NEJM again | KEYNOTE-522 study's fourth interim analysis results announced, pembrolizumab may open up a new situation in early TNBC treatment

Foreword On February 10, 2022, NEJM published the results of the fourth interim analysis of KEYNOTE-522, a Phase III clinical trial of pembrolizumab in the neoadjuvant treatment of early-stage triple-negative breast cancer (TNBC), reporting one of the primary endpoints.
For a 3-year event-free survival (EFS) rate, the EFS rate of pembrolizumab + chemotherapy (84.
5%) was significantly better than that of placebo + chemotherapy (76.
8%)
.

Study Background The KEYNOTE-522 study is a randomized, double-blind, placebo-controlled, phase III clinical trial comparing neoadjuvant chemotherapy plus pembrolizumab (postoperative adjuvant pembrolizumab) in patients with early-stage TNBC.
Efficacy and safety of neoadjuvant chemotherapy alone (with placebo adjuvant therapy after surgery)
.

Early results published in NEJM in 2020 showed that neoadjuvant chemotherapy combined with pembrolizumab improved pathological complete response rates
.

Three-year follow-up results and updated safety data for one of the primary study endpoints, EFS, are reported
.

Methods Patients The study enrolled untreated TNBC patients with T1cN1-2 or T2-4N0-2, ECOG score 0-1, and good organ function, who were randomly assigned to pembrolizumab in a 2:1 ratio.
+ chemotherapy group or placebo + chemotherapy group
.

Before randomization, patients were stratified by nodal status (+ or -), tumor size (T1/T2 or T3/T4), and frequency of carboplatin dosing (q1W or q3W)
.

Study Design Figure 1.
Trial Design [2] During the neoadjuvant phase, patients received pembrolizumab (200 mg) (pembrolizumab + chemotherapy group) or placebo (placebo + chemotherapy group) by intravenous infusion ( q3W), combined with paclitaxel (80mg/m2, q1W, 4 cycles) and carboplatin (AUC 5, q3W, or AUC 1.
5, q1W, 4 cycles), followed by doxorubicin (60mg/m2, q3W, 4 cycles) ) or epirubicin (90mg/m2, q3W, 4 cycles) and cyclophosphamide (600mg/m2, q3W, 4 cycles)
.

Patients underwent surgery 3-6 weeks after neoadjuvant therapy, including breast-conserving surgery or mastectomy with sentinel lymph node biopsy or axillary lymph node dissection
.

During the adjuvant treatment phase, patients received radiotherapy and intravenous infusion (q3W, 9 cycles) of pembrolizumab (200 mg) (pembrolizumab + chemotherapy group) or placebo (placebo + chemotherapy group)
.

Adjuvant pembrolizumab or placebo can be started at the same time as radiotherapy or two weeks after the end of radiotherapy
.

Adjunctive therapy with capecitabine was not permitted
.

The primary endpoints of the study were pathological complete response rate (pCR, ypT0/Tis ypN0) and EFS, and events were defined as disease progression preventing radical surgery, local or distant recurrence, second primary malignancy, and death from any cause
.

Secondary endpoints included overall survival (OS) rate in all patients and PD-L1-positive patients, EFS in PD-L1-positive patients, and pCR rate in all patients and PD-L1-positive patients
.

The exploratory study endpoint was distant progression-free or distant recurrence-free survival
.

All patients who received at least one investigational drug or underwent surgery were evaluated for safety
.

RESULTS: A total of 1174 patients were included in the study (784 in the pembrolizumab+chemotherapy group vs 390 in the placebo+chemotherapy group)
.

The fourth interim analysis (data cutoff, March 23, 2021) had a median follow-up of 39.
1 months (30.
0-48.
0)
.

Events occurred in 123 patients (15.
7%) in the pembrolizumab+chemotherapy group and 93 patients (23.
8%) in the placebo+chemotherapy group (HR 0.
63; 95% CI, 0.
48-0.
82; P<0.
001) (Fig.
2)
.

EFS was significantly improved in the pembrolizumab+chemotherapy group compared with the placebo+chemotherapy group according to prespecified statistical criteria (alpha level of 0.
01034)
.

The 36-month EFS rate was 84.
5% (95%CI, 81.
7-86.
9) in the pembrolizumab+chemotherapy group and 76.
8% (95%CI, 72.
2-80.
7) in the placebo+chemotherapy group.
Not reached
.

Figure 2.
EFS (Intention-to-Treat Population) The most common event in the EFS analysis was distant recurrence, which occurred in 60 patients (7.
7%) in the pembrolizumab+chemotherapy group and 51 (13.
1%) in the placebo+chemotherapy group.
%) (Table 1)
.

Table 1 Summary of the first events in the EFS analysis The OS rate data for this interim analysis are immature
.

Eighty patients (10.
2%) in the pembrolizumab+chemo arm and 55 (14.
1%) in the placebo+chemo arm died (HR 0.
72; 95% CI, 0.
51-1.
02) (Figure 3)
.

The 36-month OS rate was 89.
7% (95%CI, 87.
3-91.
7) in the pembrolizumab+chemotherapy group and 86.
9% (95%CI, 83.
0-89.
9) in the placebo-chemotherapy group; the median was not reached in either group OS
.

Figure 3.
OS (Intention-to-Treat Population) In terms of safety, during neoadjuvant and adjuvant therapy, 77.
1% of 783 patients in the pembrolizumab + chemotherapy group experienced grade ≥ 3 adverse events (AEs) related to the trial treatment , 73.
3% of 389 patients in the placebo + chemotherapy group
.

Nausea, alopecia, and anemia were the most common AEs (Table 2)
.

27.
7% of patients in the pembrolizumab+chemotherapy group and 14.
1% in the placebo+chemotherapy group discontinued the trial due to treatment-related AEs
.

Table 2 AE summary KEYNOTE-522 study This interim analysis showed that in patients with early-stage TNBC, pembrolizumab combined with neoadjuvant chemotherapy and continued use in the adjuvant phase significantly reduced the risk of EFS events by 37%, significantly The improved survival benefit has opened up a new situation for the immunotherapy of high-risk early-stage TNBC
.

References: 1.
Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Andersen J, Patt D, Danso M, Ferreira M, Mouret-Reynier MA, Im SA, Ahn JH, Gion M, Baron-Hay S, Boileau JF, Ding Y, Tryfonidis K, Aktan G, Karantza V, O'Shaughnessy J ; KEYNOTE-522 Investigators.
Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer.
N Engl J Med.
2022 Feb 10;386(6):556-567.
doi: 10.
1056/NEJMoa2112651.
PMID: 35139274.
2.
https: https://