As reported in The New England Journal of Medicine by Peter Schmid, MD, PhD, of Barts Cancer Institute, Queen Mary University of London, and colleagues, analyses in the phase III KEYNOTE-522 trial have shown that the addition of pembrolizumab to neoadjuvant chemotherapy and the use of adjuvant pembrolizumab vs placebo resulted in significant improvement in pathologic complete response rate and an apparent event-free survival benefit in women with early triple-negative breast cancer.¹

Peter Schmid, MD, PhD

Study Details

In the trial, 1,174 patients from 181 sites in 21 countries with previously untreated stage II or III triple-negative breast cancer were randomly assigned 2:1 between March 2017 and 2018 to pembrolizumab/chemotherapy (n = 784) or placebo/chemotherapy (n = 390). Neoadjuvant therapy consisted of four cycles of pembrolizumab at 200 mg or placebo every 3 weeks plus paclitaxel (80 mg/m² once weekly) and carboplatin (AUC = 5 every 3 weeks or 1.5 once weekly) for the first 12 weeks followed by four cycles of pembrolizumab or placebo plus doxorubicin (60 mg/m²) or epirubicin (90 mg/m²) plus cyclophosphamide (600 mg/m²) once every 3 weeks for the subsequent 12 weeks. After definitive surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary endpoints were pathologic complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. Event-free survival events consisted of disease progression precluding definitive surgery, local or distant recurrence or second primary tumor, and death from any cause.

For the total pembrolizumab vs placebo groups, the median age was 49 years (90% < 65 years) vs 48 years (88% < 65 years); 56% vs 57% were premenopausal; 84% vs 81% had programmed cell death ligand 1 (PD-L1)-positive disease; all had an Eastern Cooperative Oncology Group performance status of 0 or 1; 80% vs 79% had lactate dehydrogenase levels below the upper limit of normal; 57% in both groups received the weekly carboplatin schedule; primary tumor classification was T1 or T2 in 74% vs 74%; 52% vs 51% had node-positive disease; and the disease stage was II in 75% vs 75% and III in 25% vs 25%.

Pathologic Complete Response Rates

IN A PROTOCOL-DEFINED definitive analysis among the first 602 randomly assigned patients (401 in pembrolizumab group, 202 in the placebo group), pathologic complete response was achieved in 64.8% of the pembrolizumab group vs 51.2% of the placebo group (estimated treatment difference = 13.6%, 95% confidence interval [CI] = 5.4%–21.8%, P < .001). The benefit of pembrolizumab was generally consistent across subgroups, including PD-L1 expression subgroups. Pathologic complete response rates were 68.9% vs 54.9% among 334 vs 164 patients in the PD-L1–positive subgroup and 45.3% vs 30.3% among 64 vs 33 in the PD-L1–negative subgroup. In other subgroups, pathologic complete response rates were 64.8% among 210 patients vs 44.1% among 102 patients with node-positive disease and 64.9% among 191 patients vs 58.6% among 99 patients with node-negative disease; 70.2% among 295 patients vs 56.4% among 149 patients with T1 to T2 disease and 50% among 106 patients vs 36.5% among 52 patients with T3 to T4 disease; and 63.6% among 165 patients vs 56.0% among 84 patients who received the every-3-week carboplatin schedule and 66.7% among 231 patients vs 48.3% among 116 patients who received weekly carboplatin.

Event-Free Survival and Adverse Events

At the event-free survival interim analysis after a median follow-up of 15.5 months (range = 2.7–25.0 months) among patients in the intent-to-treat population, median event-free survival had not been reached in either group. Event-free survival events had occurred in 58 of 784 patients (7.4%) in the pembrolizumab group vs 46 of 390 patients (11.8%) in the placebo group (hazard ratio = 0.63, 95% CI = 0.43–0.93). At 18 months, estimated event-free survival was 91.3% with pembrolizumab vs 85.3% with placebo.

In the neoadjuvant phase, treatment-related grade ≥ 3 adverse events occurred in 76.8% of the pembrolizumab group vs 72.2% of the placebo group. Serious treatment-related adverse events occurred in 32.5% vs 19.5%. Treatment-related adverse events led to discontinuation of any study drug in 23.3% of the pembrolizumab group vs 12.3% of the placebo group. Potential immune-related adverse events occurred in 38.9% vs 18.3% of patients, with those of grade ≥ 3 occurring in 12.9% vs 1.8%; those of grade ≥ 3 occurring in at least 10 patients in the pembrolizumab group were severe skin reactions, infusion reactions, and adrenal insufficiency.

In the adjuvant phase, treatment-related adverse events of any grade occurred in 48.1% vs 43.0% of patients. Across all phases, treatment-related grade ≥ 3 adverse events occurred in 78.0% vs 73.0%. Treatment-related adverse events led to death in three patients in the pembrolizumab group (one from pulmonary embolism, one from sepsis and multiple organ dysfunction syndrome, and one from pneumonitis) and one patient in the placebo group (septic shock).

The investigators concluded: “Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.” 

DISCLOSURE: The study was funded by Merck Sharp & Dohme. Dr. Schmid has received research support from AstraZeneca, Genentech, Roche, OncoGenex Pharmaceuticals, Novartis, Astellas, and Medivation and honoraria or consultation fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma. For full disclosures of the study authors, visit nejm.org.

REFERENCE

1. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.