Results from the Phase 3 KEYNOTE-522 trial published online first in the February 27, 2022 edition of the New England Journal of Medicine (NEJM) showed that neoadjuvant pembrolizumab (Keytruda®; Merck & Co./MSD), an anti-PD-1 therapy, in combination with chemotherapy followed by adjuvant pembrolizumab as monotherapy (known as the Keytruda regimen), significantly prolonged event-free survival (EFS) compared with neoadjuvant chemotherapy followed by adjuvant placebo (the chemotherapy-placebo regimen) in patients with high-risk early-stage triple-negative breast cancer or TNBC.[1]

Pembrolizumab (Keytruda®; Merck & Co./MSD) 100mg/4mL Vial and Carton.

Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some breast cancers may test positive for estrogen receptors, progesterone receptors, or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three.

Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. Triple-negative breast cancer tends to be more common in people who are younger than 40 years of age, who are African American, or who have a BRCA1 mutation.

TNBC cancer differs from other types of invasive breast cancer. They generally grow and metastasize faster, have limited treatment options, and have, overall, a worse prognosis.

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Treatment
Pembrolizumab is an anti-PD-1 therapy. The drug is indicated for the treatment of patients diagnosed with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery. In addition, pembrolizumab, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

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Programmed cell death 1 receptor, also known as PD-1, is a cell surface molecule that regulates the adaptive immune response.

Together with its ligand, programmed cell death ligand 1, also known as PD-L1, they are immune checkpoint proteins. Found on the surface of T-cells, PD-1 is a type of protein that acts as an “off switch” that helps keep the T-cells from attacking other cells in the body. Under normal conditions, their interaction results in T-cell immune suppression. Cancer cells can hijack this pathway, and, as a result, escape immune detection. However, this process can be reversed by blocking PD-1’s interaction with PD-L1.  This inhibits T-cell proliferation, cytokine production, and cytolytic function.

In simple terms, when PD-1 binds to PD-L1, it basically tells the T-cell to leave the other cell alone. Because some types of cancer cells have large amounts of PD-L1, they can hide from an immune attack. Antibodies – such as the anti-PD-1 drug pembrolizumab that target can block the binding between PD-1 and PD-L1 and boost the immune response against cancer cells.

Previous studies
Previous studies have demonstrated promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with TNBC.

Results from one earlier study showed that after a median follow-up of 39 months, the pembrolizumab regimen reduced the risk of events or death by 37% (HR=0.63 [95% CI, 0.48-0.82]; p<0.001) versus the chemotherapy-placebo regimen. A total of 15.7% (n= 123/784) of patients who received the pembrolizumab regimen had an EFS event compared to 23.8% (n= 93/390) of patients who received the chemotherapy-placebo regimen. These results also showed that the estimated three-year EFS rates were 84.5% (95% CI, 81.7-86.9) in the pembrolizumab group compared with 76.8% (95% CI, 72.2-80.7) in the chemotherapy-placebo group. Event-free survival was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary malignancy, or death from any cause.[1]

The safety profile of the pembrolizumab regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified. Additional detailed efficacy and safety data are also featured in the publication.

Pembrolizumab in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery is approved in the U.S. for the treatment of patients with high-risk early-stage TNBC. Additional global regulatory submissions are ongoing.

“These data, which supported the U.S. Food and Drug Administration’s (FDA) approval and updates to the National Comprehensive Cancer Network® (NCCN®) guidelines, establish that pembrolizumab plus chemotherapy as neoadjuvant therapy followed by adjuvant pembrolizumab could change clinical practice for the treatment of patients with high-risk early-stage TNBC,” noted Professor Peter Schmid, FRCP, MD, Ph.D., lead, Centre for Experimental Cancer Medicine, Director, Barts Cancer Institute in London, England.

“KEYNOTE-522 is the first prospective randomized Phase 3 trial to show an improvement in event-free survival among patients with stage II and stage III TNBC,” Schmid added.

