Atezolizumab plus the chemotherapy nab-paclitaxel has been granted accelerated approval for the first-line treatment of unresectable locally advanced or metastatic, PD-L1-positive triple-negative breast cancer (TNBC) by the United States Food and Drug Administration (FDA).1 The approval was based on the results of the clinical trial IMpassion130 (NCT02425891), which was presented at the European Society for Medical Oncology (ESMO) 2018 congress and subsequently published in The New England Journal of Medicine.2,3
The characteristic feature of TNBC is that it lacks the three most common types of receptors known to fuel the growth of breast cancer-oestrogen, progesterone and the human epidermal growth factor receptor 2 (HER2).4 Therefore, common treatments like hormone therapy and drugs that target oestrogen, progesterone and HER2 are ineffective. The clinical outcome of TNBC patients is poor and the overall median survival varies with 18 months as an approximate.4 Chemotherapy remains the primary systemic treatment at present and guidelines in general support the use of single-agent taxanes or anthracyclines as first-line therapy.4,5 In TNBC, the expression of programmed death ligand-1 (PD-L1) occurs mainly in tumor-infiltrating immune cells rather than in tumor cells inhibiting anti-cancer tumor response.6 Thereby inhibiting the PD-L1 may subsequently reinstate the anti-cancer immune responses.6
Atezolizumab, the new addition to TNBC therapy, is an immune checkpoint inhibitor.7 It targets PD-L1 selectively to prevent interaction with the receptors, programmed death-1 (PD-1) and B7-1 (a costimulatory cell-surface protein), reversing T-cell suppression.7 Furthermore, nab-paclitaxel, the standard-of-care for TNBC, a taxane, enhances tumor-antigen release and antitumor responses to immune checkpoint inhibition.5 Also, taxanes activate the toll-like receptor activity and promote dendritic cell activity.5 Thus, the simultaneous action of atezolizumab and nab-paclitaxel have the potential to expedite the antitumor response towards TNBC.5
The new approval of the combination is based on the safety and efficacy results from IMpassion130, which is an international, randomized, double bind and placebo-controlled trial.2 The trial randomly assigned equal number of patients (n=451) with locally advanced or metastatic TNBC to two groups, atezolizumab and placebo respectively.2 Both groups received the nab-paclitaxel chemotherapy.2 In this intention-to-treat population, atezolizumab plus nab-paclitaxel significantly reduced the risk of disease progression or death (Progression-free survival: PFS) compared with placebo with nab-paclitaxel (HR=0.80; 95% CI: 0.69-0.92; p=0.0025).2
In the subgroup analysis, patients whose tumors expressed PD-L1, median PFS was 7.5 months for patients receiving atezolizumab with nab-paclitaxel and 5 months for those receiving placebo with nab-paclitaxel (HR=0.62; 95% CI: 0.49-0.78; p<0.0001).2 Objective response rate in patients with confirmed responses was 53% compared to 33% of the atezolizumab and the placebo-containing arms.2
Presenting the overall survival results, at ESMO congress 2018, lead study author Peter Schmid, MD, PhD, St. Bartholomew’s Breast Cancer Centre, Barts Health NHS Trust, London, United Kingdom, commented “In the PD-L1 positive (+) subgroup, we see a nearly 10-month overall survival difference with atezolizumab plus nab-paclitaxel, which I think is a key encouragement to see this drug as a new standard”.8
The investigators have further reported that the adverse events were consistent with the known safety profiles of each agent.2 According to the FDA announcement, the most common adverse effects of atezolizumab with nab-paclitaxel were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting and decreased appetite.1 The recommended atezolizumab dose for patients with TNBC whose tumors express PD-L1 is 840 mg administered as an intravenous infusion over 60 minutes, followed by 100mg/m2 nab-paclitaxel. For each 28-day cycle, atezolizumab is administered on days 1 and 15, and nab-paclitaxel is administered on days 1,8, and 15 until disease progression or unacceptable toxicity.1,2
In conclusion, atezolizumab is the first immunotherapy to be approved for PD-L1 positive metastatic TNBC. In combination with nab-paclitaxel, it has prolonged the PFS among patients with TNBC in both the intention-to-treat population and the PD-L1 + subgroup. This could pave the way for a new era in the management of TNBC.
1. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer: US Food and Drug Administration. (Accessed March 14 2019, at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm633065.htm).
2. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108-21.
3. Liobl S, Lucas PC, Nekljudova V. Abstract. A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy with atezolizumab or placebo in patients with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo. B 59, European Society for Medical Oncology (ESMO) 2018 Munich, Germany.
4. den Brok WD, Speers CH, Gondara L, et al. Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed. Breast Cancer Res Treat. 2017;161(3):549-56.
5. Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)dagger. Ann Oncol. 2018;29(8):1634-57.
6. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-7.
7. Tecentriq (atezolizumab): summary of product characteristics. Roche Registration, Welwyn Garden City, United Kingdom; 2018.
8. FDA Approves First Immunotherapy for Breast Cancer, Medscape Medical News. (Accessed March 15 2019, at https://www.medscape.com/viewarticle/910121).