Neoadjuvant chemotherapy and immunotherapy in Luminal B-like breast cancer: results of the phase II GIADA trial.

Abstract

PURPOSE\nThe role of immunotherapy in hormone receptor (HR)-positive, HER2-negative breast cancer (BC) is underexplored.\n\n\nEXPERIMENTAL DESIGN\nThe neoadjuvant phase II GIADA trial (NCT04659551, EUDRACT 2016-004665-10) enrolled stage II-IIIA premenopausal patients with Luminal B (LumB)-like BC (HR-positive/HER2-negative, Ki67 greater than or equal to 20% and/or histologic Grade 3). Patients received: three 21-days cycles of epirubicin/cyclophosphamide followed by eight 14-days cycles of nivolumab, triptorelin started concomitantly to chemotherapy, and exemestane started concomitantly to nivolumab. Primary endpoint was pathological complete response (pCR; ypT0/is, ypN0).\n\n\nRESULTS\nA pCR was achieved by 7/43 patients (16.3%; 95%CI 7.4-34.9), the rate of Residual Cancer Burden class 0-I was 25.6%. pCR rate was significantly higher for patients with PAM50 Basal BC (4/8, 50%) as compared to other subtypes (LumA 9.1%; LumB 8.3%; p=0.017). Tumor infiltrating lymphocytes (TILs), immune-related gene expression signatures, and specific immune cells subpopulations by multiplex immunofluorescence were significantly associated with pCR. A combined score of Basal subtype and TILs had an AUC of 0.95 (95%CI 0.89-1.00) for pCR prediction. According to multiplex immunofluorescence, a switch to a more immune activated tumor microenvironment occurred following exposure to anthracyclines. Most common Grade greater than or equal to 3 treatment-related adverse events (AEs) during nivolumab were: γ-glutamyltransferase (16.7%), alanine aminotransferase (16.7%), and aspartate aminotransferase (9.5%) increase. Most common immune-related AEs were endocrinopathies (all Grade 1-2; including adrenal insufficiency, n=1).\n\n\nCONCLUSIONS\nLuminal B-like BCs with a Basal molecular subtype and/or a state of immune activation may respond to sequential anthracyclines and anti-PD-1. Our data generate hypotheses that, if validated, could guide immunotherapy development in this context.