Metastatic triple-negative breast cancer (MTNBC) is associated with a median overall survival (OS) of 17.5 months for first-line chemotherapy and 12 months for subsequent courses of treatment with an objective response rate (ORR) of 23% and 31% to 34%, respectively. With such poor outcomes, there is a need for treatment that can enhance response and prolong survival.
Programmed death-ligand 1 (PD-L1) binds to PD-1 receptors found on T cells. This binding results in the inactivation of T-cells, permitting cancer cells to go undetected. While not found in normal breast tissue, PD-L1 is expressed in up to 30% of patients with TNBC. Pembrolizumab is a highly selective, humanized monoclonal anti-PD-1 antibody that acts as an immune checkpoint inhibitor (ICI) to prevent binding of programmed death ligands to the PD-1 receptors, allowing the activation of an antitumor response.
KEYNOTE-119 was a randomized, international, multicenter, open-label phase III trial designed to assess whether pembrolizumab monotherapy offered benefit compared with single-drug chemotherapy for patients with previously treated MTNBC.
To be eligible for the study, patients had to have received one or two previous systemic treatments for MTNBC with documented disease progression. Other requirements were treatment with an anthracycline or a taxane, adequate organ function (ECOG performance status of 0 or 1), and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Among the exclusion criteria were that patients could not have received previous therapy with an anti-PD-1, PD-L1, PD-L2, or anti co-inhibitory T-cell receptor agent; chemotherapy, targeted small molecule therapy, or radiotherapy within the past 2 weeks; or had an adverse event unless it resolved to grade 1 or lower.
Patients in the pembrolizumab group received 200 mg IV every 3 weeks, while those in the chemotherapy group received investigator-choice chemotherapy (ICC) with either capecitabine, eribulin, gemcitabine, or vinorelbine. Pembrolizumab was continued until there was disease progression, intolerable toxicity, withdrawal of patient consent at the investigator’s discretion, upon completion of 35 courses of treatment, or upon complete response. If disease progression was present after the ICI was discontinued, a second course of pembrolizumab could be administered, provided that other anticancer agents had not been administered in the interim.
In the chemotherapy group, therapy was continued until disease progression or intolerable adverse events. Patients in the chemotherapy group could not cross over to the pembrolizumab group, and patients in the pembrolizumab group could not undergo a dose reduction, although the monoclonal antibody could be held for up to 12 weeks in the presence of a serious adverse event.
PD-L1 expression was assessed using the Combined Positive Score (CPS), which is the number of PD-L1 staining cells (i.e., tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multipled by 100. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), ORR, disease control rate, duration of response (DOR), safety, and tolerability. Outcomes were assessed in these categories: patients with PD-L1 CPS of >20, PD-L1 CPS of >10, PD-L1 CPS of >1, and all patients.
A total of 622 patients (median age 52 years) took part in the trial, with 312 assigned to the pembrolizumab group and 310 receiving chemotherapy. All but two patients were female, with about 85% under age 65 years in both groups. After a median time since randomization of approximately 31 months, almost all patients had discontinued treatment (96% in the pembrolizumab group and 92% in the chemotherapy group).
For the PD-L1 CPS of >10, 77% of the pembrolizumab-treated patients and 89% of the chemotherapy-treated patients died; median survival was 12.7 months and 11.6 months, respectively. For those with PD-L1 CPS of >1, OS was 84% for the pembrolizumab-treated group, and 91% of the chemotherapy-treated patients died; median survival was 10.7 months and 10.2 months, respectively. In the total intention-to-treat analysis, 85% of the pembrolizumab-treated patients and 88% of the chemotherapy-treated patients died; median survival was 9.9 months and 10.8 months, respectively. These differences were not statistically significant. However, in a post-hoc analysis of patients with a PD-L1 CPS of >20, 70% of the pembrolizumab-treated patients and 92% of the chemotherapy-treated patients died, and median survival was 14.9 months and 12.5 months, respectively; this difference was statistically significant (hazard ratio 0.58, CI 0.38-0.88).
Median PFS and DOR were similar between the treatment groups but were associated with PD-L1 CPS status for pembrolizumab. The ORR was also similar between the groups.
Assessment of tolerability found that 21% of the ICC-treated compared with 45% of the chemotherapy-treated group required dose modifications due to the occurrence of adverse events with 14% and 36% of each treatment group, respectively, experiencing grade 3 to 4 treatment-related adverse events. Three percent of patients in both groups died due to adverse events.
Pharmacists working with patients with MTNBC should be aware of the limitations of ICC therapy in this population.
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