KEYNOTE-522: Breast Cancer Practice-Changing Potential

Prof Peter Schmid


September 29, 2019

This transcript has been edited for clarity.

I'm Peter Schmid. I'm a medical oncologist and I work at Bart's Hospital in London.

The KEYNOTE-522 trial is the first randomised phase 3 trial of an immune checkpoint inhibitor in early triple negative breast cancer. We've seen data in metastatic triple negative breast cancer with immune checkpoint inhibitors showing a clear benefit in survival. When it comes to early triple negative breast cancer, obviously we hope to cure more patients.

The trial has two primary endpoints.

One is what we call path CR, and this means the disappearance of old cancer after neoadjuvant chemotherapy at the time of surgery.

The second endpoint is a longer-term endpoint looking at event free survival (EFS), meaning the reduction in recurrences. At this early time point, we have the final data for path CR, and they show a clear and statistically significant benefit for the addition of pembrolizumab to neoadjuvant chemotherapy. The difference in the path CR is about 13.6%, with the path CR rate in the experimental arm with pembrolizumab of nearly 65%, which is a rate of path CR we have never seen before in triple negative breast cancer.

At this early time point with 15 months follow up we see a strong signal in terms of event free survival, with a hazard ratio of 0.63, but it did not yet meet the predefined boundaries of statistical significance. But it's the very early first analysis and subsequent analysis will follow in the near future.

Could this affect clinical practice?

I think the results have the potential to be practice changing. We will need more EFS data for final implementation of this. But unfortunately in triple negative breast cancer recurrences occur very soon if patients don't achieve a pathological complete response with neoadjuvant chemotherapy.

So I would assume in the next few months, we will see stronger and then, likely in my opinion, significant data in event free survival. And then I think it's very difficult not to incorporate immune therapy into a neoadjuvant treatment regimen if we show we significantly increase the path CR rates, but we also reduce recurrences, which are very closely linked with survival in triple negative breast cancer.

Is data starting to show which patient groups benefit from this treatment?

I think it's very early for defining subgroups of patients who may have more or less of a benefit. At the moment the benefit seems to be consistent, and interestingly enough, the benefit is also consistent across subgroups defined by PDL-1 expression. Patients with PDL-1 positive tumours had a similar sized benefit in terms of path CR compared to patients with PDL-1 negative tumours.

This is in contrast to some of the data we see in the metastatic setting, but maybe down to the plasticity and the dynamics of the tumour biology, in this early disease setting. We will do a large range of correlative science and studies and we'll have to link them with both path CR but also with event free survival. We'll learn a lot over time in order to fine tune our treatment and see, does everyone need pembrolizumab? Is there a group of patients who need something possibly even better? But at the moment, this is a very strong signal that is consistent across all subgroups.

Is the ground shifting between chemotherapy, immunotherapy, and combination therapies?

I think what we're learning in triple negative breast cancer is internal and looking across early disease as well as metastatic disease, that the best way of giving immune therapy at the moment seems to be combination. The single agent activity of checkpoint inhibitors in advanced disease is limited. And we had results of the KEYNOTE-119 trial yesterday, which demonstrated that the patients in second or third line therapy who received single agent immune therapy did not do better than patients who received chemotherapy. However, the trial also showed an explorative subgroup of patients who have inflamed tumours with a lot of PDL-1 expression immune cells there, that in this small subgroup immune therapy, a single agent therapy may still have a role. But overall, I think the evidence is coming together that we do need to combine immune therapy with chemotherapy, and possibly other treatments in the future.

That's based on the first positive phase 3 trial in metastatic disease. And it's now based on the first positive phase 3 trial in early triple negative breast cancer.

Are you optimistic for early triple negative breast cancer patients?

I'm hugely enthusiastic about the progress we've made both in metastatic triple negative breast cancer over the last few years but also now in early triple negative breast cancer.

If you go back 5 years and when most parts of the world were still using just anthracycline taxane combinations as neoadjuvant therapy in early triple negative breast cancer, the path CR rates were around 40%. With platinum, which is our control arm in KEYNOTE-522, we get this up to around 52%, which is already a big, big step.

With immune therapy, we are now at nearly 65%. And that is a massive difference going from 40% to 65%, knowing that there's a very strong association with this path CR and long-term outcome.

We've also introduced, in the last few years now, treatment post neoadjuvant chemotherapy for those patients who do not achieve a path CR. For example, simple chemotherapy at that time can also reduce the recurrences by about 40%.

So as a result, I'm delighted to say that we see fewer and fewer recurrences, but unfortunately, every single recurrence we still see is one too many.

But the results are clearly in the right direction. And showing us that we hopefully will improve long-term outcome for patients with triple negative breast cancer. There's still a lot of work to do. But what we have achieved over the last year has given me a lot of hope.


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