TNBC: Neoadjuvant pembrolizumab plus chemo followed by adjuvant pembrolizumab shows improvement in OS compared to neoadjuvant chemo alone
Prof Peter Schmid - Barts Cancer Institute, London, UK
The KEYNOTE-522 trial actually was the first phase III trial to investigate the addition of an immune checkpoint inhibitor to pre-operative chemotherapy and to continue with the immune checkpoint inhibitor after surgery in patients with early stage, with stage 2 or stage 3, triple-negative breast cancer. The trial used what I would call the most effective chemotherapy regimen, so a combination of 12 weeks of paclitaxel/carboplatin followed by 12 weeks of AC or EC and either all the way through with pembrolizumab plus immune checkpoint inhibitor or with placebo. Then patients underwent surgery and continued either with placebo or pembrolizumab for another six months.
The trial had two primary endpoints, a short-term endpoint with pCR and we presented actually here in Barcelona five years ago a significant and meaningful increase in pCR rates by 13.6%. A second primary endpoint was event free survival, so the prevention of recurrences, which we presented a couple of years ago and we reduced the risk of recurrence by about 35%.
Now, here at ESMO today we present the long-term update. We have now 75 months, so just over six years of follow-up, and that’s really important for triple-negative breast cancer because in triple-negative breast cancer we know that the majority of recurrences happen in the first 2-3 years, about 90% in the first five years. There’s fortunately very little expected beyond five years. If we look at the event free survival curves now with more than six years follow-up, they are plateauing, we see only a few additional events that have occurred since the year 3 analysis and now year 5 analysis. The delta, the absolute delta, in terms of event free survival is about 9%, from 81% to 72% with patients who only receive chemotherapy and placebo. The hazard ratio for event free survival is 0.65.
But the key new data here in ESMO is that we now finally have the overall survival data and it’s fantastic to see from a patient perspective that practically all of that event free survival benefit is translated into an overall survival benefit. The hazard ratio is 0.66, that is, at this early timepoint, a 5% delta in absolute overall survival but also means a reduction in the risk of death by about 34%, the first time we’ve achieved this in triple-negative breast cancer. It’s also obviously meaningful as it means that we can cure a substantially higher number of patients.
In terms of long-term safety data, there is no new signal; it’s pretty much what we expected. So our conclusion from the data now is we have a trial that’s positive in both primary endpoints, pCR and event free survival but has also now demonstrated a substantial benefit in overall survival which is the key secondary endpoint, meaning that we reduce the risk of death by 34% for patients with high-risk early triple-negative breast cancer.
The clinical impact of these data has actually already been implemented. What we call the KEYNOTE-522 regimen, so a regimen of chemotherapy and immune therapy, has become the standard of care. In many, many, I would say most, countries across the world it has been approved, it’s the new standard. But the clinical impact is also that fortunately now we see substantially fewer recurrences in the metastatic setting so we can cure more patients and there’s nothing more humbling than being part of that.
