Articles 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 Peter Schmid*, Hope S Rugo*, Sylvia Adams, Andreas Schneeweiss, Carlos H Barrios, Hiroji Iwata, Véronique Diéras, Volkmar Henschel, Luciana Molinero, Stephen Y Chui, Vidya Maiya, Amreen Husain, Eric P Winer, Sherene Loi, Leisha A Emens, for the IMpassion130 Investigators† Summary Lancet Oncol 2020; 21: 44–59 Background Immunotherapy in combination with chemotherapy has shown promising efficacy across many different Published Online tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study November 27, 2019 assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or https://doi.org/10.1016/ metastatic triple-negative breast cancer. S1470-2045(19)30689-8 See Comment page 3 Methods In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and *Contributed equally community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically †Investigators are listed in the documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group appendix performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method Barts Cancer Institute, Queen Mary University of London, (block size of four) and an interactive voice–web response system. Randomisation was stratified by previous taxane London, UK (Prof P Schmid MD); use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab University of California 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m² of San Francisco Comprehensive body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, Cancer Center, University of California, San Francisco, CA, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression- USA (Prof H S Rugo MD); free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the Perlmutter Cancer Center, intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 New York University Langone expression). The final progression-free survival results were previously reported at the first interim overall survival Medical Center, New York, NY, USA (Prof S Adams MD); analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune National Center for Tumor cell-positive patients could only be formally tested if overall survival was significantly different between the treatment Diseases, Heidelberg University groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891. Hospital and German Cancer Research Center, Heidelberg, Germany Findings Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned (Prof A Schneeweiss MD); to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention- Centro de Pesquisa Clínica, to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data Hospital São Lucas, Pontifícia cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6–22·8) in the atezolizumab group and 17·5 months Universidade Católica do Rio Grande do Sul, Porto (8·4–22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI Alegre, Brazil (C H Barrios MD); 19·0–22·6) with atezolizumab and 18·7 months (16·9–20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI Latin American Cooperative 0·72–1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, Oncology Group, Porto Alegre, Brazil (C H Barrios); Grupo median overall survival was 25·0 months (95% CI 19·6–30·7) with atezolizumab versus 18·0 months (13·6–20·1) Oncoclínicas, Porto Alegre, with placebo (stratified HR 0·71, 0·54–0·94]). As of Sept 3, 2018 (the date up to which updated safety data were Brazil (C H Barrios); Aichi Cancer available), the most common grade 3–4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab Center Hospital, Nagoya, Japan group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil (Prof H Iwata MD); Department of Medical Oncology, Institut count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in Curie, Paris, France the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel (V Diéras MD); Department of [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been Medical Oncology, Centre reported since the primary clinical data cutoff date (April 17, 2018). Eugène Marquis, Rennes, France (V Diéras); F Hoffmann-La Roche, Basel, Interpretation Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 Switzerland (V Henschel PhD, indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population A Husain MD); Genentech, but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with South San Francisco, CA, USA (L Molinero PhD, S Y Chui MD, PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified V Maiya MD); Dana-Farber statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, Cancer Institute, Boston, MA, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need. USA (Prof E P Winer MD); Peter MacCallum Cancer Funding F Hoffmann-La Roche and Genentech. 44 www.thelancet.com/oncology Vol 21 January 2020 Articles Copyright © 2019 Elsevier Ltd. All rights reserved. Centre, University of Melbourne, Melbourne, VIC, Introduction survival estimates of approximately 18 months or less Australia (Prof S Loi MD); and University of Pittsburgh Triple-negative breast cancer constitutes 15–20% of cases with available treatments. Because of the promising Medical Center Hillman Cancer of breast cancer and is defined by the absence of efficacy of checkpoint inhibition in other tumour types,9–13 Center, Pittsburgh, PA, USA oestrogen receptors, progesterone receptors, and over- inhibitors of PD-L1 and PD-1 as monotherapy or in (Prof L A Emens MD) expression or gene amplification of HER2 on the surface combination with chemotherapy have been investigated Correspondence to: of cancer cells.1 Until the first report of the IMpassion130 in triple-negative breast cancer.14–16 The higher prevalence Prof Peter Schmid, Barts Cancer Institute, 2 trial, chemo therapy was the standard of care for first-line of PD-L1 expression in triple-negative breast cancer Queen Mary University of systemic treatment for patients with triple-negative compared with hormone receptor-positive breast cancer London, London EC1M 6BQ, UK breast cancer that has advanced or metastasised.3–5 In subtypes further supports this therapeutic approach.17–21 [email protected] several countries, such as Japan, and in Europe, other The phase 3 study, IMpassion130,2 evaluated atezoli- See Online for appendix approved treatment options are bevacizumab in zumab, a monoclonal antibody targeting PD-L1, plus nab- combination with chemotherapy and poly (ADP-ribose) paclitaxel compared with placebo plus nab-paclitaxel as a polymerase inhibitors (eg, olaparib and talazoparib) for first-line treatment for patients with unresectable locally patients with BRCA-mutant, HER2-negative tumours.6–8 advanced or metastatic triple-negative breast cancer. At Prognoses remain poor, with reported median overall the time of primary analysis of IMpassion130, the final Research in context Evidence before this study improvement in median overall survival in patients with PD-L1 We searched PubMed for clinical trials published between immune cell-positive disease. This preplanned second interim June 30, 2009, and July 30, 2019, in any language using the overall survival analysis, which was done after 534 (59%) of search terms “PD-L1” or “PD-1” or “immunotherapy” or 902 deaths had occurred in the intention-to-treat population “immune checkpoint” in combination with “TNBC” or “triple- (80% information fraction) also showed no significant negative breast cancer”. We identified a feasibility study of a difference in overall survival between the groups in the personalised peptide vaccine and a phase 1–2 study planning to intention-to-treat population. Although the overall survival enrol patients with triple-negative breast cancer to evaluate an results provide evidence for the clinical benefit in patients with RNA vaccine. Several studies reported increased expression of PD-L1 immune cell-positive disease,