Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial

Summary

Background

Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.

Methods

In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice–web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m² of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.

Findings

Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6–22·8) in the atezolizumab group and 17·5 months (8·4–22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0–22·6) with atezolizumab and 18·7 months (16·9–20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72–1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6–30·7) with atezolizumab versus 18·0 months (13·6–20·1) with placebo (stratified HR 0·71, 0·54–0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3–4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).

Interpretation

Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.

Funding

F Hoffmann-La Roche and Genentech.

Introduction

Triple-negative breast cancer constitutes 15–20% of cases of breast cancer and is defined by the absence of oestrogen receptors, progesterone receptors, and overexpression or gene amplification of HER2 on the surface of cancer cells.¹ Until the first report of the IMpassion130 trial,² chemotherapy was the standard of care for first-line systemic treatment for patients with triple-negative breast cancer that has advanced or metastasised.3, 4, 5 In several countries, such as Japan, and in Europe, other approved treatment options are bevacizumab in combination with chemotherapy and poly (ADP-ribose) polymerase inhibitors (eg, olaparib and talazoparib) for patients with BRCA-mutant, HER2-negative tumours.6, 7, 8 Prognoses remain poor, with reported median overall survival estimates of approximately 18 months or less with available treatments. Because of the promising efficacy of checkpoint inhibition in other tumour types,9, 10, 11, 12, 13 inhibitors of PD-L1 and PD-1 as monotherapy or in combination with chemotherapy have been investigated in triple-negative breast cancer.14, 15, 16 The higher prevalence of PD-L1 expression in triple-negative breast cancer compared with hormone receptor-positive breast cancer subtypes further supports this therapeutic approach.17, 18, 19, 20, 21

The phase 3 study, IMpassion130,² evaluated atezolizumab, a monoclonal antibody targeting PD-L1, plus nab-paclitaxel compared with placebo plus nab-paclitaxel as a first-line treatment for patients with unresectable locally advanced or metastatic triple-negative breast cancer. At the time of primary analysis of IMpassion130, the final progression-free survival analysis and the first interim overall survival analysis were done (clinical data cutoff April 17, 2018). The study met its coprimary progression-free survival endpoints, showing clinical benefit with atezolizumab plus nab-paclitaxel when compared with placebo plus nab-paclitaxel in both the intention-to-treat population and the subgroup of patients with tumours that express PD-L1 on immune cells that cover 1% or more of the tumour area (PD-L1 immune cell-positive patients).² The treatment effect in the PD-L1 immune cell-positive patient subgroup was a clinically meaningful benefit: the median progression-free survival was 7·5 months (95% CI 6·7–9·2) with atezolizumab plus nab-paclitaxel versus 5·0 months (3·8–5·6) with placebo plus nab-paclitaxel (hazard ratio [HR] 0·62, 95% CI 0·49–0·78], p<0·0001).² Based on these final progression-free survival results, the US Food and Drug Administration granted accelerated approval on March 8, 2019, to atezolizumab plus nab-paclitaxel as a first-line treatment for patients with unresectable locally advanced or metastatic triple-negative breast cancer with tumours that express PD-L1 on immune cells that cover 1% or more of the tumour area (PD-L1 immune-cell positive).²² The European Commission has also approved atezolizumab plus nab-paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer with tumours that are PD-L1 positive (≥1% PD-L1 expression) and who have not received previous chemotherapy for metastatic disease.²³

Research in context

Evidence before this study

We searched PubMed for clinical trials published between June 30, 2009, and July 30, 2019, in any language using the search terms “PD-L1” or “PD-1” or “immunotherapy” or “immune checkpoint” in combination with “TNBC” or “triple-negative breast cancer”. We identified a feasibility study of a personalised peptide vaccine and a phase 1–2 study planning to enrol patients with triple-negative breast cancer to evaluate an RNA vaccine. Several studies reported increased expression of PD-L1 and PD-1 in triple-negative breast cancer, suggesting that inhibition of the PD-L1–PD-1 immune checkpoint could result in clinical benefit in this disease. Promising responses and duration of response in phase 1 studies evaluating single-drug atezolizumab, pembrolizumab, or avelumab had been reported. A tolerable safety profile and increased proportions of patients achieving a response compared with single-drug approaches had been reported for the combination of atezolizumab plus nab-paclitaxel in a phase 1b study.

