KEYNOTE-012: A phase Ib study of pembrolizumab (MK-3475) in patients (pts) with metastatic triple-negative breast cancer (mTNBC)

Abstract

Objective: To determine efficacy and safety of pembrolizumab, a humanized IgG4 monoclonal antibody against programmed death receptor 1 (PD-1), in pts with mTNBC. Methods: In the phase 1b KEYNOTE-012 study, women with metastatic ER−/PR−/HER2− breast cancer expressing programmed death receptor ligand 1 (PD-L1) received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity. An ECOG PS of 0 or 1, no systemic steroid therapy, and no active brain metastases were required for enrollment. PD-L1 positivity was defined as staining in the stroma or in ≥1% of tumor cells as assessed by a prototype immunohistochemistry assay using the 22C3 antibody. Adverse events (AEs) were monitored and graded per CTCAE v4.0. Response was assessed every 8 weeks per RECIST v1.1 by central review. Primary end point was the overall response rate (ORR). Results: Of the 111 pts with evaluable mTNBC samples screened for PD-L1 expression, 65 (59%) had PD-L1–positive tumors. Of the 32 pts enrolled, mean age was 52 years, and 46.9% of pts had received ≥3 prior lines of therapy for metastatic disease. The confirmed ORR was 18.5% in the 27 pts evaluable for response per RECIST v1.1 by central review (Table). As of November 10, 2014, median follow-up duration was 9.9 months. Median time to response was 18 weeks (range, 7-32). Median duration of response was not reached (range, 15-40+ weeks), with 3 of 5 responders on treatment for ≥11 months. The 6-month progression-free survival rate was 23.3%. Treatment-related AEs occurred in 56.3% of pts and were of grade 3-5 severity in 15.6%. One case of treatment-related disseminated intravascular coagulation led to death. Conclusions: Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity, including durable responses, in women with heavily pretreated, PD-L1–positive, mTNBC. These results support the continued development of pembrolizumab in this population. Pts Evaluable for Response N = 27 ORR 5 (18.5%) Best overall response Complete response 1 (3.7%) Partial response 4 (14.8%) Stable disease 7 (25.9%) Progressive disease 12 (44.4%) No assessment 3 (11.1%) Clinical trial identification: EudraCT number 2012-005771-14, released April 7, 2014 Disclosure: L. Pusztai: Research funding from Merck Sharp & Dohme. C.K. Gause and V. Karantza: Employee of Merck & Co., Inc. All other authors have declared no conflicts of interest.