NEJM Data Highlight Neoadjuvant Pembrolizumab Benefit in TNBC

The neoadjuvant combination of pembrolizumab plus chemotherapy led to a higher pathological complete response rate compared with placebo/chemotherapy in patients with early triple-negative breast cancer, across various patient subgroups.

Peter Schmid, MD, PhD

Peter Schmid, MD, PhD, associate professor of oncology and urology at Johns Hopkins Medicine

Peter Schmid, MD, PhD

The neoadjuvant combination of pembrolizumab (Keytruda) plus chemotherapy led to a higher pathological complete response (pCR) rate compared with placebo/chemotherapy in patients with early triple-negative breast cancer (TNBC), across various patient subgroups, according to results from the phase III KEYNOTE-522 trial published in the New England Journal of Medicine.1

Results showed that, at the first interim analysis, the pembrolizumab/chemotherapy regimen led to a pCR rate of 64.8% (95% CI, 59.9-69.5) compared with 51.2% (95% CI, 44.1-58.3) in patients who received placebo/chemotherapy (95% CI, 5.4-21.8; P <.001). Moreover, the addition of pembrolizumab to chemotherapy led to a 37% reduction in the risk of disease progression or death (HR, 0.63; 95% CI, 0.43-0.93).

“These results suggest that immune checkpoint inhibitors added to neoadjuvant chemotherapy may increase the percentage of patients with triple-negative breast cancer who have a pathological complete response,” first author Peter Schmid, MD, Barts Cancer Institute, and coinvestigators wrote.

In the phase III KEYNOTE-522 trial, patients with previously untreated stage II/III TNBC were randomized 2:1 to receive either neoadjuvant therapy with 4 cycles of 200 mg of pembrolizumab every 3 weeks plus paclitaxel and carboplatin (n = 784) or placebo every 3 weeks plus paclitaxel/carboplatin (n = 390). Both arms also received an additional 4 cycles of pembrolizumab or placebo, and doxorubicin/cyclophosphamide or epirubicin/cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to 9 cycles.

Patients were enrolled from March 2017 to September 2018. To be eligible, patients had to be ≥18 years old with centrally confirmed, newly diagnosed, previously untreated, nonmetastatic TNBC in all foci, an ECOG performance status of 0 or 1, and adequate organ function. The trial also permitted those with bilateral or multifocal primary tumors and inflammatory breast cancers.

The coprimary endpoints were pCR at the time of definitive surgery and event-free survival (EFS) in the intent-to-treat population.

Baseline characteristics were similar between arms. The median age was 48.5 years, and 88.5% of patients were <65 years old. Most patients had PD-L1—positive disease (82.5%) and 86.9% of patients had an ECOG performance status of 0.

At the second interim analysis, which was a median follow-up of 15.5 months (range, 2.7-25.0), 1167 patients received the first neoadjuvant treatment, 1095 received the second neoadjuvant treatment, 1138 had undergone surgery, and 861 patients received adjuvant treatment. The median duration of treatment was 51.1 weeks with pembrolizumab/chemotherapy arm and 54.1 weeks with placebo/chemotherapy.

At this analysis, 7.4% in the pembrolizumab/chemotherapy arm and 11.8% in the placebo/chemotherapy arm either had disease progression that prevented definitive surgery, local or distant recurrence, a second primary tumor develop, or died.

Results of the primary analysis reported activity with pembrolizumab across various subgroups, including pathological stage. Patients with ypT0/ypN0 disease had a higher pCR with pembrolizumab/chemotherapy (14.5 percentage-point difference; 95% CI, 6.2-22.7) as well as those with ypT0/Tis (14.8 percentage-point difference; 95% CI, 6.8-23.0).

Patients with positive lymph node involvement benefitted more with the combination of pembrolizumab/chemotherapy versus placebo with a 13.8-percentage point difference in pCR (5.4-21.8). Also, the improvement with pembrolizumab was seen regardless of age, but was more pronounced in patients ≥65 years old (22.3 percentage points; 95% CI, —2.1-43.5).

Those with an ECOG performance status of 0 also benefitted more from the PD-1 inhibitor and chemotherapy (16.4 percentage points; 95% CI, 7.3-25.4) compared with those an ECOG status of 1 (—2.6 percentage points; 95% CI, –22.1 to 18.9).

