Elsevier

The Lancet

Volume 396, Issue 10257, 10–16 October 2020, Pages 1090-1100
The Lancet

Articles
Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial

https://doi.org/10.1016/S0140-6736(20)31953-XGet rights and content

Summary

Background

Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC.

Methods

This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II–III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ≥1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing.

Findings

Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20·6 months (IQR 8·7–24·9) in the atezolizumab plus chemotherapy group and 19·8 months (8·1–24·5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50–65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34–49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6–27; one-sided p=0·0044 [significance boundary 0·0184]). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57–79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38–61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4–35; one-sided p=0·021 [significance boundary 0·0184]). In the neoadjuvant phase, grade 3–4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group).

Interpretation

In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile.

Funding

F Hoffmann-La Roche/Genentech.

Introduction

Triple-negative breast cancer (TNBC), defined by the absence of immunostaining for oestrogen and progesterone receptors and lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2), has the worst prognosis among the subtypes of breast cancer. Early-stage TNBC, defined as stages I–III, accounts for 10–20% of new diagnoses of early breast cancer.1 Multiagent chemotherapy regimens have shown benefit as preoperative (neoadjuvant) or postoperative (adjuvant) therapy for the treatment of early TNBC in improving both disease-specific and overall survival outcomes, and are recommended for most patients to reduce the risk of relapse.2, 3, 4 Neoadjuvant therapy also provides an opportunity to collect biological and prognostic information during response to guide further treatment. Although adjuvant therapy is still more common globally, the neoadjuvant treatment approach is considered standard practice, and its use is becoming more frequent.5, 6 Among chemotherapy regimens used for early TNBC, sequential use of a taxane and anthracycline plus cyclophosphamide7, 8, 9 is one of the preferred regimens in international guidelines.2, 3 Despite treatment with anthracycline-taxane-based therapy and adjuvant capecitabine in patients with residual disease at surgery, 5-year metastasis-free survival is approximately 70%, and approximately 30–40% of patients develop metastatic disease and die of the cancer.7, 10, 11 Improvements in long-term treatment outcomes for patients with early-stage TNBC are needed. In clinical trials for neoadjuvant therapy in TNBC, patients with pathological complete response have a 76% lower risk of having an event-free survival event compared with patients with residual disease.12 Thus, pathological complete response is an accepted surrogate endpoint for long-term outcomes in clinical trials.

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.

Among chemotherapy options to combine with immunomodulatory therapy such as atezolizumab, nab-paclitaxel is potentially advantageous because of the opportunity to avoid immunosuppressive effects from the concurrent steroid use required with other taxanes, including paclitaxel,8 and the high rate of tumour cell death caused by nab-paclitaxel resulting in the release of tumour antigens.13 These antigens might prime the anticancer T-cell immune response that is enhanced when atezolizumab inhibits programmed cell death ligand 1 (PD-L1)-mediated immune suppression. The sequence of nab-paclitaxel followed by doxorubicin plus cyclophosphamide was chosen in the present study because doxorubicin plus cyclophosphamide has a higher frequency of steroid use, which could again lead to immunosuppressive effects during initial treatment with atezolizumab. Therefore, treatment with nab-paclitaxel first might maximise the potential for a robust initial immune response.14, 15

The first phase 3 demonstration of the benefit of immune checkpoint inhibitor therapy in metastatic TNBC was from the IMpassion130 trial.16 IMpassion130 showed that atezolizumab combined with nab-paclitaxel resulted in statistically significant progression-free survival benefit and clinically significant overall survival benefit in patients with metastatic TNBC and PD-L1-expressing immune cells covering 1% or more of tumour area (defined as PD-L1 positive). Furthermore, the safety profile of atezolizumab combined with nab-paclitaxel was shown to be acceptable. In the present trial, IMpassion031, we evaluated the efficacy and safety of atezolizumab or placebo in combination with neoadjuvant chemotherapy, consisting of sequential nab-paclitaxel followed by doxorubicin-cyclophosphamide, for the treatment of early-stage TNBC.

Section snippets

Study design and patients

In this randomised, multicentre, multinational, double-blind, phase 3 study with a two-stage adaptive enrichment design, we assessed the efficacy and safety of neoadjuvant atezolizumab in combination with nab-paclitaxel followed by doxorubicin plus cyclophosphamide in patients with early-stage TNBC who were treatment naive. Based on the potential for differences in efficacy across PD-L1 subgroups, as seen in the IMpassion130 study in metastatic TNBC,16 IMpassion031 incorporated an adaptive

Results

Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility, of whom 122 (25%) were ineligible: 84 (18%) did not meet eligibility criteria, 22 (5%) withdrew consent, and 16 (4%) were ineligible for other reasons. The remaining 333 patients (205 during study stage 1 and 128 during study stage 2) were randomly assigned to the atezolizumab plus chemotherapy group (n=165) or the placebo plus chemotherapy group (n=168; figure 1).

At the time of clinical cutoff

Discussion

In this randomised, multicentre, multinational, double-blind, phase 3 trial of patients with early-stage TNBC, the addition of atezolizumab to nab-paclitaxel followed by doxorubicin plus cyclophosphamide significantly improved pathological complete response rate regardless of PD-L1 status, with an acceptable safety profile. The pathological complete response benefit of atezolizumab plus chemotherapy was observed across subgroups, regardless of PD-L1 status, stage II versus III disease, or lymph

Data sharing

Qualified researchers can request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (//www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm

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