Clinical trialPhase 3Breast cancer

Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer

N Engl J Med · 20241174 patients (784 in the pembrolizumab–chemotherapy group and 390 in the placebo–chemotherapy group)

Schmid P, Cortes J, Dent R, McArthur H, Pusztai L, Kümmel S, et al. N Engl J Med. 2024. 391:1981-1991

Study type: Clinical trial
Study name: KEYNOTE-522
Phase: Phase 3
Design: Randomised, placebo-controlled trial (2:1 randomisation ratio) — final overall survival report
Sample size: 1174 patients (784 in the pembrolizumab–chemotherapy group and 390 in the placebo–chemotherapy group)
Source: N Engl J Med · 2024
Trial registration: NCT03036488

In plain words

In this study, women with stage 2 or 3 triple-negative breast cancer were given chemotherapy before surgery together with the immunotherapy drug pembrolizumab or with a placebo (dummy drug), and after surgery the same treatment (pembrolizumab or placebo) was continued. After about six years of follow-up, more patients were alive at 5 years in the group that received pembrolizumab (about 87% versus 82%). The side effects matched what was already known about these drugs. Decisions about treatment should be made with your own doctor.

Key results

86.6% vs 81.7% (pembrolizumab–chemotherapy vs placebo–chemotherapy)

Estimated overall survival at 60 months

P = 0.002

84.0–88.8 in the pembrolizumab–chemotherapy group; 77.5–85.2 in the placebo–chemotherapy group

95% CI of overall survival at 60 months

75.1 months (range 65.9–84.0)

Median follow-up

Data cut-off: 22 March 2024

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 group

Neoadjuvant, cycles 1 to 4 (every 3 weeks): pembrolizumab 200 mg IV day 1 + paclitaxel 80 mg/m² IV days 1, 8 and 15 + carboplatin AUC 5 day 1 (or AUC 1.5 days 1, 8 and 15). Cycles 5 to 8 (every 3 weeks): pembrolizumab 200 mg day 1 + doxorubicin 60 mg/m² (or epirubicin 90 mg/m²) + cyclophosphamide 600 mg/m² day 1. After surgery: 9 cycles of pembrolizumab 200 mg every 3 weeks. All drugs IV.

2Placebo–chemotherapy group

The same neoadjuvant chemotherapy (paclitaxel 80 mg/m² weekly + carboplatin AUC 5 every 3 weeks or AUC 1.5 weekly for 4 cycles, then doxorubicin 60 or epirubicin 90 mg/m² + cyclophosphamide 600 mg/m² every 3 weeks for 4 cycles) with placebo every 3 weeks, and after surgery 9 cycles of placebo every 3 weeks.

Source of the regimen details: FDA label for Keytruda (DailyMed, section 14.20, KEYNOTE-522) and the abstract of the paper

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 (tumour larger than 1 cm and up to 2 cm with lymph node involvement, or larger than 2 cm regardless of nodes), regardless of PD-L1 expression; active autoimmune disease requiring systemic treatment in the past 2 years or a need for immunosuppression was an exclusion criterion. Randomisation 2:1, stratified by nodal status, tumour size and carboplatin schedule (every 3 weeks or weekly).

Endpoints

Primary endpoints: pathological complete response and event-free survival. Overall survival was a secondary endpoint, and this paper reports its final results.

Safety and side effects

According to the abstract, adverse events were consistent with the known safety profiles of pembrolizumab and chemotherapy. The exact rate of grade 3 or higher adverse events is not given in the abstract.

Clinical significance and place in guidelines

This final report shows that adding pembrolizumab to chemotherapy before surgery and continuing it after surgery improves not only pathological complete response and event-free survival but also overall survival in stage 2 and 3 triple-negative breast cancer. The exact status of drug approvals and clinical guideline recommendations should be checked in up-to-date sources, as the abstract does not address them.

Limitations

Overall survival was a secondary endpoint of the trial. The abstract does not give details of adverse events (such as the rate of grade 3 or higher events), the hazard ratio or subgroup analyses; the full text of the paper should be consulted for these.

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.