KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)

Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2−negative endocrine-refractory metastatic breast cancer

“…27 The KEYNOTE-522 study was a large randomized phase III trial that demonstrated the addition of neoadjuvant and adjuvant pembrolizumab to a chemotherapy regimen of a taxane+carboplatin followed by an anthracycline+cyclophosphamide with Open access adjuvant pembrolizumab improved the pCR rate from 51.2% to 64.8%. 28 Results from the phase III IMpas-sion132 trial evaluating atezolizomib with several chemotherapies including capecitabine as first-line therapy for TN MBC will contribute to our understanding of the use of chemo-immunotherapy in metastatic TNBC. 29 For HR+ endocrine-refractory MBC, there is more limited data for chemo-immunotherapy.…”

Role of Immunotherapy in Triple-Negative Breast Cancer

“…34 The KEYNOTE-522 trial (NCT03036488) reported that pembrolizumab added to paclitaxel plus carboplatin and then to an anthracycline plus cyclophosphamide as neoadjuvant therapy, followed by surgery plus an additional 9 cycles of adjuvant pembrolizumab, improved pCR rates from 51.2% to 64.8%, and 18-month event-free survival (EFS) rates from 85.3% to 91.3% (hazard ratio [HR], 0.63; 95% CI, 0.43-0.93). 35 These results need to be confirmed with extended follow-up data and weighed against long-term immune-related toxicity. In this trial, less benefit was seen in node-negative patients, underscoring the conclusion that the risks of this 5-agent regimen may outweigh the benefits for patients with early-stage node-negative TNBC and TNBC with high TIL levels, who have excellent outcomes with current standardof-care regimens.…”

“…66 Furthermore, the utility of PD-L1 expression as a reliable biomarker is limited by several issues: its varying expression over time and metastatic sites; the discrepancy among different PD-L1 assays, particularly when staining immune cells 67 ; the observations that some PD-L1-negative patients respond to ICIs 68 ; and recent trials in the early disease setting that show little to no correlation of PD-L1 expression with benefit specific to ICIs, including the KEYNOTE-522 and NeoTRIPaPDL1 trials. 36,69 Emerging potential biomarkers of immunotherapy response in TNBC include high tumor mutational burden (TMB), TILs, and transcriptional signatures of immune infiltration. High TMB with variably defined cutoffs correlates with response to PD-1/L1 inhibitors across various cancer types, [70][71][72][73][74][75] but the prevalence of high TMB .10 mutations/Mb in breast cancer is low: 3% of primary tumors and 8% of metastatic tumors.…”

Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes

“…In the Keynote-522, the first phase III trial that demonstrated the effectiveness of anti-PD1 therapy in neoadjuvant setting, 1174 TNBC patients were randomized 2:1 to receive chemotherapy (carboplatin + paclitaxel followed by AC or EC) plus pembrolizumab or placebo followed by pembrolizumab alone or placebo after surgery. In this study, the addition of the pembrolizumab resulted in a statistically significant and clinically meaningful increase in pCR rate of 13.6% (64.8% vs. 51.2%, p = 0.00055) regardless of the PD-L1 expression status [49]. Data from the subgroup analysis presented at the last San Antonio Breast Cancer Symposium (SABCS) showed that patients with the most aggressive disease, such as stage III tumors, derived more benefit from the incorporation of the anti-PD1 to chemotherapy.…”

“…However, data from Keynote-522 and NeoTRIPaPDL1 trials [49,50] investigating the efficacy of pembrolizumab or atezolizumab in combination with conventional chemotherapy as a neoadjuvant approach revealed that PD-L1 expression significantly increased pCR rates irrespective of ICI addition. Therefore, the use of PD-L1 expression as a predictive marker of ICI efficacy remains controversial in early BC settings.…”