Clinical trialPhase 3Breast cancer

Pembrolizumab for Early Triple-Negative Breast Cancer

N Engl J Med · 20201174 patients

Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. N Engl J Med. 2020. 382:810-821

A newer report of this study has been published: Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer (2024)

Study type: Clinical trial
Study name: KEYNOTE-522
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (2:1 ratio)
Sample size: 1174 patients
Source: N Engl J Med · 2020
Trial registration: NCT03036488

In plain words

In triple-negative breast cancer (which has no hormone receptors and no HER2) with a larger tumour or affected lymph nodes, adding the immunotherapy drug pembrolizumab to chemotherapy before surgery and continuing it after surgery increased the chance that the tumour had disappeared completely by the time of surgery, and with more than 6 years of follow-up it raised the chance of being alive after 5 years from 81.7% to 86.6%.

Key results

64.8% vs 51.2%

Pathological complete response

Difference 13.6 percentage points (95% CI 5.4–21.8); P<0.001; first 602 patients

84.5% vs 76.8%

36-month event-free survival

HR 0.63 (95% CI 0.48–0.82); P<0.001; NEJM 2022

86.6% vs 81.7%

60-month overall survival

P=0.002; median follow-up 75.1 months; NEJM 2024

78.0% vs 73.0%

Treatment-related grade 3 or higher adverse events

Including deaths in 0.4% vs 0.3%

Drugs in this study:Carboplatin (Paraplatin)Cyclophosphamide (Endoxan)Doxorubicin (Adriamycin)Paclitaxel (Taxol)Pembrolizumab (Keytruda)

Dose and schedule cards

Neoadjuvant pembrolizumab + chemotherapy, then adjuvant pembrolizumab (KEYNOTE-522)

High-risk early TNBC: tumour larger than 1 cm and up to 2 cm with nodal involvement, or larger than 2 cm regardless of nodal status; independent of PD-L1; no active autoimmune disease requiring systemic treatment in the past 2 yearsCycle length: Every 21 daysOn the page “Breast cancer” · Early HER2-negative disease: chemotherapy, immunotherapy and adjuvant therapy

Drug	Dose	Route	Schedule
Neoadjuvant, cycles 1–4
Pembrolizumab	200 mg (or 400 mg every 6 weeks)	IV, 30 min; before chemotherapy	Day 1
Paclitaxel	80 mg/m²	IV	Days 1, 8 and 15
Carboplatin	AUC 5 (or AUC 1.5 weekly)	IV	Day 1 (or days 1, 8 and 15)
Neoadjuvant, cycles 5–8
Pembrolizumab	200 mg	IV	Day 1
Doxorubicin or epirubicin	60 mg/m² (epirubicin 90 mg/m²)	IV	Day 1
Cyclophosphamide	600 mg/m²	IV	Day 1
Adjuvant, after surgery
Pembrolizumab	200 mg (or 400 mg every 6 weeks)	IV	Day 1, 9 cycles

Cycle length: Every 21 days
Duration: Neoadjuvant 24 weeks (8 doses of 200 mg), then adjuvant up to 27 weeks (9 doses of 200 mg or 5 doses of 400 mg)

If the disease progresses, or unacceptable pembrolizumab-related toxicity occurs, during the neoadjuvant phase, adjuvant pembrolizumab is not given.

On the page “Breast cancer” · Early HER2-negative disease: chemotherapy, immunotherapy and adjuvant therapy

KEYNOTE-522

Early triple-negative breast cancer, before and after surgeryEach drug’s schedule in the tableOn the page “KEYNOTE-522 regimen: pembrolizumab and chemotherapy in triple-negative breast cancer”

Early triple-negative breast cancer, before and after surgery

Drug	Dose	Route	Schedule
Phase 1: 12 weeks
Pembrolizumab	200 mg	IV	Every 3 weeks
Paclitaxel	80 mg/m²	IV	Weekly
Carboplatin	AUC 5 every 3 weeks (or AUC 1.5 weekly)	IV	Day 1
Phase 2: 4 cycles
Pembrolizumab	200 mg	IV	Day 1
Doxorubicin or epirubicin	60 or 90 mg/m²	IV	Day 1
Cyclophosphamide	600 mg/m²	IV	Day 1
Phase 3: after surgery
Pembrolizumab	200 mg	IV	Every 3 weeks, 9 doses

Cycle schedule: Phase 2 every 21 days; pembrolizumab every 3 weeks in all phases
Duration: 24 weeks before surgery, then 27 weeks of pembrolizumab

Doses as in KEYNOTE-522. Pembrolizumab 400 mg every 6 weeks is an approved alternative.

Dose source:.