“The study of pembrolizumab in earlier disease states has long been a critical aspect of our clinical program,” Roy Baynes, MD, Ph.D. senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories.

“We are incredibly proud that the New England Journal of Medicine has chosen to publish data from this pivotal neoadjuvant/adjuvant trial of pembrolizumab in high-risk early-stage TNBC for the second time,” Baynes added.

“Results from KEYNOTE-522, in which the pembrolizumab regimen showed a significant 37% reduction in the risk of EFS events compared to neoadjuvant chemotherapy, represent an important advance and support earlier intervention with pembrolizumab in these patients,” he continued.

Study Design
KEYNOTE-522 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488). The dual primary endpoints are pathological complete response (pCR), defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and EFS, defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause in all patients randomized. Secondary endpoints include pCR rate using alternative definitions, overall survival (OS) in all patients randomized, pCR rate according to all definitions, EFS and OS in patients whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1), safety and health-related quality of life assessments. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

  • Pembrolizumab (every three weeks) plus paclitaxel (weekly) and carboplatin (weekly or every three weeks) for four cycles, followed by pembrolizumab plus cyclophosphamide and either doxorubicin or epirubicin (every three weeks) for four cycles as neoadjuvant therapy prior to surgery, followed by nine cycles of pembrolizumab (every three weeks) as adjuvant therapy post-surgery (n=784); or
  • Placebo (every three weeks) plus paclitaxel (weekly) and carboplatin (weekly or every three weeks) for four cycles, followed by placebo plus cyclophosphamide and either doxorubicin or epirubicin (every three weeks) for four cycles as neoadjuvant therapy prior to surgery, followed by nine cycles of placebo (every three weeks) as adjuvant therapy post-surgery (n=390).

KEYNOTE-522 Study Results
The KEYNOTE-522 study met the success criterion for the dual primary endpoint of pCR at the first interim analysis; pCR was observed in 64.8% of patients who received pembrolizumab plus chemotherapy (n=260/401), an increase of 13.6% (p=0.00055) from 51.2% in patients who received placebo plus chemotherapy (n=103/201). At the fourth interim analysis, KEYNOTE-522 met the success criterion for the dual primary endpoint of EFS. The trial also evaluated OS, a key secondary endpoint.

Although the OS data did not cross the boundary for statistical significance at the fourth interim analysis, there was a 28% reduction in the risk of death with the pembrolizumab regimen versus the chemotherapy-placebo regimen (HR=0.72 [95% CI, 0.51-1.02]). The study is continuing to allow for additional follow-up of OS.

For the combined neoadjuvant and adjuvant phases, treatment-related adverse events Grade 3 or higher occurred in 77.1% of patients receiving the pembrolizumab regimen (n=783) and in 73.3% of patients receiving the chemotherapy-placebo regimen (n=389). Treatment-related adverse events led to death in 0.5% of patients receiving the pembrolizumab regimen (n=4) and 0.3% of patients receiving the chemotherapy-placebo regimen (n=1). No new safety concerns were identified.

Adverse events
Immune-mediated adverse events (AEs) of any grade occurred in 33.5% of patients receiving the pembrolizumab regimen and 11.3% of patients receiving the chemotherapy-placebo regimen. A higher incidence of endocrine disorders was observed with the pembrolizumab regimen as compared to the chemotherapy-placebo regimen. Immune-mediated AEs led to death in 0.3% of patients receiving the pembrolizumab regimen (n=2) and no patients receiving the chemotherapy-placebo regimen. Most immune-mediated AEs occurred during the neoadjuvant phase rather than the adjuvant phase.

Clinical trials
Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple-Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522) – NCT03036488

Highlights of Prescribing information
Pembrolizumab (Keytruda®; Merck & Co./MSD)(Prescribing Information)

Reference
Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O’Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549. PMID: 32101663.

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