A new secondary analysis of the phase 3 KEYNOTE-522 clinical trial has found that adding pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab improved outcomes in patients with early triple-negative breast cancer (TNBC) enrolled in East and Southeast Asian countries. The study, published on November 15, 2023 in JAMA Network Open, provides evidence supporting the use of this immunotherapy regimen as a standard of care for early TNBC patients in Asian countries.
The KEYNOTE-522 trial was a multicenter, double-blind, randomized clinical study that enrolled 1,174 patients between March 2017 and September 2018. This secondary analysis focused specifically on the 216 patients (18.4% of the total study population) who were enrolled at sites in Korea, Japan, Taiwan, and Singapore. The study was funded by Merck & Co., the manufacturer of pembrolizumab (Keytruda).
The purpose of this subgroup analysis was to evaluate the efficacy and safety outcomes of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared to neoadjuvant chemotherapy alone in early TNBC patients from Asian countries. This is an important area of investigation, as breast cancer incidence has been increasing in many Asian countries in recent decades, with mortality rates remaining stable or increasing, in contrast to decreasing trends seen in Western countries.
Eligible patients were adults with newly diagnosed, previously untreated, nonmetastatic TNBC (tumor stage T1c and nodal stage N1-2 or tumor stage T2-4 and nodal stage N0-2). Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and were eligible regardless of tumor PD-L1 expression status. The study excluded patients with metastatic disease.
Of the 216 patients included in this analysis, 136 were randomized to receive pembrolizumab plus chemotherapy and 80 to receive placebo plus chemotherapy. All patients were female, with a median age of 46 years (range 24-71 years). The majority (87.5%) had an ECOG performance status of 0, and 75.9% had tumors that were PD-L1 positive (combined positive score ≥1). Baseline characteristics were generally well-balanced between the two treatment groups.
In the neoadjuvant phase, patients received 4 cycles of pembrolizumab or placebo plus carboplatin and paclitaxel, followed by 4 cycles of pembrolizumab or placebo plus doxorubicin or epirubicin and cyclophosphamide. After surgery, patients in the pembrolizumab arm received 9 cycles of adjuvant pembrolizumab, while those in the placebo arm received 9 cycles of placebo.
The primary endpoints were pathological complete response (pCR) at the time of definitive surgery and event-free survival (EFS). Secondary endpoints included pCR and EFS in PD-L1 positive patients, overall survival (OS), and safety.
The results showed a significantly higher pCR rate in the pembrolizumab plus chemotherapy group compared to the placebo plus chemotherapy group (58.7% vs 40.0%, for a treatment difference of 18.7%). This benefit was observed regardless of tumor PD-L1 status. In patients with PD-L1 positive tumors, the pCR rates were 61.4% vs 41.7% for the pembrolizumab and placebo groups, respectively.
Event-free survival was also improved with pembrolizumab. At 36 months, the EFS rate was 91.2% in the pembrolizumab group compared to 77.2% in the placebo group (hazard ratio 0.35, 95% CI 0.17-0.71). The most common first EFS event in both groups was distant recurrence. Median EFS was not reached in either group at the time of analysis.
Overall survival data were immature at the time of this analysis, but showed a favorable trend for pembrolizumab. The 36-month OS rate was 95.6% in the pembrolizumab group vs 81.6% in the placebo group (hazard ratio 0.24, 95% CI 0.09-0.62).
Regarding safety, treatment-related adverse events of any grade occurred in 99.3% of patients receiving pembrolizumab plus chemotherapy and 100% of those receiving placebo plus chemotherapy. The most common adverse events in the pembrolizumab group were alopecia, nausea, and anemia. Grade 3-4 treatment-related adverse events occurred in 80.1% of pembrolizumab-treated patients and 81.0% of placebo-treated patients.
Immune-mediated adverse events and infusion reactions occurred in 36.8% of patients in the pembrolizumab group and 21.5% in the placebo group. The most common of these in pembrolizumab-treated patients were hypothyroidism, infusion reactions, hyperthyroidism, and severe skin reactions. There were no treatment-related deaths reported.
The authors concluded that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to clinically meaningful improvements in pCR and EFS compared to neoadjuvant chemotherapy alone in patients with early TNBC enrolled in Asian countries. They stated that these findings support the use of this regimen as a standard-of-care therapy for early TNBC patients in Asian countries.
There are some important limitations to consider when interpreting these results. As a secondary subgroup analysis, this study was not powered for formal statistical hypothesis testing, and the results should be considered descriptive. Additionally, the analysis only included patients from certain East and Southeast Asian countries (Korea, Japan, Taiwan, and Singapore), so the generalizability to other Asian populations may be limited.
Nevertheless, these findings have potentially significant clinical implications for the treatment of early TNBC in Asian countries. The magnitude of benefit seen with pembrolizumab in this Asian subgroup appears to be at least as large as, if not larger than, that observed in the overall KEYNOTE-522 study population. This suggests that Asian patients with early TNBC may derive substantial benefit from the addition of pembrolizumab to standard neoadjuvant chemotherapy.
The results are particularly noteworthy given the increasing incidence of breast cancer in many Asian countries and evidence suggesting potential differences in tumor biology and microenvironment between Asian and non-Asian breast cancer patients. The robust efficacy observed, along with a manageable safety profile consistent with the known effects of pembrolizumab, supports the incorporation of this immunotherapy regimen into standard practice for eligible patients with early TNBC in Asian countries.
However, several questions remain that warrant further investigation. Longer follow-up will be needed to determine the impact on overall survival. Additionally, biomarker analyses may help identify which patients are most likely to benefit from the addition of pembrolizumab. Future studies examining potential differences in response or toxicity between Asian and non-Asian populations could also provide valuable insights.
It is worth noting that regulatory authorities in several countries, including Japan, have already approved pembrolizumab in combination with chemotherapy for the neoadjuvant treatment of patients with high-risk early-stage TNBC, based on the overall results of the KEYNOTE-522 trial. The current subgroup analysis provides further support for the use of this regimen specifically in Asian populations.
In conclusion, this secondary analysis of the KEYNOTE-522 trial demonstrates that adding pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly improves outcomes for patients with early TNBC enrolled in East and Southeast Asian countries. These results are consistent with and potentially more pronounced than those seen in the overall study population. While some limitations exist, the findings support the use of this immunotherapy-chemotherapy combination as a new standard of care for eligible early TNBC patients in Asian countries. Ongoing research will help further refine patient selection and optimize treatment strategies for this aggressive form of breast cancer.
References
Takahashi M, Cortés J, Dent R, et al. Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023;6(11):e2342107. Published 2023 Nov 1. doi:10.1001/jamanetworkopen.2023.42107
