Atezolizumab Plus nab-Paclitaxel in the Treatment of Metastatic Triple-Negative Breast Cancer With 2-Year Survival Follow-up: A Phase 1b Clinical Trial

Abstract

Importance: The humanized monoclonal antibody atezolizumab targets programmed death-ligand 1 and has demonstrated durable single-agent activity in a subset of metastatic triple-negative breast cancers. To extend the observed activity, combinatorial approaches are being tested with standard cytotoxic chemotherapies known to induce immunogenic tumor cell death.

Objective: To examine the safety, tolerability, and preliminary clinical activity of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancers.

Design, setting, and participants: This phase 1b multicohort study enrolled 33 women with stage IV or locally recurrent triple-negative breast cancers and 0 to 2 lines of prior chemotherapy in the metastatic setting from December 8, 2014, to April 30, 2017, at 11 sites in the United States. The median follow-up was 24.4 months (95% CI, 22.1-28.8 months).

Interventions: Patients received concurrent intravenous atezolizumab and intravenous nab-paclitaxel (minimum 4 cycles).

Main outcomes and measures: The primary end point was safety and tolerability. Secondary end points included best overall response rate by Response Evaluation Criteria in Solid Tumors, version 1.1; objective response rate; duration of response; disease control rate; progression-free survival; overall survival; and biomarker analyses.

Results: The 33 women had a median age of 55 years (range, 32-84 years) and received 1 or more doses of atezolizumab. All patients (100%) experienced at least 1 treatment-related adverse event, 24 patients (73%) experienced grade 3/4 adverse events, and 7 patients (21%) had grade 3/4 adverse events of special interest. No deaths were related to study treatment. The objective response rate was 39.4% (95% CI, 22.9%-57.9%), and the median duration of response was 9.1 months (95% CI, 2.0-20.9 months). The disease control rate was 51.5% (95% CI, 33.5%-69.2%). Median progression-free survival and overall survival were 5.5 months (95% CI, 5.1-7.7 months) and 14.7 months (95% CI, 10.1-not estimable), respectively. Concurrent nab-paclitaxel neither significantly changed biomarkers of the tumor immune microenvironment (programmed death-ligand 1, tumor-infiltrating lymphocytes, CD8) nor impaired atezolizumab systemic immune activation (expansion of proliferating CD8+ T cells, increase of CXCL10 chemokine).

Conclusions and relevance: In this phase 1b trial for metastatic triple-negative breast cancers, the combination of atezolizumab plus nab-paclitaxel had a manageable safety profile. Antitumor responses were observed, including in patients previously treated with a taxane.

Trial registration: ClinicalTrials.gov identifier: NCT01633970.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Adams has received research funding from Amgen, Genentech, and Merck. Dr Diamond has received research funding from Bayer, Bristol-Myers Squibb, CASI Pharmaceuticals, Genentech/Roche, MedImmune, Millennium, OncoMed, Rexahn Pharmaceuticals, Scripps Hospital, and Taiho Pharmaceutical, as well as travel- or accommodations-related expenses from Takeda. Dr Hamilton has a consulting or advisory role with Cascadian Therapeutics, Flatiron Health, Genentech/Roche, Lilly, and Pfizer, and has received research funding from Abbvie, Acerta Pharma, AstraZeneca, BerGenBio, Boehringer Ingelheim, Cascadian Therapeutics, Curis, eFFECTOR Therapeutics, Eisai, Fujifilm, Genentech/Roche, H3 Biomedicine, Hutchison MediPharma, Immunomedics, Kadmon, Lilly, Lycera, Macrogenics, Mallinckrodt, MedImmune, Medivation, Mersana, Merus, Millennium, Novartis, Nucana OncoMed, Pfizer, PharmaMar, Radius Health, Rgenix, Stem CentRx, Syndax, Takeda, TapImmune Inc., Tesaro, TetraLogic Pharmaceuticals, Verastem, and Zymeworks. Dr Pohlmann reports a leadership interest with Immunonet BioSciences; reports stock or other ownership interests with Immunonet BioSciences; has a consulting or advisory role with Heron, Immunonet BioSciences, OncoPlex Diagnostics, Personalized Cancer Therapy, and Pfizer; has received research funding from Advanced Cancer Therapeutics, Caris Centers of Excellence, Cascadian Therapeutics, Fabre-Kramer, Genentech/Roche, Pfizer, and Pieris Pharmaceuticals; and declares a patent (immunological compositions as cancer biomarkers and/or therapeutics; US Patent and Trademark Office No. US 20120201820; invention title: Immunological Compositions as Cancer Therapeutics). Dr Tolaney has received research funding from Genentech; personal fees for research funding/consulting from Lilly, Novartis, AstraZenca, Merck, Pfizer, Nektar, and Eisai; a grant from Exelixis; and personal fees for consulting from Nanostring. Drs Chang, Zhang, Iizuka, Foster, Molinero, and Funke are employees of Roche/Genentech. Dr Powderly reports employment and a leadership role with BioCytics and Carolina BioOncology Institute; stock or other ownership interests with BioCytics, Bluebird Bio, Carolina BioOncology Institute, Juno Therapeutics, Kite Pharma, Lion Biotechnologies, and Ziopharm Oncology; a consulting or advisory role with AstraZeneca/MedImmune, Bristol-Myers Squibb, Curis, Genentech/Roche, and TopAlliance BioSciences Inc; a speakers’ bureau role with Bristol-Myers Squibb, Dendreon, Genentech/Roche, and Merck; research funding from Abbvie, AstraZeneca/MedImmune, Bristol-Myers Squibb, Corvus Pharmaceuticals, Curis, EMD Serono, Genentech/Roche, Incyte, Lilly/ImClone, Macrogenics, Seattle Genetics, and Top Alliance BioScience; and intellectual property for cellular immunotherapy being developed with BioCytics.

Figures

Figure 1.. Study Flowchart

The study flowchart shows enrolled and treated patients in the metastatic triple-negative breast cancer cohort of this phase 1b study. The number of patients screened for eligibility for this cohort of patients is not available. Treatment and study discontinuations and reasons are depicted. No patients were lost to follow-up. The safety and biomarker expansion cohorts are also shown with a breakdown of evaluable samples for each biomarker (programmed death-ligand 1 [PD-L1], CD8, and tumor-infiltrating lymphocytes [TILs]) and matched pretreatment and posttreatment samples available.

Figure 2.. Clinical Activity of Atezolizumab Plus nab-Paclitaxel

A, Plot of tumor regression from baseline as measured by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in all evaluable patients (n = 32). Each bar represents an evaluable patient. B, Changes in tumor burden over time (n = 32). C, Kaplan-Meier estimate of RECIST progression-free survival (PFS) in the overall study population (N = 33). D, Kaplan-Meier estimate of overall survival (OS) in the overall study population (N = 33).