Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC).

Abstract

506 Background: The GeparNuevo trial investigated the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor (CPI), to standard neoadjuvant chemotherapy (NACT) in patients with early TNBC. Durvalumab increased the pathological complete response (pCR) rate particularly in patients treated with durvalumab alone before start of chemotherapy (Loibl et al. Ann Oncol 2019). Methods: GeparNuevo randomized patients with cT1b-cT4a-d tumors and centrally confirmed TNBC to durvalumab (D) 1.5 g i.v. or placebo every 4 weeks. D/placebo monotherapy (0.75 g i.v.) was given for the first 2 weeks (window phase), followed by D/placebo plus nab-paclitaxel 125 mg/m² weekly for 12 weeks, followed by D/placebo plus epirubicin/cyclophosphamide (EC) q2 weeks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocytes (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). The primary objective was pCR (ypT0 ypN0). Secondary time-to-event endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Results: A total of 174 patients were enrolled between June 2016 and September 2017. The pCR rate with durvalumab was 53.4% versus placebo 44.2% (OR 1.45, 95% CI 0.80–2.63, unadjusted Wald p = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR 2.22, 95% CI 1.06–4.64, p = 0.035; interaction p = 0.048). After a median follow-up of 42.2 months, 34 events occurred in 174 patients. 3-year iDFS in pCR vs non pCR was 92.0% vs 71.9% (log-rank p = 0.002). 3-year iDFS was 84.9% with durvalumab vs 76.9% with placebo (HR 0.54, 95%CI 0.27-1.09, stratified log-rank p = 0.0559); 3-year DDFS 91.4% vs 79.5% (HR 0.37, 95%CI 0.15-0.87, p = 0.0148); 3-year OS 95.1% vs 83.1% (HR 0.26, 95%CI 0.09-0.79, p = 0.0076). No difference was seen in iDFS, DDFS and OS between the window and no window cohort. Conclusions: Durvalumab added to neoadjuvant chemotherapy in TNBC significantly improved long-term outcome despite a small pCR increase and no continuation after surgery. It needs to be questioned whether adjuvant therapy with CPI is needed at all. Clinical trial information: NCT02685059.

Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer

“…In the recently reported KEYNOTE-522 study (NCT03036488) 5 , pembrolizumab, a PD-1 inhibitor, was found to significantly but moderately increase the rates of pathological complete response (pCR) and significantly improve event-free survival (EFS) when added to a neoadjuvant regimen of anthracycline, taxanes and carboplatin in patients with stage II and III TNBC. Similar magnitude of EFS improvements have been reported in smaller studies 6 , 7 . PD-L1 protein is known to be highly expressed on the breast cancer TIL and correlations between both markers have been observed 8 .…”

Untangling Triple-Negative Breast Cancer Molecular Peculiarity and Chemo-Resistance: Trailing Towards Marker-Based Targeted Therapies

“…Finally, durvalumab (Imfinzi) combined with neoadjuvant anthracycline and taxane-based chemotherapy substantially improved survival rates in patients with early TNBC, according to GeparNUEVO phase II trial, as announced in the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting. The findings of the trial showed that patients in the durvalumab arm obtained a complete response of 53.4% compared to 44.2% of patients in the placebo arm [36].…”

Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

“…In comparison to tumors such as melanoma and lung, immunotherapy in breast cancer has only shown a modest benefit in certain subsets of patients. Initial studies with ICI monotherapy in advanced triple negative breast cancer (TNBC) showed disappointing results [ 1 , 2 , 3 ], necessitating combination therapy with other neoplastic agents [ 4 , 5 ]. Currently, the FDA has approved pembrolizumab in two indications for the treatment of breast cancer based on results of phase III clinical trials combining it with standard of care chemotherapy in a subset of patients with TNBC [ 4 , 6 ].…”