Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study

Abstract

Purpose: Immune checkpoint inhibition has been demonstrated to be an effective anticancer strategy. Several lines of evidence support the study of immunotherapy in triple-negative breast cancer (TNBC). We assessed the safety and antitumor activity of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab in patients with advanced TNBC.

Methods: KEYNOTE-012 (ClinicalTrials.gov identifier: NCT01848834) was a multicenter, nonrandomized phase Ib trial of single-agent pembrolizumab given intravenously at 10 mg/kg every 2 weeks to patients with advanced PD-L1-positive (expression in stroma or ≥ 1% of tumor cells by immunohistochemistry) TNBC, gastric cancer, urothelial cancer, and head and neck cancer. This report focuses on the TNBC cohort.

Results: Among 111 patients with TNBC whose tumor samples were screened for PD-L1 expression, 58.6% had PD-L1-positive tumors. Thirty-two women (median age, 50.5 years; range, 29 to 72 years) were enrolled and assessed for safety and antitumor activity. The median number of doses administered was five (range, 1 to 36 doses). Common toxicities were mild and similar to those observed in other tumor cohorts (eg, arthralgia, fatigue, myalgia, and nausea), and included five (15.6%) patients with grade ≥ 3 toxicity and one treatment-related death. Among the 27 patients who were evaluable for antitumor activity, the overall response rate was 18.5%, the median time to response was 17.9 weeks (range, 7.3 to 32.4 weeks), and the median duration of response was not yet reached (range, 15.0 to ≥ 47.3 weeks).

Conclusion: This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated, advanced TNBC. A single-agent phase II study examining a 200-mg dose given once every 3 weeks (ClinicalTrials.gov identifier: NCT02447003) is ongoing.

Fig 1.

Antitumor activity of pembrolizumab based on RECIST v1.1 assessed by central review. (A) Best percentage change from baseline in the sum of the longest diameters of target lesions. (B) Longitudinal change from baseline in the sum of the longest diameters of target lesions. (C) Time to and durability of response. For each panel, only patients who received at least one pembrolizumab dose and who had evaluable tumor measurements based on RECIST v1.1 assessed by central review at baseline and at least one postbaseline assessment were included (n = 24). Reasons for treatment discontinuation in patients whose change from baseline per RECIST v1.1 by central review was ≤ 20% are indicated; because patients were managed by investigator assessment, reasons for discontinuation are based on RECIST v1.1 by investigator review. In panel C, length of bars equals time to last imaging assessment by central review. RECIST, Response Evaluation Criteria in Solid Tumors.

Fig 2.

Kaplan-Meier estimates of (A) progression-free survival based on Response Evaluation Criteria in Solid Tumors v1.1 assessed by central review and (B) overall survival.