Despite revolutionizing the management of various solid tumours, more limited success has thus far been achieved with immune-checkpoint inhibition in women with advanced-stage breast cancer. Now, data from two cohorts of KEYNOTE-086, a phase II trial designed to explore the efficacy of monotherapy with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab in different treatment settings in women with triple-negative breast cancer (TNBC), provide further insight on the optimal use of these agents.

Women in cohort A (with previously treated metastatic TNBC, n = 170) and in cohort B (with previously untreated, programmed cell death 1 ligand 1 (PD-L1)-positive metastatic TNBC, n = 84) received intravenous pembrolizumab on a 3-weekly basis for up to 2 years. The primary end point in cohort A was safety and in cohort B was safety and overall response rate.

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Treatment-related adverse events of any grade were reported in 60.6% and 63.1% of women in cohort A and cohort B, respectively, with 12.9% and 9.5% having grade ≥3 adverse events. Notably, overall response rates (ORRs) were 5.3% in cohort A (5.7% in women with PD-L1-positive disease), compared with 21.4% in cohort B and nearly half (44.4%) of these responses were ongoing at the time of analysis. Median overall survival durations were 9.0 months and 18.0 months in cohort A and cohort B, respectively.

Lead author Sylvia Adams highlights: “The most striking observation is that clinical activity is vastly different by line of therapy.” This observation has important implications, both for patient management and for future research. Even in the first-line setting, ORRs to pembrolizumab were lower than those typically associated with chemotherapy; however, among women who did respond, many of the responses were more durable and ongoing at the time of analysis. This finding highlights the need for robust biomarkers of responsiveness to pembrolizumab. Furthermore, the ORRs observed in this trial might be improved upon by the addition of pembrolizumab to chemotherapy.

Adams summarizes: “This is the largest study of single-agent PD-1–PD-L1 inhibition in metastatic breast cancer to date,” adding “while response rates are lower than those observed with chemotherapy, the durability of responses and associated survival is impressive and confirms that immunotherapy is a game changer (or at least a new treatment option) for women with TNBC and can improve survival in at least a subset of patients.”