Immunotherapy Significantly Extends Survival in Triple-Negative Breast Cancer

Early-stage triple-negative breast cancer (TNBC) is a subtype with fewer treatment options and a poorer outlook than hormone-positive or HER2-positive breast cancers. Integrating immunotherapies into treatment is therefore an important source of hope. On July 26, 2021, the FDA approved an immunotherapy given with chemotherapy as neoadjuvant (preoperative tumor-shrinking) treatment and then continued as single-agent adjuvant (postoperative) treatment: pembrolizumab , for high-risk, early-stage triple-negative breast cancer . Pembrolizumab with chemotherapy had previously been approved for patients with PD-L1-positive metastatic TNBC. At the ESMO Congress 2024, long-term overall survival results were presented from KEYTNOTE-522 , the study that led to FDA approval of pembrolizumab in early-stage TNBC, confirming the treatment's effectiveness.

Final KEYNOTE-522 Results

The final KEYNOTE-522 results confirm that integrating pembrolizumab into the regimen has fundamentally changed patient treatment. However, careful patient selection and close monitoring of adverse effects remain crucial.

The Study's Importance and Results

The phase III KEYNOTE-522 study had previously shown statistically and clinically meaningful improvements in coprimary endpoints such as pathological complete response (pCR) and event-free survival . These improvements were achieved by adding pembrolizumab to standard chemotherapy in 1,174 patients with early-stage triple-negative breast cancer (TNBC) .

In the final analysis, after a median follow-up of 75.1 months, 115 of 784 patients (14.7%) in the pembrolizumab group had died, compared with 85 of 390 (21.8%) in the control group. The hazard ratio (HR) was 0.66 , with a 95% confidence interval (CI) of 0.50–0.87, reaching the study's prespecified significance threshold of p=0.0015 .

5-year overall survival rates were 86.6% in the pembrolizumab group and placebo patients had a rate of 81.7%. Similarly, the 5-year event-free survival (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).

Impact on Clinical Practice

The placebo group's 5-year event-free survival rate was 72.2%, so it is important to remember that many patients achieve good outcomes with chemotherapy alone. To avoid immunotherapy adverse effects, we therefore need to identify which patients may have a favorable course without it.

In 35% of patients receiving pembrolizumab and 13.1% of those receiving placebo, immune-mediated adverse effects were reported. These are important because they may delay surgery in the preoperative period and jeopardize patient outcomes. Given that immunotherapy is not reimbursed for these patients in many countries, integrating pembrolizumab into treatment regimens also requires careful financial consideration.

In the study, the rate of treatment-related grade ≥3 adverse effects was 77.1% in the pembrolizumab group and 73.3% in the placebo group. Therefore, monitoring long-term safety is critical, and balancing potential survival benefit against toxicity risk will be important.

Other Notable Treatment Approaches

Given the adverse effects of combined chemotherapy and immunotherapy regimens, an exploratory study presented at the congress examined short-term, chemotherapy-free neoadjuvant treatment in patients with TNBC and high tumor-infiltrating lymphocytes (TILs) . Before surgery, patients received combinations of nivolumab and ipilimumab or nivolumab and the LAG3 inhibitor relatlimab . Pathological complete response rates were 33% with nivolumab + ipilimumab and 47% with nivolumab + relatlimab. Regarding adverse effects, 23.3% of patients in the nivolumab + ipilimumab group developed grade 3-4 events. These promising efficacy data obtained without chemotherapy are noteworthy, particularly for nivolumab + ipilimumab, if its adverse effects are manageable.

Conclusion

Both studies emphasize the need for careful patient selection and monitoring. Early-stage TNBC treatment strategies aiming for chemotherapy regimens with fewer adverse effects will need further refinement. At the same time, biomarker research may help identify more accurately the patients most likely to benefit from immunotherapy. Monitoring long-term adverse effects and exploring patient-specific approaches will also contribute to more personalized treatment options.