by Eric P Winer, Oleg Lipatov, Seock-Ah Im, Anthony
Goncalves, Eva Muñoz-Couselo, Keun Seok Lee, Peter Schmid, Kenji Tamura, Laura
Testa, Isabell Witzel, Shoichiro Ohtani, Nicholas Turner, Stefania Zambelli,
Nadia Harbeck, Fabrice Andre, Rebecca Dent, Xuan Zhou, Vassiliki Karantza,
Jaime Mejia, Javier Cortes, KEYNOTE-119 investigators
The Lancet Oncology: VOLUME
22, ISSUE 4, P499-511, APRIL 01, 2021
Background
Pembrolizumab showed durable antitumour activity and
manageable safety in metastatic triple-negative breast cancer in the single-arm
KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab
with chemotherapy for second-line or third-line treatment of patients with
metastatic triple-negative breast cancer.
Methods
KEYNOTE-119 was a randomised, open-label, phase 3 trial done
at 150 medical centres (academic medical centres, community cancer centres, and
community hospitals) in 31 countries. Patients aged 18 years or older, with
centrally confirmed metastatic triple-negative breast cancer, Eastern
Cooperative Oncology Group performance status of 0 or 1, who had received one
or two previous systemic treatments for metastatic disease, had progression on
their most recent therapy, and had previous treatment with an anthracycline or
taxane were eligible. Patients were randomly assigned (1:1) using a block
method (block size of four) and an interactive voice-response system with
integrated web-response to receive intravenous pembrolizumab 200 mg once every
3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per
investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine
(60% enrolment cap for each; chemotherapy group). Randomisation was stratified
by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative
[CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus
de-novo metastatic disease at initial diagnosis. Primary endpoints were overall
survival in participants with a PD-L1 combined positive score (CPS) of 10 or
more, those with a CPS of 1 or more, and all participants; superiority of
pembrolizumab versus chemotherapy was tested in all participants only if shown
in those with a CPS of one or more. The primary endpoint was analysed in the
intention-to-treat population; safety was analysed in the
all-subjects-as-treated population. This Article describes the final analysis
of the trial, which is now completed. This trial is registered with ClinicalTrials.gov,
number NCT02555657.
Findings
From Nov 25, 2015, to April 11, 2017, 1098 participants were
assessed for eligibility and 622 (57%) were randomly assigned to receive either
pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up
was 31·4 months (IQR 27·8–34·4) for the pembrolizumab group and 31·5 months
(27·8–34·6) for the chemotherapy group. Median overall survival in patients
with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9–16·3) for the
pembrolizumab group and 11·6 months (8·3–13·7) for the chemotherapy group
(hazard ratio [HR] 0·78 [95% CI 0·57–1·06]; log-rank p=0·057). In participants
with a CPS of 1 or more, median overall survival was 10·7 months (9·3–12·5) for
the pembrolizumab group and 10·2 months (7·9–12·6) for the chemotherapy group
(HR 0·86 [95% CI 0·69–1·06]; log-rank p=0·073). In the overall population,
median overall survival was 9·9 months (95% CI 8·3–11·4) for the pembrolizumab
group and 10·8 months (9·1–12·6) for the chemotherapy group (HR 0·97 [95% CI
0·82–1·15]). The most common grade 3–4 treatment-related adverse events were
anaemia (three [1%] patients in the pembrolizumab group vs ten [3%]
in the chemotherapy group), decreased white blood cells (one [<1%] vs 14
[5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and
neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab
group and 58 (20%) patients in the chemotherapy group had serious adverse
events. Three (<1%) of 601 participants had treatment-related adverse events
that led to death (one [<1%] in the pembrolizumab group due to circulatory
collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia
and sepsis and one [<1%] haemothorax).
Interpretation
Pembrolizumab did not significantly improve overall survival
in patients with previously treated metastatic triple-negative breast cancer
versus chemotherapy. These findings might inform future research of
pembrolizumab monotherapy for selected subpopulations of patients, specifically
those with PD-L1-enriched tumours, and inform a combinatorial approach for the
treatment of patients with metastatic triple-negative breast cancer.
