Updated Data Further Support KEYNOTE-522 Regimen as SOC in High-Risk, Early-Stage TNBC

Neoadjuvant treatment with pembrolizumab (Keytruda) plus chemotherapy, followed by adjuvant pembrolizumab, improved overall survival (OS) vs neoadjuvant chemotherapy alone in patients with high-risk, early-stage triple-negative breast cancer (TNBC), with a positive trend observed in key subgroups, according to data from exploratory analyses of the phase 3 KEYNOTE-522 trial (NCT03036488).1

Findings shared during the 42nd Annual Miami Breast Cancer Conference, showed that the hazard ratio (HR) for OS in patients with RCB-0 status was 0.66 (95% CI, 0.36-1.23); the 60-month OS rate in the pembrolizumab arm (n = 498) was 95.4% vs 94.5% in the placebo arm (n = 219). In those with RCB-1 status, the HR for OS was 1.35 (95% CI, 0.46-3.96), with 60-month OS rates of 88.4% and 93.2% in the pembrolizumab (n = 69) and placebo (n = 45) arms, respectively. In those with RCB-2 status, the HR for OS was 0.50 (95% CI, 0.31-0.80); in this group, the OS rates at 60 months was 77.8% in the pembrolizumab arm (n = 144) and 63.3% in the placebo arm (n = 79). Lastly, in those with RCB-3 status, the HR for OS was 1.26 (95% CI, 0.68-2.34), with 60-month OS rates of 37.5% and 38.5% in the pembrolizumab (n = 40) and placebo (n = 26) arms, respectively.

Investigators also examined OS according to PD-L1 combined positive score (CPS), overall disease stage, and nodal status. In those with a PD-L1 CPS of 10 or higher, the HR for OS was 0.69 (95% CI, 0.41-1.15). In those with a PD-L1 CPS under 10, the HR for OS was 0.68 (95% CI, 0.48-0.95). In those with stage II disease, the HR for OS was 0.59 (95% CI, 0.40-0.86), whereas in those with stage III disease, the HR for OS was 0.76 (95% CI, 0.50-1.15). In those with positive nodal status, the HR for OS was 0.65 (95% CI, 0.46-0.91); in those with negative status, the HR was also 0.65 (95% CI, 0.40-1.05). In those with T2N0 disease at baseline, the HR for OS was 0.51 (95% CI, 0.29-0.90).

“The present exploratory analyses demonstrate that the addition of pembrolizumab to neoadjuvant chemotherapy not only increased pathologic complete response [pCR] rate but also shifted more participants to lower RCB categories across the entire spectrum of participants with residual disease,” Heather McArthur, MD, MPH, of UT Southwestern Medical Center, and colleagues, wrote in a poster on the data. “Consistent with the intention-to-treat [ITT] population, the OS benefit with pembrolizumab has a positive trend in the subgroups, including those defined by PD-L1 expression, nodal status, overall disease status, and baseline T2N0 status.”

McArthur is a professor of internal medicine and a member of its Division of Hematology and Oncology at UT Southwestern Medical Center, in Dallas, Texas, as well as clinical director of the Breast Cancer Program at the Harold C. Simmons Comprehensive Cancer Center.

Keeping Up With KEYNOTE-522: Design, Population, Objectives

The prospective, randomized, placebo-controlled, phase 3 trial enrolled patients with newly diagnosed TNBC that was nonmetastatic, defined as tumor stage T1c, nodal stage N1-2, or tumor stage T2-4, nodal stage N0-2. Patients were at least 18 years of age and had an ECOG performance status of either 0 or 1. They were required to have tissue sample available for PD-L1 evaluation.

Study participants were randomly assigned 2:1 to the pembrolizumab or placebo arm. In the neoadjuvant setting, patients received pembrolizumab at 200 mg or placebo once every 3 weeks for 4 cycles plus paclitaxel at 80 mg/m2 once weekly plus carboplatin at area under the curve of 5 mg/mL per minute once every 3 weeks or 1.5 mg/mL per minute once weekly in the first 12 weeks. The second neoadjuvant treatment cycle consisted of pembrolizumab or placebo for 4 additional cycles plus doxorubicin at 60 mg/m2 or epirubicin at 90 mg/m2 plus cyclophosphamide at 600 mg/m2 once every 3 weeks for 12 weeks. Those who completed or discontinued the first neoadjuvant cycle were permitted to begin the second neoadjuvant cycle or undergo surgery. In the adjuvant setting, patients were given pembrolizumab or placebo once every 3 weeks for up to 9 cycles. Radiation was also allowed in the adjuvant setting.

