The KEYNOTE-522 trial is the first placebo controlled randomised phase III trial of immune therapy in early triple negative breast cancer. It investigated the benefit of adding pembrolizumab to neoadjuvant chemotherapy and also of continuing pembrolizumab afterwards as adjuvant therapy for a total duration of one year for the immune therapy.
To describe the background, triple negative breast cancer is an aggressive subtype of breast cancer. It often affects younger women. The standard treatment for triple negative breast cancer is chemotherapy and, until recently, there was a lack of targeted therapies which is fortunately now changing. Patients with early triple negative breast cancer who we hope to cure would routinely get a combination of chemotherapy and then surgery. Often or most commonly we give chemotherapy before surgery in the form of neoadjuvant chemotherapy. When we give anthracycline taxane combinations we achieve what we call a pathCR, the complete disappearance of the cancer, in around 40%. When we add in platinum that goes up to about 50-52%. I think that’s important because there’s a plethora of data showing that patients who achieve a pathCR, the complete disappearance of the cancer at the time of surgery, have a very good long-term outcome. There’s a strong association with the event free survival with a hazard ratio of 0.24. There’s an even stronger association of pathCR with overall survival with a hazard ratio of 0.16. In other words, patients who have a pathCR have a recurrence free survival of 90-95% over the next five years which is when most recurrences would usually occur for triple negative breast cancer.
On the other hand, patients who unfortunately don’t achieve or experience a pathCR have a relatively high risk of disease recurrence of around 40% over the first 3-5 years. So what we’re trying to achieve in triple negative breast cancer is increasing those pathCR rates knowing that they are, at least for chemotherapy, linked with a reduction in recurrences and then an improved overall survival.
The KEYNOTE-522 trial used probably the most intensive chemotherapy regimen we can give and that’s twelve weeks of carboplatinum paclitaxel followed by twelve weeks of AC or EC chemotherapy. Patients were randomised two to one to get added to that chemotherapy the pembrolizumab or placebo. So they had twelve weeks of immune therapy or placebo before surgery together with chemotherapy. Then patients had surgery and after surgery patients carried on with pembrolizumab or placebo for another six months, so for a total duration of one year of the immune treatment. The trial had two dual primary endpoints. The first endpoint is pathCR and that’s an endpoint we expect very early on. The second primary endpoint is event free survival and that’s obviously an endpoint that takes a little bit of time before we unfortunately see those recurrences occurring.
The data presented at ESMO 2019 are the final results for pathCR and they show a statistically significant and, in my opinion, meaningful increase in the pathCR rates by 13.6% to 64.8% pathCR rates in patients who receive pembrolizumab and chemotherapy. Interestingly, patients who had PD-L1 positive tumours, as well as patients who had PD-L1 negative tumours, seemed to derive a relative similar benefit in terms of increasing pathCR rates with the addition of pembrolizumab.
At this point in time we have a short follow-up of only about 15 months and despite that very short follow-up the very first and very early analysis for event free survival already shows a separation of the curves. The estimated 18 months event free survival is 91% for patients receiving pembrolizumab and 85% for patients receiving placebo. The hazard ratio behind there is 0.63 which is, although not statistically significant at this point in time where we had a very, very high bar for statistical significance, hugely encouraging because it shows us that it’s very likely, in my opinion, that the benefits in pathCR will translate into benefits in EFS, in other words, reduce recurrences and hopefully improve survival and cure rates of patients.
If we look at safety of the regime, it’s obviously a hugely important point in patients in a curative disease setting. In the neoadjuvant phase safety is largely dominated by chemotherapy. The toxicity profiles look like chemotherapy profiles. If you look at the severe toxicities or moderate toxicity they’re very much comparable between the pembrolizumab and placebo arm with only subtle differences. If you look at the adjuvant phase where patients received pembrolizumab or placebo alone, the rate of moderate to severe toxicities is very low and, again, relatively comparable between the two arms and, most importantly, comparable and consistent with what we know for immune checkpoint inhibitor single agent but also for immune checkpoint inhibitors when given with chemotherapy.
If you look specifically at those rare events which are possibly immune mediated, they are rare - pneumonitis, colitis, hepatitis, very rare in this trial. The most common immune mediated effect, as expected, I would say, are changes in the thyroid function – hypofunction as well as hyperfunction which is usually very well manageable with medication although that has to be long-term medication.
If I would summarise where we are with KEYNOTE-522 at this point in time, we have the final results – a significant and meaningful benefit. A difference of 13.6% in pathCR rates with a pathCR rate of 64.8% for patients receiving pembrolizumab and chemotherapy. We have a very strong, not yet significant, result in event free survival which is very encouraging at this point in time. We have a reassuring safety profile at this point in time but longer follow-up, of course, is required and will happen for event free survival, overall survival but also for safety.
Why did you use the pathological complete response as an endpoint?
Pathological complete response rates have shown to have a strong association with long-term outcome with event free survival i.e. with reduction of recurrences, as well as with overall survival. In addition, and probably as a result of this both, the FDA and the EMA are using pathCR rates as an early readout for early breast cancer trials in triple negative breast cancer and as a basis for what we call accelerated approval. They will then require to see a later on time benefit in terms of event free survival but there are examples where new medications were approved based on differences in pathCR rates.
So from my perspective, showing an increase in pathCR rates is hugely important and hugely relevant. There’s an interesting discussion ongoing in the immune therapy world where we often see more impressive results in time endpoints, for example overall survival, in advanced cancer studies compared to response rates. When we designed KEYNOTE-522 we hoped to see a pathCR difference but we said it is possible that we don’t see a difference and still have a very substantial benefit in long-term outcome. Now, the fact that we have seen a significant and meaningful difference in pathCR is hugely encouraging and I personally would expect to see an even better effect in EFS but we have to wait for those results before the final results and hopefully see that they are statistically significant as well.