Research in context
Evidence before this study
We searched PubMed from July 1, 2012, to July 1, 2017, for clinical trials and reviews using the search terms “programmed cell death 1” or “programmed cell death ligand 1” or “PD-L1” or “PD-1” or “immunotherapy” or “immune checkpoint” in combination with “TNBC” or “triple-negative breast cancer” or “triple-negative breast carcinoma” and “early.” No further exclusion criteria were used, and the search was not limited to English language publications. We identified an unmet clinical need in early-stage TNBC. At study start, approved therapies for systemic management of early TNBC included cytotoxic chemotherapy with an alkylating agent, anthracycline, and taxane. Addition of platinum drugs to paclitaxel was known to increase pathological complete response rate, although with increased haematological toxicities and uncertain long-term benefit. Adjuvant capecitabine might have been considered in cases of residual disease. Additionally, tumour-infiltrating lymphocytes were known to be favourable prognostic factors in patients with early breast cancer and were correlated with pathological complete response. Higher tumour-infiltrating lymphocyte counts were also known to be correlated with PD-1 and PD-L1 expression levels, which were highest in triple-negative tumours among breast carcinomas. Furthermore, early-phase trials of immune checkpoint blockade monotherapy in early TNBC showed promising results, thus warranting further research on the potential of combination treatment with chemotherapy to maximise therapeutic benefits and achieve a curative treatment, especially in the early disease setting. These findings provide a compelling rationale to test whether inhibition of PD-L1 combined with neoadjuvant treatment with nab-paclitaxel, anthracycline, and cyclophosphamide will result in improved outcomes for patients with early-stage TNBC.
Added value of this study
The IMpassion031 study results contribute to the growing body of evidence on the use of cancer immunotherapy in combination with chemotherapy as neoadjuvant treatment for early-stage TNBC, as shown in clinical studies such as I-SPY 2, GeparNuevo, KEYNOTE-522, and NeoTRIPaPDL1. IMpassion031 showed efficacy of atezolizumab in combination with neoadjuvant nab-paclitaxel followed by doxorubicin plus cyclophosphamide for patients with stage II or III TNBC. This regimen led to a statistically significant and clinically meaningful improvement in the rate of pathological complete response compared with placebo and chemotherapy, regardless of PD-L1 status, with a tolerable safety profile consistent with the known risks of the individual study drugs. Atezolizumab did not compromise the ability to receive chemotherapy. Commonly reported adverse events were similar between groups and were mostly driven by chemotherapy. Results support the clinical activity of checkpoint inhibitor-based combinations as neoadjuvant treatment of early-stage TNBC.
Implications of all the available evidence
The IMpassion031 results showed that addition of atezolizumab to neoadjuvant chemotherapy with nab-paclitaxel followed by doxorubicin plus cyclophosphamide provides clinical benefit in the potentially curable setting of early-stage TNBC. Patients derived pathological complete response benefit regardless of PD-L1 status.