COMMENTARY

ESMO: monarchE Abemaciclib 'Landmark' HR+ Breast Cancer Study

Prof Stephen Johnston

Disclosures

September 20, 2020

Prof Stephen Johnston, lead author of the monarchE study on how adding abemaciclib reduces recurrence in high-risk hormone receptor positive human epidermal growth factor receptor 2 negative early breast cancer.

This transcript has been edited for clarity.

My name is Professor Stephen Johnston. I'm a medical oncologist and professor of breast cancer medicine at the Royal Marsden Hospital in London.

What were the monarchE headline findings?

We report the results from the monarchE trial which is a large global randomised trial in high-risk early breast cancer in patients with hormone receptor positive node positive disease.

Many of these patients with hormone positive breast cancer, the most common form, are often very effectively treated by their surgery and standard of care treatment with a low chance of recurrence. But there's a group who have high-risk features based on their level of nodal involvement, or the high grade of the cancer, or high proliferation.

Despite the standard of care, often including chemotherapy and radiotherapy, these patients can have up to a 20% chance of their cancer coming back in the first 5 years.

Now, what we've been wanting to do is add a therapy to reverse that resistance to hormone therapy, and the CDK4/6 inhibitors have become standard of care in advanced disease where they've overcome hormone resistance and improve outcomes.

So this trial looked at abemaciclib in the early breast cancer setting, choosing specifically those patients with high-risk features. And then when they had completed their standard therapy - 95% of them had received chemotherapy - then they were randomised to either abemaciclib for 2 years plus hormone treatment, versus hormone therapy alone.

This was a pre-planned interim analysis, which was statistically significant, and it has shown that at the 2-year mark we have had a 25% reduction in the risk of the cancer coming back.

So patients who were on just hormone therapy alone, at 2 years 11.3% of those patients had had a recurrence of their cancer, whereas less than 8% had had recurrence if they received abemaciclib.

So an absolute difference of 3.5%, but a 25% reduction in risk in that first 2 years. So this is clinically very meaningful, it's statistically significant. It's an event-driven analysis, so the data are robust. And this therefore could become a new standard option for these patients who are deemed to be at high-risk based on the features that we use to enrol them in the trial.

How would you assess these results?

I think the reason it's been described really as a landmark study is that in this type of breast cancer, hormone receptor positive breast cancer, we haven't really had a breakthrough in early breast cancer for nearly 20 years. That was since drugs called aromatase inhibitors were shown to be better than tamoxifen and became standard of care at the turn of the century.

So since then we have not really made a further leap forward, particularly in the high-risk patients, that despite giving them absolutely everything, including chemotherapy and prolonged hormone treatment, they still have a relatively high risk of recurrence.

So to me, the two things that were pleasing were one, the design of the trial was right.

The control arm behaved as we would have suspected, and the high rate of recurrence was demonstrated in those on endocrine therapy alone. Too often these types of trials have been done, and the control arm performs better than they thought in the design of the trial, and the trial is negative.

So seeing that your predictions of how those patients would behave, and the level of risk, came true meant that we got the design right.

And then obviously the second thing was to see that adding the therapeutic of choice, which we've used in advanced disease and we know can treat primary endocrine resistance, was having that early impact in stopping recurrence. It was mainly sites of distant metastases. The biggest reductions were in preventing patients developing bone and liver metastases within those first 2 years. And that is very clinically significant if we can impact that early on.

The trial will carry on and we'll need more follow-up to see how the curves continue to separate. But this was an analysis that was pre-planned, the events declared that this was statistically significant, and that's allowed us to release the results and for, hopefully, the medication to be filed for approval.

When might we see this in UK clinical practice?

I think the approval is being sought with the FDA in the United States, by the end of this year submissions go in.

I suspect the submission in Europe will go in next year. And then if it is approved and licensed, then within the UK we have obviously the National Institute for Health and Care Excellence (NICE) which is the organisation that looks at the cost-effectiveness of the treatment.

But if we are preventing metastatic disease, which has quite a significant impact not only for patients but also in terms of use of healthcare resources, and we're having that early impact to a significant extent, then I think it will be calculations that will have to be done to see that this is an effective use of resource.

This treatment isn't being recommended for all ER+ breast cancer patients. It's a very select group. It probably represents about 15% of all ER+ breast cancers, which is the most common subtype. But those patients who do present with high nodal burden, or high-grade tumours, know that they're at increased risk. So I think there will clearly be a demand in those select patients for whom this therapy could be applicable.

What are your next steps?

We want to follow the trial up but we're already starting to plan another trial in the UK, where we look at patients who have tumours before they go for surgery. Their nodes may not be involved, and we gave them a 2-week exposure of letrozole, which is the hormone treatment.

And if those patients don't have a drop in their proliferation, called Ki-67, we've already shown in a big UK trial called POETIC that those patients have up to a 20% chance of recurrence in 5 years.

So these patients may have smaller tumours, not necessarily have involved nodes, but because of inherent biological resistance in their cancer, they have the same level of high risk. So we're going to launch a trial in the UK called POETIC-A, whereby we will use short exposure to the drug before surgery across all patients that are hormone receptor positive and postmenopausal, to pick out those that are at high risk, and then randomise them to abemaciclib or a control arm.

So we want to expand out the therapy, but again same principle, identify those at risk of developing recurrence and target them rather than a blanket approach of using the drug for all-comers and only finding a very small percentage of patients who derive the benefit. Because that I think is one of the lessons from this trial, that correct selection of patients allows you to use the therapy more effectively, and that ultimately has got to be better for patients and also more cost effective for the health service.

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