The final results of the KEYNOTE-522 trial confirm the potential of pembrolizumab to change patient management, though careful patient selection and toxicity monitoring are essential.“The final overall survival (OS) data from the KEYNOTE-522 trial represents some of the most significant findings observed in early-stage breast cancer treatment,” stated Dr. Carmen Criscitiello from the European Institute of Oncology in Milan, Italy, commenting on data reported at the 2024 ESMO Congress (Barcelona, September 13-17; LBA4).
Previous data from the phase III KEYNOTE-522 trial showed that adding pembrolizumab to standard chemotherapy in 1,174 early-stage triple-negative breast cancer (TNBC) patients led to statistically and clinically meaningful improvements in the dual primary endpoints of pathological complete response (pCR) (N Engl J Med. 2020; 382:810-821) and event-free survival (EFS) (N Engl J Med. 2022; 386:556-567).
In the final analysis, with a median follow-up of 75.1 months, 115 deaths (14.7%) were recorded in the pembrolizumab group (784 patients), compared to 85 deaths (21.8%) in the control group (390 patients), reaching the predefined significance threshold of 0.00503 (hazard ratio [HR] 0.66; 95% CI: 0.50-0.87; P=0.0015).
The 5-year OS rate was 86.6% in the pembrolizumab group compared to 81.7% in the placebo group. Additionally, the 5-year EFS rate was 81.2% in the pembrolizumab group and 72.2% in the placebo group (HR 0.65; 95% CI: 0.51-0.83). Dr. Criscitiello noted, “These results confirm the potential of pembrolizumab as a key component in the treatment regimen for high-risk, early-stage TNBC, positioning pembrolizumab plus chemotherapy as a new standard of care. These data are particularly significant as TNBC is a subtype associated with poor prognosis and limited treatment options. Integrating immunotherapy early in treatment could transform the management of these patients.”
Reflecting on the pivotal data from KEYNOTE-522 and its impact on clinical practice, Dr. Criscitiello added, “The 5-year EFS rate of 72.2% in the placebo group shows that many patients achieve favorable outcomes with chemotherapy alone. Therefore, it is crucial to identify patients who may have good prognoses without immunotherapy to avoid immune-related toxicities.” Among patients receiving pembrolizumab, 35.0% reported immune-mediated adverse events of any grade, compared to 13.1% in the placebo group. This consideration is important pre-surgery, as immune-related side effects may lead to surgery delays and impact patient outcomes. “Additionally, there are financial considerations to incorporating pembrolizumab into treatment plans, as access to and reimbursement for immunotherapy may be restricted in certain countries. While the benefits of pembrolizumab are clear, considering these factors is essential for responsibly integrating the KEYNOTE-522 regimen into clinical practice,” she remarked.
The incidence of ≥grade 3 treatment-related adverse events was 77.1% in the pembrolizumab group and 73.3% in the placebo group. Dr. Criscitiello emphasized, “Long-term safety monitoring will be crucial, and understanding the balance between potential survival benefits and toxicity risks is key to assessing this regimen’s overall long-term value.”
Given the toxicity associated with combined chemotherapy and immunotherapy, an exploratory study presented at the conference compared two cohorts (15 patients each) of TNBC patients with high tumor-infiltrating lymphocytes (TILs) who received short-term chemotherapy-free neoadjuvant therapy before surgery: nivolumab combined with ipilimumab or nivolumab combined with the anti-LAG3 agent relatlimab (LBA11). The primary endpoint, pCR, was achieved by 33% in the nivolumab-plus-ipilimumab group and 47% in the nivolumab-plus-relatlimab group. Overall, 7 patients (23.3%) experienced grade 3-4 adverse events, with 6 patients receiving nivolumab and ipilimumab. Dr. Criscitiello commented, “These efficacy data are particularly promising given the absence of chemotherapy and the manageable toxicity, especially in the nivolumab-plus-relatlimab group.”
Both studies underscore the importance of careful patient selection and monitoring, especially when considering treatment toxicity. Dr. Criscitiello highlighted the need to refine these treatment strategies and anticipate the development of lower-toxicity regimens for early-stage TNBC in the future. “We also need to continue exploring different immunotherapy combinations, including those with other novel agents, to maximize efficacy and minimize toxicity,” she said. Other areas of focus include biomarker research to better identify patients most likely to benefit from immunotherapy, monitoring late-stage toxicity (particularly in chemotherapy-free regimens), and exploring personalized approaches based on patient and tumor characteristics, potentially including genomic and immune features.
- Reference
1.Schmid P, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Overall survival results from the phase 3 KEYNOTE-522 study. ESMO Congress 2024, LBA4
2.Nederlof I, et al. Neoadjuvant nivolumab/relatlimab or nivolumab/ipilimumab in triple negative breast cancer with high tumor-infiltrating lymphocytes (TILs). ESMO Congress 2024, LBA11
