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Anti-CDK4/6 in Metastatic Breast Cancer Showed Further Benefits at SABCS

At the San Antonio Breast Cancer Symposium (SABCS), an update of the phase III monarchE trial showed an increasing benefit from the addition of abemaciclib (Verzenio) to adjuvant endocrine therapy for hormone receptor (HR)-positive/HER2-negative breast cancer, regardless of Ki-67 status.

Meanwhile, the phase II RIGHT Choice trial demonstrated the superiority of ribociclib (Kisqali) plus endocrine therapy over chemotherapy as first-line treatment for premenopausal patients with aggressive, advanced HR-positive/HER2-negative disease.

In this second of four exclusive roundtable videos from MedPage Today, moderator Hope S. Rugo, MD, of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, is joined by Joyce O’Shaughnessy, MD, of Baylor University Medical Center, Texas Oncology, and U.S. Oncology in Dallas, and Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, to discuss the results of these two trials.

Following is a transcript of their remarks:

Rugo: Hello, I’m Hope Rugo from the University of California San Francisco’s Comprehensive Cancer Center. I’m here at [SABCS] 2022 with my colleagues, Dr. Joyce O’Shaughnessy and Dr. Jennifer Litton. And we are going to have a roundtable and discuss some of the really exciting new developments and updates on certain studies that were presented here at the meeting. And we hope that you enjoy our discussion.

So we have a lot of exciting things. We saw some activity of T-DXd [trastuzumab deruxtecan; Enhertu] in the late-line hormone receptor-positive [setting]. Of course, we already completed the phase III trial, so it’s a little bit of an afterthought, but still important to have.

But we also saw a lot of other exciting data at San Antonio in hormone receptor-positive disease. Just sort of thinking about the different areas that we could highlight, we saw an updated analysis from monarchE — abemaciclib in early-stage disease. We saw a fascinating trial called the RIGHT Choice looking at combination chemo versus endocrine therapy and ribociclib in the metastatic setting. And then we saw, of course, a bunch of oral SERD [elective estrogen receptor degrader], PROTAC, and the AKT inhibitor capivasertib.

So I don’t think we want to go through all of the details, but maybe we can just talk about monarchE, and then a little bit about an overview of the other parts we saw in the metastatic setting.

Litton: Yeah, when I was thinking — as we think about where to use the CDKs, especially in the first-line, I think that we’ve seen these hints from other trials and this one really helped us put through, you don’t need to go through …

Rugo: The RIGHT Choice.

Litton: The RIGHT Choice. Yes, I’m sorry.

Rugo: So maybe just mention what the design was of the RIGHT Choice.

Litton: So it was looking at combination chemotherapy versus endocrine therapy with CDK, which was ribociclib. And we’ve seen that from other studies, some hints. But we’ve always been taught for a long time that if you have liver mets or you have visceral disease, you absolutely have to go to chemotherapy. But the time-to-treatment, all of that, with the CDK inhibitors. I’ve been going to them now first-line over combination chemo, even with significant liver metastases, now for a bit, and I think this was really reassuring. This is the right answer.

Rugo: Yeah, I think so too. I think that these patients did not have visceral crisis, but they had symptomatic disease and so you could have presumably had bone-only disease that was symptomatic, but double the progression-free survival [PFS] is very, very impressive, I think. And the study was also done in kind of unique countries, right? So it was done in countries in Asia, but then also Egypt, Lebanon, and a couple of other countries, which I am not remembering, but countries that I think have for a long time used chemo first. So I think it was a nice thing to have those countries all participate in this trial.

O’Shaughnessy: Yeah, yeah. Premenopausal, right? Pre-perimenopausal really on purpose…

Rugo: Only the younger women. Yes.

O’Shaughnessy: Right. Doing a really high-risk group. And yeah, so it was reassuring. And time-to-response was very similar with the chemotherapy. That’s obviously super important, but it was much longer PFS, 12 to 24 months. It’s a big difference there.

Rugo: And what did you think about the monarchE data, Joyce?

O’Shaughnessy: It’s great.

Rugo: It’s so exciting.

O’Shaughnessy: I really think now we’re at the point where we’re really saying this is a definite, definite big advance in our lifetime. Really something we’ve been waiting for that next leap in the adjuvant, the high-risk adjuvant setting — and that’s what most of our patients die of, is high-risk HR-positive breast cancer, HER2-negative breast cancer. And so now with 42 months median follow-up, so 3.5 [years] median follow up, we have a hazard ratio that’s still right around 0.65. So it’s a one-third reduction from an iDFS [invasive disease-free survival] standpoint and 35% reduction in the risk of a distant event. Survival is still very, very immature. But there’s fewer deaths now on the abemaciclib arm.

But what’s really interesting is there’s about 250 women who have metastatic disease still being followed on the monarchE trial for survival and 125 with abemaciclib.

Rugo: I know it’s double. I mean, it’s just a huge difference.

O’Shaughnessy: It’s huge. And no new safety signals. The thing is, in that trial 46% of patients needed a dose reduction. So that’s great. We really need to use those dose reductions, but still about 19% of patients stopped therapy because of toxicity. I think we can do better than that. Now that we know we’ve got a really active agent in hand and stuff. In 2 years, and the curves keep pulling apart. That’s the thing, they look like the old tamoxifen curves where you stop and they keep pulling apart. Stephen Johnston, MD, did a wonderful job presenting — he kept using the word carryover effect.

Rugo: We talked about it. Remember, we had this big conversation about the fact that this looked like endocrine therapy with carryover effect.

O’Shaughnessy: Yeah. So it was very, very positive. I think the worry about the curves coming back together again that we saw in PENELOPE-B, I think that’s gone. I think that worry is gone. It’s really now compelling to offer this to the patients, the ASCO and NCCN [American Society of Clinical Oncology and National Comprehensive Cancer Network] went with the intent-to-treat population for eligibility, basically high-risk node positive.

Rugo: Yeah. And I think that it’s also, we are still seeing that Ki-67 with this, cutoff of 20% that for some reason the FDA hung their hat on, actually is prognostic but not predictive of benefit. And if anything, those curves have continued to separate for the low Ki-67 patients as well. So it’s clearly not the right decision to select patients based on Ki-67 alone. And I was really fascinated that it went from 2-point something to 4-point something to 6-point something percent as you’re following patients. And, everybody’s off therapy. I mean, this is long, you’re almost 4 years of follow up. So it’s really, really, very, very nice data to see and how we’ll go from there, and understand whether or not ribociclib also plays well there in the future with the NATALEE trial.

Watch episode 1: New Developments in HER2-Positive Breast Cancer at SABCS 2022

  • Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams. Follow

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