On the page “KEYNOTE-522 regimen: pembrolizumab and chemotherapy in triple-negative breast cancer”

KEYNOTE-522 (triple-negative breast, before and after surgery)

High-risk early triple-negative breast cancerCycle length: 21-day cyclesOn the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

High-risk early triple-negative breast cancer

Drug	Dose	Route	Schedule
Cycles 1 to 4
Pembrolizumab	200 mg	IV	Day 1 every 3 weeks
Paclitaxel	80 mg/m²	IV	Days 1, 8 and 15
Carboplatin	AUC 5 every 3 weeks or AUC 1.5 weekly	IV	Day 1 (or days 1, 8 and 15)
Cycles 5 to 8
Pembrolizumab + doxorubicin (or epirubicin) + cyclophosphamide	200 mg + 60 (or 90) + 600 mg/m²	IV	Day 1 every 3 weeks
After surgery
Pembrolizumab	200 mg	IV	Every 3 weeks

Cycle length: 21-day cycles
Duration: 8 cycles before surgery, then 9 cycles of pembrolizumab after surgery

Doses as described for the trial in the FDA label for pembrolizumab.

On the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

High-risk early triple-negative breast cancer (KEYNOTE-522)

Before and after surgeryCycle length: Every 21 daysOn the page “Pembrolizumab (Keytruda)” · Early stages: before and after surgery or with chemoradiotherapy (FDA label)

Before and after surgery

Drug	Dose	Route	Schedule
Before surgery, cycles 1 to 4
Pembrolizumab	200 mg every 3 weeks	IV infusion over 30 minutes	Day 1
Cycles 1 to 4
Paclitaxel + carboplatin	80 mg/m² weekly + AUC 5 every 3 weeks (or AUC 1.5 weekly)	IV	Days 1, 8 and 15
Cycles 5 to 8
Doxorubicin (or epirubicin) + cyclophosphamide + pembrolizumab	60 (or 90) + 600 mg/m² + 200 mg	IV	Day 1 every 3 weeks
After surgery
Pembrolizumab	200 mg every 3 weeks (or 400 every 6 weeks)	IV infusion over 30 minutes	Day 1

Cycle length: Every 21 days
Duration: 24 weeks before surgery (8 doses of 200 or 4 doses of 400), then up to 27 weeks after surgery (9 doses of 200 or 5 doses of 400)

Patients whose disease progressed on treatment before surgery, or who had unacceptable toxicity from pembrolizumab, should not receive treatment after surgery. Blood cortisol at baseline, before surgery and as needed.

On the page “Pembrolizumab (Keytruda)” · Early stages: before and after surgery or with chemoradiotherapy (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab + chemotherapy (784 patients)

Neoadjuvant, cycles 1 to 4: pembrolizumab 200 mg IV every 3 weeks + paclitaxel 80 mg/m² weekly (days 1, 8 and 15) + carboplatin AUC 5 every 3 weeks or AUC 1.5 weekly (days 1, 8 and 15).

Cycles 5 to 8: pembrolizumab 200 mg every 3 weeks + doxorubicin 60 mg/m² or epirubicin 90 mg/m² + cyclophosphamide 600 mg/m² every 3 weeks.

After surgery (adjuvant): 9 cycles of pembrolizumab 200 mg every 3 weeks.

2Placebo + chemotherapy (390 patients)

The same neoadjuvant chemotherapy with placebo, then 9 cycles of placebo after surgery.

Source of the regimen details: Abstract of the paper and the FDA label for Keytruda (Clinical Studies section, KEYNOTE-522; 2026 version)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with previously untreated stage II or III triple-negative breast cancer (TNBC) (tumour larger than 1 to 2 cm with lymph node involvement, or larger than 2 cm regardless of nodes), regardless of PD-L1 expression.

Endpoints

Dual primary endpoints: pathological complete response (pCR; no invasive cancer in the breast and negative nodes) at surgery, and event-free survival (EFS) in the intention-to-treat population. Overall survival was a key secondary endpoint.

Safety and side effects

Treatment-related grade 3 or higher adverse events across all phases occurred in 78.0% of the pembrolizumab group and 73.0% of the placebo group (deaths: 3 patients [0.4%] versus 1 patient [0.3%]). Immune-mediated adverse events (such as thyroid disorders, adrenal insufficiency and hypophysitis) need close monitoring and sometimes permanent hormone replacement.

Clinical significance and place in guidelines

KEYNOTE-522 changed the standard of care for stage II–III TNBC. The FDA approved this regimen in July 2021. The event-free survival (NEJM 2022) and overall survival (NEJM 2024) results confirmed a durable benefit. ESMO guideline (Pan-Asian adapted version 2024): cT2–4 N0 or node-positive TNBC should be treated with neoadjuvant chemotherapy plus pembrolizumab [I, A], and pembrolizumab should continue for nine adjuvant cycles regardless of pCR [I, A].

Limitations

The separate contribution of carboplatin, and whether adjuvant pembrolizumab is needed in patients with pCR, cannot be separated in this design; lasting immune adverse events (such as hypothyroidism and adrenal insufficiency) must be weighed in patients with curable disease.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.