KEYNOTE-522: Neoadjuvant pembro chemo vs placebo chemo, followed by adjuvant pembro vs placebo for early TNBC
Dr Jay Andersen - Compass Oncology West Cancer Center, Tigard, USA
KEYNOTE-522 was a preoperative as well as adjuvant trial in triple negative breast cancer patients comparing standard backbone of chemotherapy with randomisation to pembrolizumab, which is a PD-L1 antibody, versus placebo. Patients received 24 weeks of standard chemotherapy that was taxane, platinum, anthracycline based and then they had a randomisation between pembrolizumab, a PD1 antibody, versus placebo concurrent during the chemotherapy phase for every three weeks. Then the patients went to surgery and one of the primary endpoints was pathologic complete response at the time of surgery. Then in the adjuvant setting they continued study drug, either pembrolizumab or the placebo, for nine additional treatments every three weeks.
What were the results?
At ESMO in September one of the primary endpoints, pathologic complete response, was released and that improved from 51% to 64%. That is a dramatic improvement compared to standard chemotherapy alone, historically that has been in the range of 40-50%. We believe that pathologic complete response is a surrogate endpoint for improved longer term outcomes so that’s a big inroad into this type of disease, triple negative, which has a lack of targeted therapies indicated for it.
Interestingly also at ESMO they presented early data regarding event free survival and it’s early. At 18 months we’re seeing an improvement in EFS from 85% to 91%. That needs to be followed longer term but already there’s a signal there could be an event free survival benefit as well.
How was the toxicity profile?
When they looked at the toxicity during the concurrent chemotherapy arm the majority of the side effects were related to the chemotherapy backbone. There were some signals, though, that this therapy, the antibody, the immune therapy, can have autoimmune phenomenon like hepatitis, pneumonitis, colitis. The incidence of those episodes is under 2% whereas thyroid dysfunction can be as high as 14%. So those are some unique side effects related to the pembrolizumab.
What is the clinical relevance of these results?
The pCR is an inroad into improved outcomes. The fact that we can improve the pCR rate from 40-50% up to 64% and because that translates to improved outcomes we believe that to be a surrogate marker of benefit. To date, the standard of care for triple negative breast cancer is chemotherapy only, we don’t have other targeted therapies, so this is the first study to show a targeted therapy, in this case an immunotherapy, pembrolizumab, offering that benefit.
What are the next steps for the study?
At San Antonio 2019 they are going to release some additional subset analyses looking at differential benefits in different groups based upon stage, the PD-L1 positivity and lymph node status. So that may give us some further insight into are there certain subsets that benefit more versus not.
Anything else you’d like to add?
The FDA already gave it early therapeutic designation status but until there’s a further review of data and a further approval it’s not currently standard of care.