A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

Abstract

This study is a joint study of the German Breast Group (GBG) and the Arbeitsgemeinschaft Gynäkologische Onkologie Breast (AGO-B). Background: Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. Patients and methods: GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the windowphase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). Results: A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage !IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected v 2 P ¼ 0.287), corresponding to OR ¼ 1.45 (95% CI 0.80-2.63, unadjusted Wald P ¼ 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR ¼ 2.22, 95% CI 1.06-4.64, P ¼ 0.035; interaction P ¼ 0.048). In both arms, significantly increased pCR (P < 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P ¼ 0.045) and for PD-L1-immune cell in placebo arm (P ¼ 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.

Development and validation of a stromal immune phenotype classifier for predicting immune activity and prognosis in triple‐negative breast cancer

“…Tumor microenvironment immune activity could affect the efficacy of cytotoxic chemotherapy 11,12 . In the GeparNuevo study, durvalumab (PD‐L1 inhibitor) in addition to anthracycline taxane‐based neoadjuvant chemotherapy in early‐stage TNBC increased the pathologic complete response (pCR) rate by 9% 5 . Interestingly, we analyzed and found a tendency toward a higher pCR rate in Phenotype A (36/83) than in Phenotype B (16/55), with a marginally significant difference in the combined GEO cohort (Figure S8A, 43.37% vs 29.09%, respectively, P = .09).…”

“…Neither endocrine therapy nor routine targeted therapy, such as tamoxifen and trastuzumab, is effective in TNBC. However, immunotherapy has been proven to be a promising candidate for TNBC, and more specific biomarkers and classification methods for predicting the applicability of immunotherapy are urgently needed 3‐6 …”

Role of Immunotherapy in Triple-Negative Breast Cancer

“…33 However, the GeparNuevo trial (NCT02685059), which included earlier-stage T1b and higher disease, demonstrated that the addition of durvalumab to neoadjuvant nab-paclitaxel followed by epirubicin and cyclophosphamide did not significantly improve pCR rates in the overall trial and only improved pCR rates when durvalumab was started 2 weeks before chemotherapy, which was a subgroup analysis underpowered for significance testing. 34 The KEYNOTE-522 trial (NCT03036488) reported that pembrolizumab added to paclitaxel plus carboplatin and then to an anthracycline plus cyclophosphamide as neoadjuvant therapy, followed by surgery plus an additional 9 cycles of adjuvant pembrolizumab, improved pCR rates from 51.2% to 64.8%, and 18-month event-free survival (EFS) rates from 85.3% to 91.3% (hazard ratio [HR], 0.63; 95% CI, 0.43-0.93). 35 These results need to be confirmed with extended follow-up data and weighed against long-term immune-related toxicity.…”

Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation

“…Patients with TNBC were treated with either durvalumab (anti-PD-L1) or placebo, combined with 4 cycles of nab-paclitaxel followed by epirubicin/cyclophosphamide. A higher pathological complete response rate was seen in ICB combination patients, compared with chemotherapy alone (53.4% versus 44.2%) [22]. Despite this trial not having a pre-ICB immune induction arm, it raises the question whether induction with anthracycline chemotherapy before subsequent combination, and/or maintenance during treatment, will be the most effective therapeutic approach.…”