Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer

Abstract

The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I–III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30–57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain–Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38–0.71) and 32% (95% CI: 0.12–0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.

Immune Checkpoint Inhibition for Triple-Negative Breast Cancer: Current Landscape and Future Perspectives

“…Among PDL1 positive patients, the pCR rate was 59% and among PDL1 negative patients, the pCR rate was 32%. No significant difference was observed ( P = 0.26) ( 35 ).…”

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study

“…Consequently, these patients may be eligible for additional immune checkpoint blockade in the neoadjuvant setting. Foldi et al recently reported promising results in a phase I/II trial, wherein PD-L1-positive TNBC were associated with higher pCR rates than PD-L1-negative TNBC, independent of the pre-NAC sTILs levels [ 49 ]. The GeparNuevo trial suggested similar results, as the addition of durvalumab before the start of anthracycline/taxane-based NAC seemed to increase pCR rates in TNBC patients [ 50 ].…”

“…The GeparNuevo trial suggested similar results, as the addition of durvalumab before the start of anthracycline/taxane-based NAC seemed to increase pCR rates in TNBC patients [ 50 ]. The International Immuno-Oncology Biomarker Working Group developed a risk management framework for the implementation of combined PD-L1 and TILs assessment in breast cancer [ 44 ], as several studies reported a strong correlation between PD-L1 positive immune cells and high sTILs levels [ 49 , 51 – 54 ]. Biologically, TNBCs require infiltration by sTILs to be designated as PD-L1 positive.…”

Application of Microfluidic Systems for Breast Cancer Research

“…Modern drug and biological anticancer falls into six categories: cytostatic drugs, small-molecule inhibitors, monoclonal antibodies (MAbs), chimeric antigen-specific receptor-transfected T cells (CAR-Ts), virotherapy, and vaccine therapy (Figure 7) [17]. Cytostatic drugs, such as cyclophosphamide, doxorubicin, and paclitaxel, are the most common chemotherapy drugs in breast cancer, and are often used in combinations [216,217]. A focal theme in cytostatic drugs is the CDK4/6 cell-cycle checkpoint proteins, which are inhibited by ribociclib, palbociclib, and abemaciclib [218][219][220].…”