Neoadjuvant and Adjuvant Pembrolizumab Extends Survival in Early-Stage TNBC

Peter Schmid, MD, PhD

Results from the phase 3 KEYNOTE-522 trial (NCT03036488) in patients with early-stage triple-negative breast cancer (TNBC) showed that neoadjuvant pembrolizumab (Keytruda) plus chemotherapy, followed by adjuvant pembrolizumab, generated a statistically significant improvement in overall survival (OS) vs neoadjuvant chemotherapy plus placebo, followed by adjuvant placebo.¹

Findings presented at the 2024 ESMO Congress showed that the perioperative pembrolizumab regimen reduced the risk of death by 34% compared with the placebo regimen (HR, 0.66; 95% CI, 0.50-0.87; P = .00150). At a median follow-up of 75.1 months, patients treated in the pembrolizumab arm (n = 784) achieved a 5-year OS of rate of 86.6% (95% CI, 84.0%-88.8%) vs 81.7% (95% CI, 77.5%-85.2%) for those in the placebo arm (n = 390). The OS event rates were 14.7% and 21.8% for the pembrolizumab and placebo arms, respectively.

“[KEYNOTE-522] was a positive trial for its 2 primary end points—short-term pathological complete response [(pCR) rate] and event-free survival [EFS]—and most importantly, [data] demonstrated that [the pembrolizumab regimen] reduced the risk of death by 34%,” lead study author Peter Schmid, MD, PhD, of Barts Cancer Institute at Queen Mary University in London, United Kingdom, said in a press briefing at the ESMO Congress.

Previously reported data from the first interim analysis of KEYNOTE-522 at a median follow-up of 15.5 months showed that patients in the pembrolizumab arm achieved a pathological complete response (pCR) rate of 64.8% (95% CI, 59.9%-69.5%) compared with 51.2% (95% CI, 44.1%-58.3%) those in the placebo arm (estimated difference, 13.6%; 95% CI, 5.4%-21.8%; P < .001).²

Additionally, prior data from the fourth interim analysis demonstrated that the pembrolizumab regimen led to a significant improvement in event-free survival (EFS) vs the placebo regimen (HR, 0.63; 95% CI, 0.48-0.82; P < .001). The 36-month EFS rate was 84.5% (95% CI, 81.7%-86.9%) in the pembrolizumab group vs 76.8% (95% CI, 72.2%-80.7%) in the placebo group.³

In July 2021, the FDA approved pembrolizumab in combination with chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery, for the treatment of patients with high-risk, early-stage TNBC based on prior data from KEYNOTE-522.⁴

KEYNOTE-522 Overview

The randomized, double-blind trial enrolled patients at least 18 years of age with centrally confirmed TNBC in all foci. Patients needed to have newly diagnosed, previously untreated, nonmetastatic disease, defined as tumor stage T1c, nodal stage N1-2, or tumor stage T2-4, nodal stage N0-2. An ECOG performance status of 0 or 1 and adequate organ function. Notably, those with bilateral or multifocal primary tumors and inflammatory breast cancers were allowed to participate.²

Patients were randomly assigned 2:1 to the pembrolizumab vs placebo arms. 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 allowed to start the second neoadjuvant cycle or undergo surgery. In the adjuvant setting, patients received pembrolizumab or placebo once every 3 weeks for up to 9 cycles. Radiation was also permitted in the adjuvant setting.

The trial’s dual primary end points were pCR rate and EFS in the intention-to-treat population. Secondary end points included pCR and EFS in patients with PD-L1–positive tumors, and OS among all patients and those with PD-L1–positive tumors.

Additional Efficacy Data Presented at ESMO

Updated efficacy analysis showed that the pembrolizumab regimen maintained a significant improvement in EFS vs the placebo regimen in the overall population (HR, 0.65; 95% CI, 0.51-0.83). The 5-year EFS rates were 81.2% for the pembrolizumab arm vs 72.2% for the placebo arm. EFS events were reported in 20.3% of patients in the experimental arm vs 29.2% of patients in the control arm.¹

Patients who achieved a pCR on the study also experienced an OS benefit, irrespective of treatment arm. For responders, the 5-year OS rate was 95.1% for the pembrolizumab arm (n = 495) vs 94.4% for the placebo arm (n = 217; HR, 0.69; 95% CI, 0.38-1.26). In non-responders, the 5-year OS rate was 71.8% for the pembrolizumab arm (n = 289) vs 65.7% for the placebo arm (n = 173; HR, 0.76; 95% CI, 0.56-1.05).

REFERENCES:

1. Schmid P, Cortes J, Dent R, 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 III KEYNOTE-522 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA4.

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 pembrolizumab for high-risk early-stage triple-negative breast cancer. FDA. July 26, 2021. Accessed September 15, 2024. https://tinyurl.com/323cu7jh