Breast cancer

Checkpoint inhibitor scales ‘north face’ of advanced triple negative breast cancer


Pembrolizumab combined with chemotherapy prolongs survival in patients with advanced triple negative breast cancer, latest findings from the KEYNOTE-355 trial show. 

The latest findings extend a previous interim analysis published at ASCO congress in 2020 and reported by the limbic [see story here] that found that patients treated with the checkpoint inhibitor achieved four months more of progression free survival compared to the standard-of-care treated patient. 

The phase III trial randomised 847 patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer to pembrolizumab (200 mg every three weeks; n=566) plus the investigator’s choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine–carboplatin) or placebo plus chemotherapy (n=281). 

In a subgroup of patients with tumours that expressed PD-L1 with a combined positive score (CPS) of 10 or higher median overall survival was 23 months in the pembrolizumab–chemotherapy group and 16.1 months in the placebo–chemotherapy group (hazard ratio for death, 0.73; 95% CI 0.55 to 0.95). 

For those in the CPS-1 group, median OS was 17.6 months with pembrolizumab vs. 16 months with chemotherapy alone (HR = 0.86; 95% CI, 0.72-1.04). 

However, the authors noted that the significance boundary for an overall survival benefit of pembrolizumab plus chemotherapy in this subgroup was not crossed, and therefore formal testing in the intention-to-treat population was also not performed. 

Adverse events related to the trial regimen that were of grade 3 or higher occurred in 68.1% in the pembrolizumab treated group and 66.9% in the chemotherapy alone group. 

The findings of overall survival benefit according to CPS cutoffs provides further support that a CPS of 10 or more is an appropriate criterion to define the population of patients with advanced triple-negative breast cancer who would be expected to derive benefit from pembrolizumab plus chemotherapy, the researcher team noted in the paper published in the NEJM

“Our results build on findings from earlier trials involving patients with metastatic triple negative breast cancer that showed greater single agent activity with pembrolizumab and other immune checkpoint inhibitors with increasing PD-L1 expression,” they added. 

Writing in an accompanying editorial oncologist Xavier Pivot, from the Institute of Cancerology Strasbourg in Strasbourg, France said treatment for triple-negative breast cancers has always been perceived as a “north face”  – an allusion to the fact that the north face of a mountain  is usually the most formidable and challenging for mountain climbers. 

The latest results confirmed the relationship between programmed death ligand 1 (PD-L1) expression and the activity of pembrolizumab in preclinical and clinical studies, a finding that “completed the bench-to-bedside cycle”.

However, he stressed that to provide patients with the greatest access to pembrolizumab, there was a need to optimise the duration of use early in the course of disease and to anticipate the actions that will be needed to address cost. 

“This new class of immunotherapy is integral to the success of biologic agents and marks the continued improvement of breast cancer treatment. Other immunotherapies will emerge, but pembrolizumab will remain the first treatment shown to prolong overall survival, a welcome and definitive change in the treatment of a subgroup of women with advanced triple-negative breast cancer,” he concluded.

The study was funded by Merck Sharp and Dohme.

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