test the pathological complete response after the addition of pembrolizumab to dual anti-HER2 blockade and omission of chemotherapy in patients with HER2-enriched breast cancer.

Methods: WSG-KEYRICHED-1 was a single-arm, multicentre, open-label, hypothesis-generating phase 2 trial done at 15 breast cancer centres in Germany. Women aged 18 years and older, with previously untreated clinical stage T1c-T3, N0-N2, M0, primary unilateral early invasive breast cancer, and locally confirmed HER2 immunohistochemistry score 2+ or 3+ status, and hormone receptor-positive or receptor-negative status, were enrolled. Women with centrally confirmed HER2-enriched subtype by prediction analysis of microarrays 50 gene set (PAM50) and an Eastern Cooperative Oncology Group performance status of 0-1 were allocated to four cycles of intravenous pembrolizumab (200 mg every 3 weeks for 12 weeks), intravenous trastuzumab biosimilar ABP 980 (8 mg/kg loading dose, then 6 mg/kg every 3 weeks for 12 weeks), and intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks for 12 weeks). The primary outcome was the proportion of patients with a pathological complete response (defined as ypN0 or ypT0/is), assessed in the full analysis set, which included all patients who had at least one dose of trial treatment and had central tumour assessment within 3 weeks after the end of trial treatment. For the primary endpoint to be met, at least 52·2% of patients had to have a pathological complete response to support the hypothesis that the proportion of patients with pathological complete response after trial treatment would be higher than 40% with statistical significance. Safety was analysed in all patients who had at least one dose of trial treatment. The study is registered with ClinicalTrials.gov, NCT03988036, and has been completed.

Findings: Between Sept 2, 2020, and May 5, 2021, 48 women were enrolled, of whom four did not have surgery, and one had only a local pathological complete response assessment. Therefore, 43 patients with central pathological complete response assessment were included in the full analysis set. Median follow-up was 8·6 months (IQR 8·3-9·0). 20 (47%) of 43 patients had a pathological complete response by central assessment (lower bound of the one-sided 95% CI 33%), thus the null hypothesis (40% pathological complete response) could not be rejected (p=0·22). Four (8%) of 48 patients had grade 3-4 adverse events deemed related to drug treatment. The most common grade 3-4 adverse events were increased alanine aminotransferase (n=1), drug hypersensitivity (n=1), nephritis (n=1), and panic attack (n=1). Serious adverse events occurred in four (8%) of 48 patients, which were drug hypersensitivity (n=1), panic attack (n=1), pyrexia (n=1), and COVID-19 (n=1). Pembrolizumab was discontinued or postponed due to adverse events in three (6%) of 48 patients. No deaths occurred.

Interpretation: 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.

Funding: Merck Sharp & Dohme and NanoString Technologies.