Pembrolizumab monotherapy for previously treated metastatic HER2-negative breast cancer with germline APOBEC3B deletion: results of the phase II AUROR study

Background: A common germline deletion polymorphism in the APOBEC3B gene increases the rate of somatic hypermutation in breast cancer, which in turn is associated with greater neoantigen burden and immune activation. This phase II study evaluated the impact of the APOBEC3B deletion polymorphism on the response to pembrolizumab monotherapy in metastatic HER2-negative breast cancer patients. Patients and methods: Eligible patients had a confirmed diagnosis of metastatic HER2-negative breast cancer, 1-3 prior lines of therapy, and documented homozygous or heterozygous germline deletion of APOBEC3B. Patients received 200 mg of pembrolizumab intravenously every 3 weeks for up to 2 years. The primary endpoint was objective response rate. Secondary endpoints were disease control rate, progression-free survival, and overall survival. Results: All enrolled patients (N = 44) were women, 36% had PD-L1-positive tumours, and 62% had received 2 or more previous lines of therapy for metastatic disease. ORR (95% CI) was 20.5% (9.8-35.5) in the total and 30.0% (6.7-65.3) in the PD-L1-positive populations. Disease control rate (95% CI) was 52.3% (36.7-67.5) and 40% (12.2-73.8), respectively. Median PFS was 3.1 months (95% CI, 2.1-4.3), and 6-month PFS rate was 29.5% (95% CI, 18.7-46.6). Median OS was 15.2 months (95% CI, 11.7-26.5), and 12-month OS rate was 60.2% (95% CI, 46.5-77.7). Treatment-related adverse events occurred in 30 (68.2%) patients, including 1 (2.3%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumour activity in a subset of previously treated metastatic HER2- breast cancer patients with germline APOBEC3B deletion.