The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer but the optimal duration of therapy is currently unknown. In the GeparNuevo trial, the addition of durvalumab to NACT significantly improved survival despite a modest pathological complete response (pCR) increase. Interestingly, this improvement occurred in both pCR and non-pCR patients and without adjuvant durvalumab therapy.
Treatment with anti-programmed cell death protein 1 (anti- PD-1) or anti-programmed death-ligand 1 (anti-PD-L1) antibodies improved outcomes in PD-L1-positive metastatic triple-negative breast cancer (mTNBC), and has become an integral part of first-line treatment in mTNBC. Checkpoint inhibitor (CPI) therapy has entered clinical practice as a promising new neoadjuvant therapeutic approach in early TNBC (eTNBC), in particular in combination with classical chemotherapy. It was shown that adding either pembrolizumab or atezolizumab to an anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) with or without carboplatin leads to an increase in pathological complete response (pCR) rates. This pCR improvement in the neoadjuvant setting is independent of the PD-L1 status. Considering the long-term side effects of CPI immunotherapy, it is important to focus this therapy on those patients who have the highest benefit and try to limit the exposure. In the GeparNuevo trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (p= 0.287). Secondary survival endpoints of the trial are now available.
GeparNuevo is a multicentre, prospective, randomised, double-blind, placebo-controlled phase II trial investigating the efficacy of NACT, including nab-paclitaxel, followed by dose-dense epirubicin/cyclophosphamide with durvalumab vs. placebo in patients with primary non-metastatic TNBC. Women with untreated uni- or bilateral primary, non-metastatic invasive TNBC were enrolled. Participants were randomised 1:1 to durvalumab 1.5 g or placebo every four weeks. Both arms received nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every four weeks plus epirubicin/cyclophosphamide every two weeks, followed by surgery. Durvalumab was only given as part of the neoadjuvant treatment. After surgery, patients received postsurgical local and systemic treatment. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS).
Between June 2016 and October 2017, 174 patients were randomised to durvalumab (N= 88) or placebo (N= 86). After a median follow-up of 43.7 months and despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS. Three-year iDFS was significantly longer with the addition of durvalumab (85.6% vs. 77.2% with durvalumab and placebo, respectively; HR[95%CI]: 0.48[0.24-0.97]; p= 0.036). Three-year DDFS was 91.7% vs. 78.4% (HR[95%CI]: 0.31[0.13-0.74]; p= 0.005], and three-year OS was 95.2% vs. 83.5% (HR[95%CI]: 0.24[0.08-0.72], p= 0.006). A total of 34 events had occurred, 12 in the durvalumab arm and 22 in the placebo arm. Distant relapses were observed in nineteen patients (6 vs. 13), nine locoregional events (4 vs. 5), three secondary malignancies (0 vs. 3), two contralateral breast cancers (2 vs. 0) and one patient died without an event in the placebo arm. Patients with and without pCR showed improved iDFS, DDFS and OS with durvalumab compared with placebo. pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR[95%CI]: 0.22[0.05-1.06]). In the non-pCR cohort 3-year iDFS was 76.3% vs. 69.7% (HR[95%CI]: 0.67[0.29-1.54]). Survival in patients with pCR was improved by about 70% compared with patients without pCR (HR[95%CI]: 0.27[0.09-0.81]; p= 0.012). In the durvalumab pCR group, no patient experienced a distant relapse or died so far. Multivariate regression analyses for iDFS, DDFS and OS confirmed a long-term treatment effect of durvalumab, which is independent of pCR. An exploratory analysis in the non-pCR group was performed to determine whether differences in tumour size at surgery and/or nodal involvement between the arms would indicate a systematic down-staging during the neoadjuvant CPI therapy. There was no significant difference in the rate of small residual tumours in the durvalumab vs. placebo arm in the non-pCR group (82.5% vs. 78.8%, p= 0.94). The present analysis focused on late adverse events, primarily serious AEs and second cancers. None of those were reported after end of neoadjuvant treatment.
The addition of durvalumab to NACT significantly improved survival despite a modest pCR effect. This iDFS, DDFS and OS improvement occurred in both pCR and non-pCR patients and without adjuvant CPI therapy. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC. In light of these results, the value of additional adjuvant CPI therapy needs to be further assessed given the potential long-lasting side effects and financial burden of CPIs.