The addition of pembrolizumab (Keytruda; Merck) to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly improved overall survival (OS) in patients with high-risk early-stage triple-negative breast cancer (TNBC), according to data from the KEYNOTE-522 trial presented at the European Society for Medical Oncology (ESMO) Congress 2024. The study demonstrated a 34% reduction in the risk of death (HR=0.66 [95% CI, 0.50-0.87]; P =0.0015) compared to neoadjuvant chemotherapy alone. This regimen is emerging as a new standard of care for this aggressive form of breast cancer.
KEYNOTE-522: A Landmark Phase 3 Trial
The KEYNOTE-522 study (NCT03036488) is a phase 3, randomized, controlled trial that evaluated the role of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk early-stage TNBC. A total of 1174 patients were randomized 2:1 to either pembrolizumab plus chemotherapy or placebo plus chemotherapy. The pembrolizumab regimen consisted of pembrolizumab plus chemotherapy (paclitaxel and carboplatin), followed by pembrolizumab plus chemotherapy (cyclophosphamide and either doxorubicin or epirubicin) as neoadjuvant therapy, and then pembrolizumab monotherapy as adjuvant therapy (n=784). The chemotherapy-placebo regimen followed a similar structure with placebo replacing pembrolizumab (n=390).
The primary endpoints of the study were pathological complete response (pCR) and event-free survival (EFS), both of which were met in earlier interim analyses, leading to FDA approval of pembrolizumab in this setting. The final OS data presented at ESMO 2024 provided the most compelling evidence for pembrolizumab's role in improving long-term outcomes.
Overall Survival Benefit
After a median follow-up of 75.1 months (range, 65.9-84.0), the pembrolizumab regimen significantly improved overall survival (OS), a key secondary endpoint of the trial. The 5-year OS rate was 86.6% (95% CI, 84.0-88.8) for patients who received the pembrolizumab regimen versus 81.7% (95% CI, 77.5-85.2) for patients who received the chemotherapy-placebo regimen.
According to Peter Schmid, FRCP, MD, PhD, lead in the Centre for Experimental Cancer Medicine at Barts Cancer Institute in London, England, pembrolizumab is the first immunotherapy-based regimen to demonstrate a statistically significant and clinically meaningful improvement in OS as neoadjuvant treatment with chemotherapy and then as a single agent adjuvant therapy compared to pre-operative chemotherapy in patients with high-risk early-stage TNBC.
The survival benefit was observed across various subgroups, including those defined by PDL-1 expression, nodal status, and tumor size, regardless of pCR outcome. Notably, patients with residual disease after neoadjuvant therapy also benefited from pembrolizumab, with a 6% difference in 5-year OS compared to the control group.
Clinical Implications and Future Directions
Marleen Kok, MD, PhD, a group lead and medical oncologist at The Netherlands Cancer Institute in Amsterdam, emphasized the significance of the trial results in shaping future clinical practice for TNBC. She noted that pembrolizumab, in combination with chemotherapy, should now be considered the standard of care for stage II and III TNBC. The addition of pembrolizumab has been shown to reduce the number of patients with non-pCRs, thereby improving long-term outcomes. The OS benefit of 4.9% at 5 years is clinically meaningful, particularly for high-risk patients who do not achieve a pCR.
However, Kok raised questions about optimizing treatment, including identifying patients who can be cured with neoadjuvant pembrolizumab alone and whether all patients require a full year of pembrolizumab therapy. She also pointed to the need for better biomarkers to identify which patients are most likely to benefit from pembrolizumab, as TNBC currently lacks reliable predictive tools.
For patients who do not achieve a pCR, the prognosis remains poor, particularly for those with residual cancer burden (RCB) scores of 2 or 3. Novel therapeutic approaches, such as antibody-drug conjugates, next-generation immunotherapies, and new combinations, are being explored in trials for these high-risk patients.
Long-Term Quality of Life Considerations
As more patients with TNBC are being cured with multimodal therapy, long-term quality of life is becoming an increasingly important consideration. Concerns remain about the long-term adverse effects (AEs) of pembrolizumab, particularly in young women who may wish to start families. Although the overall rates of immune-related AEs were low in the KEYNOTE-522 trial, some AEs, such as adrenal insufficiency, hypophysitis, and diabetes, can have lasting impacts on patients' lives. There are also limited data on the impact of pembrolizumab on fertility, a critical issue for young breast cancer survivors.