Added value of this study

To our knowledge, IMpassion130 is the first reported phase 3 study that evaluated an antibody targeting the PD-L1–PD-1 immune checkpoint in patients with unresectable locally advanced or metastatic triple-negative breast cancer. The study met its coprimary progression-free survival endpoint in the primary analysis, showing a significant progression-free survival benefit with atezolizumab plus nab-paclitaxel compared with placebo plus nab-paclitaxel as a first-line treatment for patients with advanced or metastatic triple-negative breast cancer. Because no treatment effect was seen in the PD-L1 immune cell-negative subgroup, the clinical benefit in the intention-to-treat population was driven by the positive results in the PD-L1 immune cell-positive subgroup of patients. The first interim overall survival analysis (concurrent with the primary progression-free survival analysis) showed no significant difference in overall survival between the treatment groups in the intention-to-treat population but a clinically meaningful improvement in median overall survival in patients with PD-L1 immune cell-positive disease. This preplanned second interim overall survival analysis, which was done after 534 (59%) of 902 deaths had occurred in the intention-to-treat population (80% information fraction) also showed no significant difference in overall survival between the groups in the intention-to-treat population. Although the overall survival results provide evidence for the clinical benefit in patients with PD-L1 immune cell-positive disease, consistent with the primary analysis, this result could not be formally tested due to the prespecified statistical testing hierarchy and thus these findings can only be regarded as exploratory. The reported safety update supports an unchanged safety profile with atezolizumab plus nab-paclitaxel relative to the first interim analysis.

Implications of all the available evidence

The randomised controlled phase 3 IMpassion130 study did not suggest a significant overall survival benefit from the addition of atezolizumab to nab-paclitaxel in the intention-to-treat population of patients with unresectable, locally advanced or metastatic triple-negative breast cancer. However, providing evidence to support promising clinical activity observed in phase 1 studies evaluating drugs targeting PD-L1–PD-1 signalling, the study results did indicate clinically meaningful improvement in median progression-free and overall survival of atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive unresectable locally advanced or metastatic triple-negative breast cancer. The findings of this second interim overall survival analysis, reported here, provide evidence that the clinical benefit is consistent and maintained with extended follow-up. Approvals by US and European Union regulatory agencies, and the inclusion of this regimen in US National Comprehensive Cancer Network treatment guidelines, highlight that atezolizumab plus nab-paclitaxel could be a new standard of care for previously untreated patients with PD-L1 immune cell-positive, unresectable, locally advanced or metastatic triple-negative breast cancer.

As previously reported,² the first interim overall survival analysis and concurrent final progression-free survival analysis were done after 43% of deaths in the intention-to-treat population had occurred, with a median follow-up of 12·9 months (IQR 8·8–16·5) and 59% information fraction, which is the percentage of the total information expected at the scheduled end of the trial. With an HR for overall survival of 0·84 (95% CI 0·69–1·02, p=0·08) in the intention-to-treat population, the first interim overall survival analysis did not cross the prespecified significance boundary (α=0·0065). A Kaplan-Meier analysis of overall survival in the PD-L1 immune cell-positive subgroup that was not formally tested because of the prespecified statistical testing hierarchy (since significance in the intention-to-treat population was required to enable subsequent testing in the PD-L1 immune cell-positive subgroup) showed a median overall survival of 25·0 months (95% CI 22·6–not estimable) with atezolizumab plus nab-paclitaxel versus 15·5 months (13·1–19·4) with placebo plus nab-paclitaxel (HR 0·62, 95% CI 0·45–0·86).²

In this paper, we report the prespecified second interim overall survival analysis from the IMpassion130 study.