In a phase 2b trial, patients with metastatic triple-negative breast cancer were treated with chemotherapy (PEGylated liposomal doxorubicin plus low-dose cyclophosphamide) alongside atezolizumab (anti-PD-L1) or placebo. The combination extended progression-free survival (4.3mo) over chemotherapy alone (3.5mo), even in patients with PD-L1- tumors, several of whom experienced long-term responses. Treatment was tolerable and reduced blood lymphocyte numbers, especially Tregs. Treatment response was associated with low baseline Treg proportions and high scores of tumor inflammation.
Contributed by Alex Najibi
ABSTRACT: Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial ( NCT03164993 , 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33-0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33-0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95% CI 0.27-1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95% CI 0.27-1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4-30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.
Author Info: (1) Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo,
Author Info: (1) Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. (2) Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. (3) Department of Oncology, Rigshospitalet, Copenhagen, Denmark. (4) Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway. (5) Department of Oncology, Sygehuset Lilleb¾lt, Vejle, Denmark. (6) Department of Oncology, St. Olav University Hospital, Trondheim, Norway. (7) Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway. (8) Department of Pathology, Oslo University Hospital, Oslo, Norway. (9) Department of Radiology and Nuclear medicine, Oslo University Hospital, Oslo, Norway. (10) Department of Oncology, Oslo University Hospital, Oslo, Norway. (11) Department of Pathology, Oslo University Hospital, Oslo, Norway. (12) Department of Pathology, Oslo University Hospital, Oslo, Norway. (13) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. (14) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. (15) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. (16) Department of Oncology, Oslo University Hospital, Oslo, Norway. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (17) Department of Clinical Cancer Research, Oslo University Hospital, Oslo, Norway. jonky@ous-hf.no. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. jonky@ous-hf.no.
