Hello, I'm Dr Hope Rugo from the University of California at San Francisco's Comprehensive Cancer Center, and I'm going to review for you today a few different abstracts that were presented as posters at this year's virtual ASCO 2020.

Now, we're going to talk about patients who have hormone receptor-positive disease, treated with CDK4/6 inhibitors in the metastatic setting. Of course, this is really revolutionized our treatment for patients with hormone receptor-positive metastatic breast cancer.

Really, just, I think the biggest sea-change in how we treat these patients, even bigger than the advent of aromatase inhibitors and fulvestrant, although collectively, that made an enormous impact, this has been such a short term to introduction of these agents and then application so broadly around the world to the treatment of patients with metastatic hormone receptor-positive disease.

We were really excited last year to see survival differences that were quite dramatic in MONALEESA-7, in the first-line setting using ribociclib in patients who are premenopausal and made chemically postmenopausal, or of course, by other means, in combination with endocrine therapy, either an aromatase inhibitor or tamoxifen.

Then we also saw data from MONALEESA-3, where patients received fulvestrant in the first and second-line setting in a variety of different criteria for eligibility where survival benefit was also seen.

Then, of course, we saw benefit in the second-line setting in the MONARCH trial, looking at abemaciclib. So this, I think, further revolutionized the treatment of these agents, because before this, we thought we would not really be able to see survival differences in a patient population who has a long survival post-progression.

In this analysis that was presented by Denise Yardley on behalf of everybody who had participated in these trials, they actually looked at both MONALEESA-7 and MONALEESA-3 and tried to look at whether or not they would see a difference in progression-free survival (PFS) and overall survival (OS) in the patients who had visceral metastases and to some degree, also, at the smaller population of patients who had CNS metastases, as well.

They outlined all of the baseline characteristics and about 60% of patients had visceral metastases in each trial.

In MONALEESA-7, it turned out that tamoxifen actually prolongs the QTC a little bit longer, so it's not recommended with ribociclib. It's more, they really focused on an aromatase inhibitor. They were non-steroidal aromatase inhibitors cohort in that patient population.

A small number of patients in MONALEESA-7 (a little under 20%) had received prior chemotherapy as well. They saw an OS benefit with ribociclib versus placebo in all patients who had visceral metastases, consistent with the overall population. The median PFS was longer.

The most frequent response was a partial response, and adverse events (AEs) were no different in this patient population. We say that all the time, but it's actually really important to say that AEs were not different. Ribociclib can increase the liver enzymes, although this appears to be a relatively benign issue. It doesn't result in serious liver problems. I think the importance in saying that the outcome is the same is that, in terms of AEs, is just that, in patients who have visceral metastases, liver often is a big issue.

In fact, it was about 50% of the site of visceral metastases in this analysis. They didn't seem to see any increase in the AEs, so that's actually really, really encouraging. There were very few patients who had CNS metastases.

It's really a small group that's hard to analyze. In the tiny number of patients who had prior chemotherapy in MONALEESA-7, they could have gone on right after their prior chemotherapy. I think that that group is also very hard to analyze.

It's nice to look at the curves, the figure 2 within this poster, that looks at the event-free survival in patients who had visceral metastases, and really encouraging for our patients. I think this gives further information to suggest that, just because a patient has visceral metastases does not mean that they should receive chemotherapy.

We know that chemotherapy is going to increase the toxicity profile for patients, because they've had to get chemo, not because they don't tolerate the CDK4/6 inhibitor therapy.

Also, I think it generates resistance overall, so it's much better to treat these patients with endocrine therapy and a CDK4/6 inhibitor upfront, rather than to use chemotherapy. The only situation where chemotherapy should be used is in patients who have immediately life-threatening disease based on their visceral metastases, so, you know, pending liver failure with rising liver enzymes or respiratory issues, where the people are beginning to be hypoxic or short of breath.

Overall, I think this is really encouraging information, looking at OS, AEs, of course, the PFS in patients with visceral metastases, suggesting that we really are improving outcome, even for the patients who have what we have characterized phenotypically as endocrine-resistant disease.

You have a patient who's had their adjuvant therapy, they relapse, and they have metastases that are not bone-only, but include bone, liver, lung. They have diffuse metastases. These patients also live longer with the CDK4/6 inhibitors, as demonstrated in this data with ribociclib.

One of the questions that comes up, seeing this dramatic data and wanting the best outcome for our patients who have visceral metastases, is whether or not there's a difference between CDK4/6 inhibitors.

We don't know, and there isn't really an answer to that yet. I think we tend to go where the data exists. This is really interesting data. There are also subset analyses that are being done in the other trials as well.

It's just that the MONALEESA-7 population is this premenopausal group, and they do tend to have more visceral metastases, more de novo metastatic disease, and shorter responses to single-agent endocrine therapy.

This data, I think, particularly applies to patients who are young, have visceral metastases, and are being treated in the first-line setting. It's just really encouraging and great to see.