Already approved for metastatic melanoma, Merck & Co’s Keytruda has shown promising activity for difficult-to-treat triple-negative breast cancer.
Results of a small clinical trial, reported at the recent San Antonio Breast Cancer Conference by Rita Nanda of the University of Chicago School of Medicine, showed that patients with advanced TNBC had an 18% response rate after receiving Keytruda (pembrolizumab), despite being heavily pretreated at study entry.
“Three of the five responders remained on therapy for 48 weeks or longer,” said Dr Nanda. “This speaks to the durability of response to therapy.”
Indeed, a lasting treatment effect is one of the hallmarks of immunotherapy agents, often lasting much longer than other targeted therapies. The reason for this is that rather than engaging the tumour cell directly, Keytruda, a PD-1 checkpoint inhibitor, blocks the interaction between the cancer cell and the tumour-attacking T-cells of the patient’s immune system. Tumour cells turn the T-cell off; a checkpoint inhibitor turns them back on.
The purpose of checkpoint signalling in healthy tissue is to prevent overreaction of the immune system, such as that seen in autoimmune diseases. Tumour cells have adopted this signaling mechanism to avoid immune system surveillance.
In the current study, 32 patients with advanced TNBC were enrolled, with all patients testing positive for the PD-L1 expression prior to study entry. Of note, 58% of all TNBC patients screened for the trial had tumors that were PD-L1 positive, suggesting the broad applicability of PD-1 inhibition in the disease setting.
As stated, patients on this trial were heavily pretreated, with half the cohort having received three or more lines of treatment prior to receiving pembrolizumab.
Treatment outcomes showed that after a median follow-up of ten months, one patient had a complete response, four had partial responses, and seven were observed to have stable disease; overall, 30% of patients had a reduction in tumour burden.
“The median progression-free survival was just under two months, and the PFS rate at six months was 23%,” said Dr Nanda. Side effects were considered manageable, with the most common adverse events being arthralgia, fatigue, and myalgia and based on these results, a Phase II study for Keytruda in TNBC is planned for 2015.
Commenting on the results, Mary Disis of the University of Washington in Seattle, pointed out that TNBC was the perfect setting for a checkpoint inhibitor. “Triple negatives are the hallmark of immunogenic breast cancer tumours, and the reason people focus on this tumour sub-type is that not only is it likely to have the highest levels of TILs (tumour infiltrating lymphocytes), these TILs are likely to be CD8 positive – that’s type 1 immunity, and that’s what we need to eradicate cancer.”
Dr Disis further elaborated on the promise of immunotherapy in the setting of breast cancer in general: “Data has been recently reported across multiple tumour types: the response in kidney cancer is 30%, gastric cancer, head and neck cancer 20%, lung cancer 24%, melanoma 34%, and for TNBC we’re right in that same ballpark. So, I say onward to the rational combinations so we can drive that response rate up.”
“I think everyone needs to know about immunotherapy in the treatment of breast cancer. I think the time is here for us to be able to drive our patients toward a better therapy that would cause long-lasting protective immunity over time. So let’s move immune therapy forward in breast and really try to change the game in this disease.”
