Good news for the therapy of high-risk early-stage triple-negative breast cancer, an aggressive disease with poor treatment options: the phase 3 KEYNOTE-522 study demonstrated that pembrolizumab, a PD-1 protein inhibitor, improved by 37% the event free survival if administered in combination with chemotherapy as neoadjuvant therapy, and, subsequently, as single-agent adjuvant therapy. This is the first time an anti-PD-1 therapy has demonstrated a statistically significant event-free survival result as combined neoadjuvant and adjuvant therapy for these patients, who are usually young and experience a high recurrence rate within the first five years after diagnosis.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, thereby activating T lymphocytes and increasing the ability of the body’s immune system to help detect and fight tumor cells. It is currently approved for the treatment of advanced melanoma, non-small cell lung cancer, Hodgkin lymphoma, urothelial carcinoma and other tumors. The double-blind randomized trial enrolled 1174 patients randomized to pembrolizumab and various chemotherapy agents (paclitaxel, carboplatin, cyclophosphamide and doxorubicin or epirubicin) as neoadjuvant therapy prior to surgery, followed by 9 cycles of pembrolizumab every 3 weeks for adjuvant therapy post-surgery. The placebo arm received the same treatment except patients received the matching placebo instead of pembrolizumab.
At the median follow-up of 39 months, pembrolizumab improved event-free survival, defined as time from randomization to the first occurrence of disease progression precluding definitive surgery, local or distant recurrence, second primary cancer, or death. At the 3-year follow-up, 84.5% patients in the pembrolizumab group were alive and did not experience an event compared with 76.8% of patients in the placebo group; as previously reported, the pathological complete response was achieved by 64.8% of patients in the pembrolizumab/chemotherapy combination group versus 51.2% with chemotherapy. The trial is continuing to allow for additional follow-up of overall survival; at this fourth interim analysis there was a 28% reduction in the risk of death with pembrolizumab regimen versus the chemotherapy-placebo regimen. The safety profile of the pembrolizumab regimen was consistent with the known profiles of each regimen.
«Given the high rates of recurrence within the first five years of diagnosis, patients with high-risk early-stage triple negative breast cancer need new treatment options», said Peter Schmid, lead of Centre for Experimental Cancer Medicine, Barts Cancer Institute in London. «The study was designed to investigate whether the combined neoadjuvant and adjuvant regimen with pembrolizumab could help treat the cancer earlier. Now, with more than three years of follow-up, we see the potential of this approach. These event-free survival data are very encouraging for patients and show that this combination of pembrolizumab plus chemotherapy as neoadjuvant therapy, followed by single-agent pembrolizumab as adjuvant therapy, may offer women with high-risk early-stage triple negative breast cancer a new treatment option for this aggressive disease».
A significant proportion of patients is already cured by chemotherapy alone. Consequently, the identification of patients needing and likely to benefit from the addition of pembrolizumab is of paramount importance. This can be achieved by the development of biomarkers able to predict the best therapeutic option for each patient, limiting the economic burden of cancer therapy and avoiding patients’ overtreatment or unnecessary side effects.