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The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab alone after surgery for adult patients with locally advanced or early-stage triple-negative breast cancer who are at a high risk for recurrence.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of neoadjuvant pembrolizumab (Keytruda) plus chemotherapy, followed by adjuvant pembrolizumab alone after surgery for adult patients with locally advanced or early-stage triple-negative breast cancer (TNBC) who are at a high risk for recurrence.1
The recommendation from the committee stems from positive findings from the phase 3 KEYNOTE-522 trial (NCT03036488). At a median follow-up of 39 months, adjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab resulted in a 37% reduction in the risk of events or death compared with neoadjuvant chemotherapy followed by adjuvant placebo (hazard ratio [HR], 0.63; 95% CI, 0.48-0.82; P < .001).2 The estimated 36-month EFS rate was 84.5% (95% CI, 81.7%-86.9%) in the investigative arm vs 76.8% (95% CI, 72.2%-80.7%) in the control arm. The median EFS was not yet reached in either arm.
“This positive CHMP opinion reinforces our efforts to advance the treatment of breast cancer in Europe and expand the use of [pembrolizumab] in TNBC to potentially help even more patients with this aggressive disease who are in need of new treatment options,” Gursel Aktan, MD, vice president of global clinical development at Merck Research Laboratories, stated in a press release. “We look forward to the European Commission’s decision and are excited about the prospect of bringing the first immunotherapy regimen for high-risk, early-stage TNBC to appropriate patients in Europe.”
KEYNOTE-522 enrolled patients with newly diagnosed, previously untreated, nonmetastatic TNBC who had an ECOG performance status of 0 or 1 and acceptable organ function.
Study participants were randomized 2:1 to receive neoadjuvant therapy with 200 mg doses of pembrolizumab (n = 784) or placebo (n = 390) every 3 weeks. All patients received 4 cycles of neoadjuvant paclitaxel at 80 mg/m2 and carboplatin at area under the curve 5, followed by 4 cycles of doxorubicin at 60 mg/m2 or epirubicin at 90 mg/m2 plus cyclophosphamide at 600 mg/m2. After surgery, adjuvant pembrolizumab or placebo was continued for up to 9 cycles or until patients experienced disease recurrence or unacceptable toxicity.
The primary end points of the trial were pathological complete response (pCR) and EFS, defined by the time from randomization to the date of disease progression that precluded surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also evaluated.
Additional data published in the New England Journal of Medicine showed that the EFS benefit achieved with adjuvant pembrolizumab/chemotherapy followed by neoadjuvant pembrolizumab was mostly consistent across all prespecified subsets.
Moreover, in an analysis of distant progression-free or distant recurrence-free survival demonstrated a HR of 0.61 for distant progression, distant recurrence, or death in the pembrolizumab/chemotherapy arm vs the placebo/chemotherapy arm (95% CI, 0.46-0.82).
Although overall survival (OS) data were immature, 10.2% of patients in the investigative arm and 14.1% of those on the control arm died (HR, 0.72; 95% CI, 0.51-1.02). The estimated 36-months OS rate was 89.7% (95% CI, 87.3%-91.7%) in the pembrolizumab/chemotherapy arm vs 86.9% (95% CI, 83.0%-89.9%) in the placebo/chemotherapy arm. The median OS had not yet been reached in either treatment arm.
Prior data presented during the 2019 ESMO Congress demonstrated that patients treated in the pembrolizumab arm experienced a pCR rate of 64.8% compared with 51.2% in the placebo arm (P = .00055).3 Additionally, in a subgroup of 498 patients with PD-L–positive disease, defined as a combined positive score (CPS) of 1 or greater, pembrolizumab elicited a pCR rate of 68.9% vs 54.9% with placebo. In 97 patients with PD-L1–negative disease, defined as a CPS of less than 1, the pCR rate in the pembrolizumab arm was 45.3% compared with 30.3% in the placebo arm.
Updated safety data showed that 99.2% of patients in the pembrolizumab arm experienced at least 1 adverse effect (AE) of any grade (n = 783) compared with 100% of patients in the placebo arm (n = 389).2 Grade 3 or higher AEs were reported in 82.4% and 78.7% of patients in the pembrolizumab and placebo arms, respectively.
Treatment-related AEs (TRAEs) of any grade were observed in 98.9% and 99.7% of patients in the experimental and control arms, respectively. Notably, 77.1% of patients in the pembrolizumab arm reported grade 3 or higher TRAEs vs 73.3% of those in the placebo arm.
Common TRAEs of any grade included nausea (63.2% and 63.0% in the pembrolizumab and placebo arms, respectively), alopecia (60.2% and 56.6%), anemia (54.8% and 55.3%), neutropenia (46.9% and 47.6%), fatigue (42.1% and 38.8%), diarrhea (30.4% and 25.2%), and increased alanine aminotransferase (26.1% and 25.2%).
Discontinuation of treatment due to TRAEs occurred in 27.7% of patients in the pembrolizumab arm vs 14.1% of those in the placebo arm.
Immune-related AEs of any grade occurred in 33.5% of patients in the pembrolizumab arm compared with 11.3% of those in the placebo arm. Grade 3 or higher IRAEs were reported in 12.9% and 1.0% of patients in the pembrolizumab and placebo arms, respectively.
Previously, in July 2021, the FDA approved adjuvant pembrolizumab plus chemotherapy, followed by single-agent pembrolizumab after surgery for the treatment of patients with high-risk, early-stage TNBC. The regulatory decision was supported by findings from KEYNOTE-522.4
The CHMP recommendation will now be reviewed by the European Commission for marketing authorization in the European Union, and a final decision is expected in the second quarter of 2022.