Stratification factors included nodal status (positive vs negative), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (once weekly vs once every 3 weeks).

The dual primary end points of the study were pCR rate and event-free survival (EFS) in the ITT population. Secondary end points comprised pCR and EFS in patients with PD-L1 positivity, and OS in the ITT population.

Examining Prior Efficacy Data

Data from the interim analysis of the trial, which had a median follow-up of 15.5 months (range, 2.7-25.0), showed that neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab, significantly improved pCR vs neoadjuvant chemotherapy alone (64.8% [95% CI, 59.9%-69.5%] vs 51.2% [95% CI, 44.1%-58.3%]; difference of 13.6 percentage points).2

At the fourth interim analysis, which had a median follow-up of 39.1 months, the who received pembrolizumab were also found to have experienced a significant improvement in EFS vs those who received neoadjuvant chemotherapy alone (HR, 0.63; 95% CI, 0.48-0.82; P < .001).3 The estimated 36-month EFS rates in the respective arms were 84.5% (95% CI, 81.7%-86.9%) and 76.8% (95% CI, 72.2%-80.7%).

Based on the data from KEYNOTE-522, the pembrolizumab regimen was approved by the FDA in July 2021 for this population.4

Additionally, at the time of the alpha-controlled prespecified analysis of OS, which had a median follow-up of 75.1 months (range, 65.9-84.0), the HR was found to favor the pembrolizumab regimen over the placebo regimen (HR, 0.66; 95% CI, 0.50-0.87; P = .0015); this was noted to cross the prespecified significance boundary of 0.00503.5

Spotlighting the Seventh Efficacy Interim Analysis

For the analyses shared during MBCC, investigators evaluated OS in key prespecified subgroups, including RCB categories, PD-L1 CPS, overall disease stage, and nodal status.1 They also performed a post-hoc analysis of OS in those with T2N0 disease at baseline.

A total of 1174 patients were enrolled, with 784 randomized to the pembrolizumab arm and 390 randomized to the placebo arm. In the pembrolizumab arm, 50.1% of patients had a PD-L1 CPS of 10 or higher, 57.3% received carboplatin once weekly vs once every 3 weeks, 74.0% had a tumor size of T1 or T2, 51.7% had nodal positivity, and 75.3% had an overall disease stage of II. In the placebo arm, 53.6% of patients had a PD-L1 CPS under 10, 57.2% received carboplatin on a once weekly schedule, 74.4% had a tumor size of T1 or T2, 51.3% had positive nodal involvement, and 74.6% had an overall disease stage of II.

RCB data were missing for 33 patients in the pembrolizumab arm and 21 patients in the placebo arm. At the time of definitive surgery, 63.5% of patients in the investigative arm had RCB-0 vs 56.2% of those in the placebo arm; 8.8% vs 11.5% had RCB-1; 18.4% vs 20.3% had RCB-2; and 5.1% vs 6.7% had RCB-3.

“The addition of pembrolizumab resulted in fewer OS events in the RCB-0 and RCB-2 categories,” the study authors wrote. “The most pronounced benefit for OS was observed in the RCB-2 category. The low numbers of participants and events observed in the RCB-1 and RCB-3 categories make it difficult to draw conclusions about these subgroups.”

The study authors concluded that the data from the subgroup analyses provide further support for neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab following surgery as a standard-of-care treatment regimen in this patient population.

References

1. McArthur H, Fasching PA, Dent R, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk, early-stage triple-negative breast cancer: Overall survival and subgroup results from the phase 3 KEYNOTE-522 study. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida. Poster 46.
2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
3. Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651
4. FDA approves KEYTRUDA (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as single agent as adjuvant treatment after surgery. News release. Merck. July 27, 2021. Accessed March 7, 2025. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/
5. Schmid P, Cortes J, Dent R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. N Engl J Med. 2024;391(21):1981-1991. doi:10.1056/NEJMoa2409932