Author(s): Prof Sherko Kuemmel, MDa,b,c; Monika Graeser, PD MDa,d,e; Prof Peter Schmid, MDf; Mattea Reinisch, MDb,c; Prof Friedrich Feuerhake, MDg,h; Valery Volk, PhDg; Prof Sorin Armeanu-Ebinger, PhDi; Leon Schütz, MSci; Olga Kelemen, PhDi; Christopher Schroeder, MDi; Prof Stephan Ossowski, PhDi; Katarzyna Jóźwiak, PhDj; Athina Kostara, MDk; Iris Scheffen, MDa,d; Kerstin Lüdtke-Heckenkamp, MDl; Prof Felix Hilpert, MDm; Angela Kentsch, MDn; Carsten Ziske, MDo; Reinhard Depenbusch, MDp; Prof Michael Braun, MDq; Prof Jens Uwe Blohmer, MDc; Christine zu Eulenburg, PD PhDa,r; Prof Matthias Christgen, MDg; Stephan Bartels, PhDg; Prof Hans Heinrich Kreipe, MDg; Rachel Wuerstlein, PD MDa,s; Claudia Biehl, MDt,u; Enrico Pelz, MDv; Prof Andreas Hartkopf, MDw; Prof Nadia Harbeck, MDa,s; Oleg Gluz, PD MDa,d,x; on behalf of the West German Study Group investigators;
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.
Author Affiliations
aWest German Study Group, Moenchengladbach, Germany; bBreast Unit, Clinics Essen-Mitte, Essen, Germany; cDepartment of Gynecology with Breast Center, Charité–University Medicine Berlin, Berlin, Germany; dBreast Center Niederrhein, Ev Hospital Bethesda, Moenchengladbach, Germany; eDepartment of Obstetrics and Gynecology, University Witten-Herdecke, Witten, Germany; fQueen Mary University of London, London, UK; gInstitute of Pathology, Hannover Medical School, Hannover, Germany; hInstitute of Neuropathology, University Clinic Freiburg, Freiburg, Germany; iInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; jInstitute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany; kGynOnco Duesseldorf, Duesseldorf, Germany; lDepartment of Oncology and Hematology, Niels Stensen-Kliniken, Georgsmarienhütte, Germany; mBreast Center Hamburg, Hospital Jerusalem, Hamburg, Germany; nDepartment of Gynecology, Diakovere Henriettenstift, Hanover, Germany; oInternal Medicine, St Josef-Hospital, GFO Kliniken Troisdorf, Troisdorf, Germany; pOnkodok GmbH, Guetersloh, Germany; qBreast Center, Rotkreuz Clinics Munich, Munich, Germany; rDepartment of Medical Biometry and Epidemiology, University Medical Center Hamburg, Hamburg, Germany; sBreast Center, Department of Gynecology and Obstetrics and CCCMunich, LMU University Hospital Munich, BZKF, Munich, Germany; tDepartment of Gynecology, Klinikum Dortmund gGmbH, Dortmund, Germany; uUniversity Hospital Witten-Herdecke, Witten, Germany; vInstitute for Pathology, Viersen, Germany; wDepartment of Women’s Health, University Hospital Tübingen, Tübingen, Germany; xUniversity Clinics Cologne, Cologne, Germany;
