BACKGROUND: The current standard of care for triple-negative breast cancer (TNBC) is chemotherapy with anthracyclines or taxanes, but the overall survival (OS) for this patient population is shorter than the OS in other subtypes of breast cancer, and the risk for disease recurrence or death is high among treatment-naïve patients with stage II or III TNBC. Early data for immune checkpoint inhibitors targeting PD-1 or PD-L1 expression in combination with chemotherapy in patients with TNBC have shown antitumor activity.
METHODS: KEYNOTE-522 was a prospective, randomized, placebo-controlled, phase 3 clinical trial that compared the benefits of the PD-1 inhibitor pembrolizumab plus chemotherapy versus placebo plus chemotherapy in treatment-naïve patients with early-stage TNBC. The study included a neoadjuvant phase and an adjuvant phase, as well as a control group. Patients were randomized (2:1) to neoadjuvant therapy with 4 cycles of pembrolizumab (200 mg) plus paclitaxel and carboplatin or to placebo plus paclitaxel and carboplatin every 3 weeks, followed by 4 cycles of pembrolizumab plus doxorubicin and cyclophosphamide or epirubicin and cyclophosphamide or to placebo plus these chemotherapies. After undergoing definitive surgery, patients received adjuvant pembrolizumab plus chemotherapy or placebo plus chemotherapy every 3 weeks, for up to 9 cycles. The primary end points were pathologic complete response or event-free survival (EFS).
RESULTS: The study enrolled 1174 patients with stage II or stage III TNBC. The estimated EFS at 36 months was 84.5% in the pembrolizumab plus chemotherapy group and 76.8% in the placebo plus chemotherapy group; the median EFS was not reached in either group. In the EFS analysis, the most common event was distant recurrence (7.7 vs 13.1, respectively). The OS data were not mature at the time of the analysis. At a median follow-up of 39.1 months, 15.7% in the pembrolizumab plus chemotherapy group and 23.8% in the placebo plus chemotherapy group had an adverse event (AE) or died (hazard ratio, 0.63; 95% confidence interval, 0.48-0.82; P <.001). No new safety concerns were identified with the pembrolizumab regimen. In the combined neoadjuvant and adjuvant phases, grade 3 or 4 AEs were observed in 77.1% of patients in the pembrolizumab plus chemotherapy group and in 73.3% of patients in the placebo plus chemotherapy group. The rate of immune-mediated AEs of any grade was 33.5% in the pembrolizumab arm and 11.3% in the placebo arm, including 12.9% and 1.0% grade ≥3, respectively. Treatment-related AEs led to 4 deaths in the pembrolizumab arm and to 1 death in the placebo arm. “The results of this trial support the use of pembrolizumab plus platinum-, taxane-, and anthracycline-containing neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, as a treatment regimen for patients with high-risk, early triple-negative breast cancer, regardless of tumor PD-L1 expression status,” the researchers concluded.
Source: Schmid P, Cortes J, Dent R; for the KEYNOTE-522 investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567.
Commentary by Robert J. Ignoffo
This study evaluated the efficacy of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab plus chemotherapy in early-stage TNBC. Neoadjuvant pembrolizumab plus chemotherapy led to a higher percentage of pathologic complete response than the chemotherapy plus placebo, independent of PD-L1 expression. The use of pembrolizumab prolonged EFS across the various subgroups of TNBC.
The hazard ratio of 0.63 was significant and indicated that the risk for disease progression was 37% lower with pembrolizumab plus chemotherapy than with placebo plus chemotherapy. In addition, distant recurrence at 1 year was also lower in the pembrolizumab plus chemotherapy group. No difference was seen in patients who achieved a pathologic complete response between the groups. However, of those who did not achieve a pathologic complete response after neoadjuvant therapy, significantly more patients died in the placebo plus chemotherapy arm than in the pembrolizumab plus chemotherapy arm.
Pembrolizumab added to chemotherapy did increase the incidence of common adverse effects. The incidence of endocrine side effects and skin reactions was higher in the pembrolizumab plus chemotherapy group than in the placebo plus chemotherapy group. These adverse reactions occurred mostly during the neoadjuvant phase of treatment; they were mostly low-grade, and were successfully managed with treatment interruption, glucocorticoid administration, or hormone replacement therapy.
Overall, this regimen achieved its goal of decreasing disease progression, recurrence, and death (in the subgroup who did not achieve complete response). The data on OS will have to mature further before the impact of this regimen on OS can be determined.