Clinical trialPhase 3Breast cancer

Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer

N Engl J Med · 2022847 patients (566 in the pembrolizumab–chemotherapy group and 281 in the placebo–chemotherapy group)

Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al. N Engl J Med. 2022. 387:217-226

Study type: Clinical trial
Study name: KEYNOTE-355
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (2:1 ratio) — final overall survival analysis
Sample size: 847 patients (566 in the pembrolizumab–chemotherapy group and 281 in the placebo–chemotherapy group)
Source: N Engl J Med · 2022
Trial registration: NCT02819518

In plain words

In this study, patients with advanced or metastatic triple-negative breast cancer who had not yet had treatment for this stage received chemotherapy together with the immunotherapy drug pembrolizumab or with a placebo (dummy drug). In patients whose tumour had a lot of PD-L1 (a CPS score of ten or more), adding pembrolizumab increased the median length of life from about 16 to 23 months. This is why testing the tumour sample for PD-L1 matters for these patients. Decisions about treatment should be made with your own doctor.

Key results

23.0 months vs 16.1 months

Median overall survival (CPS ≥10)

HR for death 0.73 (0.55–0.95); two-sided P 0.0185; significance criterion met

17.6 months vs 16.0 months

Median overall survival (CPS ≥1)

HR 0.86 (0.72–1.04); P=0.1125; not significant

17.2 months vs 15.5 months

Median overall survival (intention-to-treat)

HR 0.89 (0.76–1.05); significance not tested

68.1% vs 66.9%

Treatment-related grade 3 to 5 adverse events

Treatment-related deaths 0.4% vs none

Drugs in this study:Carboplatin (Paraplatin)Gemcitabine (Gemzar)Paclitaxel (Taxol)Pembrolizumab (Keytruda)

Dose and schedule cards

Pembrolizumab + chemotherapy (KEYNOTE-355)

Recurrent unresectable or metastatic TNBC with PD-L1 CPS ≥10 (22C3), no prior chemotherapy for metastatic diseaseEach drug’s schedule in the tableOn the page “Breast cancer” · Advanced triple-negative disease or disease with a germline BRCA mutation

Recurrent unresectable or metastatic TNBC with PD-L1 CPS ≥10 (22C3), no prior chemotherapy for metastatic disease

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks (or 400 mg every 6 weeks)	IV, before chemotherapy	Day 1
Chemotherapy: one of three
Paclitaxel	90 mg/m²	IV	Days 1, 8 and 15 every 28 days
Nab-paclitaxel	100 mg/m²	IV	Days 1, 8 and 15 every 28 days
Gemcitabine + carboplatin	1000 mg/m² + AUC 2	IV	Days 1 and 8 every 21 days

Cycle schedule: Pembrolizumab every 21 days; chemotherapy on its own schedule
Duration: Pembrolizumab until progression, unacceptable toxicity or a maximum of 24 months

With CPS between 1 and 10, the overall survival benefit was not significant.

On the page “Breast cancer” · Advanced triple-negative disease or disease with a germline BRCA mutation

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 plus chemotherapy

Pembrolizumab 200 mg IV on day 1 every 3 weeks with chemotherapy of investigator's choice: nab-paclitaxel 100 mg/m² on days 1, 8 and 15 every 28 days; or paclitaxel 90 mg/m² on days 1, 8 and 15 every 28 days; or gemcitabine 1000 mg/m² + carboplatin AUC 2 on days 1 and 8 every 21 days. Pembrolizumab until progression, unacceptable toxicity or a maximum of 24 months (per the label).

2Placebo plus chemotherapy

Placebo on day 1 every 3 weeks with the same chemotherapy regimens and doses.

Source of the regimen details: FDA label for Keytruda (DailyMed, section 14.20, KEYNOTE-355) 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 locally recurrent inoperable or metastatic triple-negative breast cancer who had not previously been treated for advanced disease.

Endpoints

Primary endpoints: progression-free survival (reported previously) and overall survival in patients with a PD-L1 combined positive score (CPS) of 10 or more, CPS 1 or more, and in the intention-to-treat population. Safety was also assessed.

Safety and side effects

Treatment-related grade 3, 4 or 5 adverse events occurred in 68.1% of the pembrolizumab–chemotherapy group and 66.9% of the placebo–chemotherapy group; deaths in 0.4% of the pembrolizumab group and in no patients in the placebo group.

Clinical significance and place in guidelines

KEYNOTE-355 is the basis for using pembrolizumab with chemotherapy (paclitaxel, nab-paclitaxel or gemcitabine–carboplatin) in first-line advanced triple-negative breast cancer with PD-L1 CPS ≥10; with CPS between 1 and 10 the overall survival benefit was not significant.

Limitations

The overall survival benefit was significant only in the CPS ≥10 subgroup. Details of chemotherapy doses and adverse events are given in the full text of the paper.

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.