Additional data presented at the 2019 San Antonio Breast Cancer Symposium also showcased a clinical benefit with the addition of pembrolizumab. Specifically, a reduction in pCR with pembrolizumab was observed consistently when patients were stratified by disease stage.2

The improvement in pCR rate with the PD-1 inhibitor was seen in patients with stage IIIB disease, at 48.6% versus 23.1% in those who received placebo, representing an absolute difference of 25.6% (95% CI, -6.1% to 48.9%). Corresponding rates of pCR in patients with stage IIIA disease were 66.7% versus 42.1%, representing an absolute difference of 24.6% (95% CI, 4.3%-43.1%); in stage IIB, 56.2% versus 48.4%, for an absolute difference of 7.8% (95% CI, -7.4% to 22.8%); and for stage IIA, 73.1% versus 62.1%, for a difference of 11.0% (95% CI, -0.7 to 23.2%). Patients who were positive for lymph-node involvement were observed to have a greater pCR benefit with pembrolizumab versus placebo, at 64.8% and 44.1%, for an absolute difference of 20.6% (95% CI, 8.9%-31.9%). Patients who were negative for nodal involvement did receive benefit with the addition of pembrolizumab, but the absolute difference was 6.3% (64.9% vs 58.6%; 95% CI, -5.3% to 18.2%).

In patients with PD-L1 expression of <1 combined positive score (CPS), those on the pembrolizumab arm had a pCR rate of 45.3% versus 30.3% in the chemotherapy-alone group for an absolute difference of 18.3% (95% CI, -3.3% to 36.8%). For CPS ≥1, corresponding pCR rates were 68.9% versus 54.9% with a difference of 14.2% (95% CI, 5.3%-23.1%); in patients with CPS ≥10, rates were 77.9% versus 59.8% for a difference of 17.5% (95% CI, 6.2%-29.1%). In patients with CPS ≥20, these rates were 81.7% versus 62.5% for a difference of 18.5% (95% CI, 5.0%-32.7%).

The combination of pembrolizumab/chemotherapy was superior to chemotherapy/placebo regardless of exposure to chemotherapy. Full exposure to chemotherapy plus pembrolizumab induced a pCR of 69.7% versus 55.3% in those treated with full chemotherapy and placebo, with an absolute difference of 14.4% (95% CI, 5.1%-23.6%). In those who received less than the full chemotherapy dose, pembrolizumab induced a pCR of 51.5% versus 35.7% with placebo, for a difference of 15.4% (95% CI, -3.0%-32.1%).

At 18 months, 91.3% of patients on pembrolizumab/chemotherapy and 85.3% of those on chemotherapy/placebo were alive and without disease progression that needed surgery, were without local or distant recurrence, or without secondary primary tumor, according to Kaplan-Meier estimates.

Regarding safety, any-grade AEs in the neoadjuvant phase occurred in 99.0% of the pembrolizumab/chemotherapy arm and 99.7% of the placebo/chemotherapy arm. Grade ≥3 treatment-related AEs (TRAEs) occurred in 76.8% and 72.2% of patients, respectively. Moreover, serious TRAEs occurred in 32.5% of pembrolizumab-treated patients and 19.5% of those on placebo, the most common being febrile neutropenia (14.6% vs 12.1%, respectively), anemia (2.6% vs 2.1%), and pyrexia (2.6% vs 0.3%, respectively).

TRAEs also led to treatment discontinuation in 23.3% of the pembrolizumab/chemotherapy arm and 12.3% of the placebo/chemotherapy arm.

In the adjuvant phase, treatment-related AEs occurred in 48.1% of the pembrolizumab/chemotherapy arm (n = 547) and 43.0% of the placebo/chemotherapy arm (n = 314). The most common AE in both groups of grade ≥3 was neutropenia in 34.6% and 33.2%, respectively.

Across all phases, treatment-related grade ≥3 adverse events (AEs), across all treatment phases, were reported in 78.0% in the pembrolizumab/chemotherapy arm and 73.0% in the placebo/chemotherapy arm. Deaths were reported in 0.4% and 0.3% of patients, respectively.

“The present results are consistent with findings from previous studies of neoadjuvant pembrolizumab for the treatment of triple-negative breast cancer. In the phase Ib KEYNOTE-173 study of neoadjuvant pembrolizumab plus chemotherapy, with or without carboplatin, for locally advanced triple-negative breast cancer, the percentage of patients with a pathological complete response was 60% (90% CI, 30 to 85),” Schmid and coinvestigators wrote.


  1. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. New Eng J Med. 2020;382(9):810-821. doi: 10.1056/NEJMoa1910549.
  2. Schmid P, Park YH, Ferreira M, et al. KEYNOTE-522: phase 3 study of neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy, followed by adjuvant pembrolizumab versus placebo for early triple-negative breast cancer: pathologic complete response in key subgroups and by treatment exposure and residual cancer burden. Presented at: 2019 San Antonia Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas.
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