The addition of atezolizumab to adjuvant chemotherapy in early triple-negative breast cancer is unlikely to enhance treatment efficacy

The phase 3 Alexandra/IMpassion030 study investigated the value of adding atezolizumab to adjuvant chemotherapy in patients with early-stage triple-negative breast cancer (TNBC). Unfortunately, at the interim analysis, the hazard ratio (HR) for invasive disease-free survival (iDFS), the primary endpoint, exceeded the pre-specified futility boundary (HR>1). Although these findings do not support the combination of atezolizumab with adjuvant chemotherapy for these patients, this trial does improve our understanding of the optimal use of immunotherapy in patients with early TNBC.

 Triple-negative breast cancer (TNBC) is an aggressive and immunogenic BC subtype. Health authorities previously granted approval for the anti-PD-L1 inhibitor atezolizumab in combination with nab-paclitaxel for PD-L1-positive, metastatic TNBC. Importantly, pivotal studies have demonstrated improved outcomes with adjuvant immunotherapy in various solid tumours. When Alexandra/IMpassion030 was designed, the optimal timing of PD-(L)1 inhibitor administration in combination with chemotherapy in early TNBC was unknown. To address this gap, this study investigated the value of adding atezolizumab to standard anthracycline- and taxane-based adjuvant chemotherapy in TNBC.

Methods:

The phase 3 ALEXANDRA/IMpassion030 study enrolled patients who had completed surgery for stage II or III TNBC. In total, 2,199 patients were randomly assigned (1:1) to receive adjuvant chemotherapy with (n=1,101) or without atezolizumab (n=1,098). Adjuvant chemotherapy consisted of weekly paclitaxel for 12 cycles followed by dose-dense anthracycline-based chemotherapy for four cycles. Adjuvant atezolizumab was started at the beginning of adjuvant therapy and continued for a total of one year. The primary endpoint was invasive disease-free survival (iDFS) in the intention-to-treat population (ITT), while secondary objectives included iDFS in the PD-L1 positive and lymph node-positive subpopulations, iDFS including second primary non-breast invasive cancer, overall survival (OS), relapse-free interval (RFI), distant relapse-free interval (DRFI) and disease-free survival (DFS).

Results

After 25 months of follow-up, the HR for iDFS in the ITT population (primary endpoint) crossed the pre-specified futility boundary (HR>1), with a HR of 1.12 (0.87–1.45; p= 0.37). iDFS events were observed in 11.5% vs. 10.2% of patients in the atezo-chemo and chemo arms, respectively. In the PD-L1+ subgroup (71% of the trial population), the iDFS HR was 1.03 (0.75-1.42), with iDFS events observed in 9.8% vs. 9.3% of patients in the atezo-chemo and chemo arms, respectively. The results of the subgroup analyses, including PD-L1 status, tumour stage, nodal status, disease stage, age and ECOG performance status, were in line with the main results. OS results were not mature, with 5% OS events. At this stage, no differences between the arms were observed in OS (HR:1.20[0.82-1.75]).

Treatment-related adverse events (TRAEs) of all grades (99.7% vs. 98.3% in the atezo-chemo and chemo arms, respectively), grade 3-4 (53.7% vs. 43.5%) and treatment-related serious AEs (TRSAEs, 18.1% vs. 9.9%) were numerically higher in the atezo arm. There were three treatment-related deaths, including two in the atezo-chemo arm and one in the chemo-alone arm. The addition of atezolizumab did not compromise the administration of adjuvant chemotherapy. Treatment-emergent AEs (TEAEs) present in at least 20% of patients, such as fatigue, diarrhoea, rash, and liver enzyme changes, were numerically higher in the atezo arm. Rash, hepatitis and hypothyroidism were the most common immune-mediated AEs, but were mainly low grade.

Conclusions

At the requested interim analysis of the phase 3 ALEXANDRA/IMpassion030 trial, the  HR for iDFS in the ITT population (primary endpoint) crossed the pre-specified futility boundary (HR >1). Alongside findings from secondary efficacy endpoints, these results do not support the addition of atezolizumab to adjuvant chemotherapy in patients who underwent primary surgery for early TNBC. Although AEs were more frequent in the atezo arm, they were consistent with the known atezolizumab safety profile. Importantly, the addition of atezolizumab did not compromise the delivery of the standard-of-care chemotherapy backbone. Despite the negative outcome, the ALEXANDRA/IMpassion030 trial contributes to an improved understanding of the optimal use of immunotherapy in patients with early TNBC.

Reference

Ignatiadis M, Bailey A, McArthur H, et al. Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial. Presented at SABCS 2023; Abstract GS01-03.