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, a preplanned interim analysis of the phase III KEYNOTE-522 trial has shown improved event-free survival with the addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab in patients with early-stage triple-negative breast cancer.¹

Peter Schmid, MD, PhD

The trial supported the July 2021 approval of pembrolizumab in high-risk, early-stage, triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment and continued as adjuvant treatment on the basis of improved pathologic complete response rate and event-free survival.

Study Details

In the double-blind trial, 1,174 patients with previously untreated stage II or III triple-negative breast cancer (T1c, N1–2 or T2–4, N0–2) from sites in 21 countries were randomly assigned 2:1 between March 2017 and September 2018 to receive neoadjuvant pembrolizumab plus chemotherapy (n = 784) or placebo/chemotherapy (n = 390), followed by adjuvant pembrolizumab vs placebo. Neoadjuvant treatment consisted of four cycles of pembrolizumab at 200 mg or placebo every 3 weeks plus paclitaxel at 80 mg/m² once weekly and carboplatin at the area under the curve (AUC) of 5 every 3 weeks or AUC of 1.5 once weekly for the first 12 weeks, followed by four cycles of pembrolizumab or placebo plus doxorubicin at 60 mg/m² or epirubicin at 90 mg/m² plus cyclophosphamide at 600 mg/m² every 3 weeks for the next 12 weeks. After definitive surgery, patients in the pembrolizumab group received the agent and those in the control group received placebo every 3 weeks for up to nine cycles. Randomization stratification factors were nodal status, tumor size, and frequency of carboplatin dosing.

The primary endpoints were pathologic complete response and event-free survival, defined as time to disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. A prior report from the study showed that the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a significantly higher rate of pathologic complete response.²

Event-Free Survival

Median follow-up at the fourth planned interim analysis (data cutoff in March 2021) was 39.1 months (range = 30.0–48.0 months). An event-free survival event occurred in 123 patients (15.7%) in the pembrolizumab group and 93 patients (23.8%) in the control group (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.48–0.82, P < .001). Estimated event-free survival at 36 months was 84.5% (95% CI = 81.7%–86.9%) vs 76.8% (95% CI = 72.2%–80.7%). First events consisted of progression of disease that precluded definitive surgery in 1.8% vs 3.8% of patients, local recurrence in 3.6% vs 4.4%, distant recurrence in 7.7% vs 13.1%, second primary cancer in 0.8% vs 1.0%, and death from any cause in 1.9% vs 1.5%. The hazard ratio for distant disease progression– and distant recurrence–free survival was 0.61 (95% CI = 0.46–0.82), with estimated 36-month rates of 87.0% vs 80.7%.

In stratification subgroup analyses, hazard ratios were 0.65 (95% CI = 0.46–0.91) among 408 vs 196 patients with positive nodal status and 0.58 (95% CI = 0.37–0.91) among 376 vs 194 with negative nodal status, 0.51 (95% CI = 0.36–0.73) among 581 vs 290 with tumor size T1/T2 and 0.84 (95% CI = 0.55–1.28) among 203 vs 100 with T3/T4, and 0.60 (95% CI = 0.42–0.86) among 444 vs 220 receiving weekly carboplatin and 0.65 (95% CI = 0.42–0.99) among 334 vs 167 receiving carboplatin every 3 weeks. In an analysis according to PD-L1 status, hazard ratios were 0.67 (95% CI = 0.49–0.92) among 656 vs 317 with PD-L1–positive disease (combined positive score ≥ 1) and 0.48 (95% CI = 0.28–0.85) among 128 vs 69 with PD-L1–negative status.

In a prespecified exploratory analysis among patients who achieved a pathologic complete response, event-free survival events occurred in 27 (5.5%) of 494 vs 16 (7.4%) of 217 patients (HR = 0.73, 95% CI = 0.39–1.36); estimated 36-month event-free survival rate was 94.4% vs 92.5%. Among patients without a pathologic complete response, events occurred in 96 (33.1%) of 290 vs 77 (44.5%) of 173 patients (HR = 0.70, 95% CI = 0.52–0.95); estimated 36-month rate was 67.4% vs 56.8%.

Data on overall survival were immature at the time of analysis. Death occurred in 80 patients (10.2%) in the pembrolizumab group and 55 patients (14.1%) in the control group (HR = 0.72, 95% CI = 0.51–1.02), with an estimated 36-month overall survival of 89.7% (95% CI = 87.3%–91.7%) vs 86.9% (95% CI = 83.0%–89.9%).

Adverse Events

Adverse events occurred predominantly during the neoadjuvant phase. For the combined phases, treatment-related grade ≥ 3 adverse events occurred in 77.1% of the pembrolizumab group vs 73.3% of the control group; the most common events in both groups were neutropenia (34.5% vs 34.4%), decreased neutrophil count (18.6% vs 23.1%), and anemia (18.0% vs 14.9%). In the adjuvant phase, grade ≥ 3 treatment-related adverse events occurred in 6.3% vs 2.7%. Serious treatment-related adverse events occurred in 34.1% vs 20.1% of patients, most commonly febrile neutropenia (15.1% vs 12.1%). Discontinuation of study treatment due to treatment-related adverse events occurred in 27.7% vs 14.1% of patients. Immune-mediated adverse events of any grade occurred in 33.5% (grade ≥ 3 in 12.9%) vs 11.3% (grade ≥ 3 in 1.0%). Treatment-related adverse events led to death in four patients (0.5%) vs one patient (0.3%).

The investigators concluded: “In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone.” 

DISCLOSURE: The study was funded by Merck Sharp and Dohme. Dr. Schmid has received research support from Astellas Pharma, AstraZeneca, F. Hoffmann–La Roche, Genentech, Medivation, Novartis, and OncoGenex Pharmaceuticals; has served as an advisor or consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, F. Hoffmann–La Roche, Merck, Novartis, Pfizer, and Puma Biotechnology; and has served on a data and safety monitoring board for Novartis.

REFERENCES

1. Schmid P, Cortes J, Dent R, et al: Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567, 2022.

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