Addition of durvalumab (Dur) upon progression to bevacizumab (Bev) maintenance in advanced HER2-negative (HERNEG) breast cancer (BC): Safety, efficacy and biomarkers

Abstract

Background: As opposed to other malignancies, immunotherapy has yielded limited efficacy in BC. We have found in animal models of HERNEG BC that chronic hypoxia secondary to prolonged Bev was associated to anti-tumor immune suppression and tumor PD-L1 upregulation. These events rendered HERNEG BC animal models sensitive to PD-L1 blockade in combination with Bev. We sought to explore this concept in the clinics in a pilot phase IB trial in HERNEG BC patients with disease progression (PD) on Bev maintenance by adding the anti-PD-L1 antibody Dur. Methods: HER2NEG metastatic patients with PD to Bev maintenance for a minimum of six weeks after first-line taxane+Bev were enrolled. Dur (10 mg/kg q14d) was added to maintenance Bev (10 mg/kg q14d). Patients were evaluated every 56 days (iRECIST). Before the first Dur dose and every 4 weeks until PD, peripheral-blood mononuclear cells (PBMCs) were phenotyped in order to monitor 24 lymphoid and non-neutrophil myeloid subpopulations. The primary endpoint was PFS time. Secondary endpoints were toxicity assessed with NCI CTC AE V. 4.03 and relative changes (%) in PBMCs subpopulations. Results: 24 patients were accrued. Median age was 56 and 12 (50%) patients were triplenegative. Median (range) Bev exposure during maintenance before entering trial was 11 (6- 22) months. Grade 3 toxicity included pneumonitis (1 patient) and hypertension (2 patients), related to Dur and Bev respectively. Grade 1/ 2 toxicity was observed in 18 (66%) patients. Median PFS was 76 days; 8 patients (33%) are still in the trial. Four patients have not experienced PD yet after 100+ days. Best response was SD (9 patients, 38%). Sixty-two per cent of the patients reached the first evaluation with SD; all of them had a 1.2- to 3.5-fold increase in CD8 effector memory T-cells (CD8EM) in PBMCs after the first Dur dose. All but one patient that experienced PD in the first evaluation had no change or a decrease up to 3.2- fold in CD8EM in PBMCs. Conclusions: Bev maintenance could expand the therapeutic niche of immunotherapy in HERNEG BC, evidenced by the efficacy of Dur in this context at low toxicity cost in this phase 1B study. Patients experiencing benefit showed detectable changes in CD8EM in PBMCs.