‘Reassuring’ New Breast Cancer Survival Data on Fulvestrant Plus CDK4/6 Inhibitors


At the recent virtual American Society of Clinical Oncology (ASCO) annual meeting, investigators updated overall survival (OS) data from the phase III PALOMA-3 and MONALEESA-3 trials, showing that the CDK 4/6 inhibitors palbociclib (Ibrance) and ribociclib (Kisqali), respectively, have each maintained prolonged survival benefits in patients with hormone receptor (HR)-positive/HER2-negative advanced breast cancer.

In this final of four exclusive episodes, MedPage Today brought together three leaders in the field — moderator Hope S. Rugo, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, is joined by Jennifer Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, and William J. Gradishar, MD, of Northwestern Medicine Feinberg School of Medicine in Chicago — for a virtual roundtable discussion about what these updates mean for the current and upcoming treatment for patients experiencing disease progression on frontline endocrine therapy.

Episode one: PARP Inhibitors for Early, BRCA-Mutant Breast Cancer

Episode two: New Data on Role of Gene Assays in Breast Cancer Treatment

Episode three: New Developments in Triple-Negative Breast Cancer Therapies

Following is a transcript of their remarks:

Rugo: Hello. I’m Hope Rugo, a professor of medicine and director of Breast Oncology in Clinical Trials Education at the University of California San Francisco’s Comprehensive Cancer Center. We are going to talk about some interesting updates from ASCO 2021. With me today are my excellent colleagues, very knowledgeable and key opinion leaders in breast cancer. Dr. Jennifer Litton is professor of medicine and vice president of clinical research at MD Anderson’s Comprehensive Cancer Center, and Dr. Bill Gradishar, who is professor of medicine and chief of hematology-oncology at Northwestern University. Both of my colleagues are experienced clinical trialists and clinicians who specialize in breast cancer.

Okay. Well, at ASCO in 2021, we certainly saw lots of exciting new data in the area of breast cancer. But one area that was discussed was sort of a longer follow-up of already-positive trials and gave us some additional information about the characteristics of patients who benefit from CDK4/6 inhibitors combined with endocrine therapy in two very different trials.

Also, but most importantly, these two trials, PALOMA-3, and MONALEESA-3, gave us a longer-term follow-up of overall survival, the sort of gold endpoint for all clinical trials.

Bill, could you tell us a little bit about those two presentations and what your take-home messages are?

Gradishar: Well, I think that foundationally we think of CDK4/6 inhibitors as important drugs in the ER-positive disease, and the data that was presented at ASCO only reaffirms that because some of the pivotal trials that we’ve heard about for the last several years were updated. The two that we’re going to talk about are PALOMA-3 and MONALEESA-3.

These were trials that looked at the comparison of fulvestrant versus fulvestrant plus a CDK. In the case of PALOMA-3, it was palbociclib. In the case of MONALEESA, it was ribociclib. We knew these trials showed a clear improvement in PFS [progression-free survival] before, and we’ve been waiting on the survival from these trials. Now with longer follow-up, certainly in the PALOMA-3, we see that effect.

Where the effect is most pronounced are in those patients who did not receive prior chemotherapy in the advanced disease setting. But clearly with 6 years of follow-up, I think, it is. In the presentation that was given at ASCO, there is a separation of the curve showing an advantage for treatment with palbociclib.

The other, I think, equally important part of that presentation, was there was an effort to look at subsets of patients based on whether they had ESR mutations, PI3-kinase mutations, or p53 mutations.

As a generalization, if you have one of those things present, your prognosis is worse than if you don’t. But if you’re getting the CD4/6 inhibitor palbociclib, you still get an advantage over endocrine therapy alone — again, you make up for some of that bad prognosis that comes with those particular mutations.

In the MONALEESA-3 trial, again, we have longer follow-up. There is a survival benefit that was demonstrated, that still continues now at the 5-year mark. This trial also included patients who could have received chemotherapy, and it was clear there was an advantage for those patients as well. But I think the data is consistent. It’s reassuring. As Jen said before we started the discussion, CDK4/6 inhibitors are good.

Rugo: Yeah, it’s so funny. Also, I think that it was nice that we didn’t see any new side effects. It’s not like there is any cumulative toxicity from these agents, which is really quite different for most of the drugs we give, I suppose, except for trastuzumab. I mean, we just didn’t see cumulative toxicities.

I did think that in addition to the biomarker data, this issue of prior chemotherapy or not, and what it does to your response. Remember, in PALOMA-3, you could had any number of lines of endocrine therapy. A third of the patients had prior chemo, whereas in MONALEESA-3 and MONARCH 2, you could not have received anything. MONALEESA-3, of course, had the two subsets, but one group could have had one endocrine therapy, but nothing else.

It does tell us something maybe about what we see and when we should be putting targeted agents in. What did you think, Jennifer?

Litton: I think one of the clinical questions I get asked all the time is if someone has visceral events, they’ve got a liver met[astases], am I scared to … “I should go right to chemo,” because that’s what we were taught. I think, from looking at this data, the time to response, where it’s placed, this data absolutely supports the use of a CDK endocrine therapy even in these more advanced settings.

I also thought what was really interesting is when these first came out we were really concerned that there were these massive progressors right after … I think that they also really tried to look at that with this PFS2 [time to second progression-free survival], which is a really hard other endpoint to look at, but really not showing that you might respond, but then do so much worse. That’s not what was shown and it doesn’t pan out in the overall survival. I think that puts a lot of worries to rest to some of that early chatter of the CDK inhibitors.

Rugo: That’s a really good point. I mean, I thought all of these trials now looked at PFS2, and time to chemotherapy has shown that it’s all better if you’ve got the CDK4/6 inhibitor. I think that’s particularly encouraging when we know that you get similar benefit — even if you have, for example, a PIK3CA mutation — even though your prognosis overall is worse.

I think we’re going to see more data and what happened to those patients who had prior CDK4/6 inhibitors, who then received a PI3-kinase inhibitor had PIK3CA mutations — for example, in SOLO1 and BYLieve. It’s very interesting to see what happens because we used to think each PFS would be shorter, right? But it doesn’t seem to be the case so much anymore.

There is also a lot of new endocrine therapies that are out there. I think that we’re really waiting for an oral SERD [selective estrogen receptor degrader]. I know we’ve been waiting for a long time. But there are two phase III trials I think that completed accrual. But what did you think, Bill, about all of the new data that was presented? I think there were SERMs [selective estrogen receptor modulators], SERCAs [selective estrogen receptor covalent antagonists], and SERDs. Lots of agents.

Gradishar: Yeah. Well, I guess I would sum it up as saying, “let the SERD wars begin,” because what we basically saw at ASCO was a series. I don’t know, there must have been half a dozen different trials that were largely phase I. Thematically, they are looking at patients who are ER-positive disease, they have gotten prior therapy. All of them have a fraction of their patients with documented estrogen receptor mutations in them. All of them showed that there is activity and a suggestion that the toxicity, which is different between them, is so far tolerable.

Many of these companies that are developing these drugs are leaping from the phase I to the phase III. They are putting all their chips on the phase III. As you mentioned, Hope, there are trials that are either monotherapy trials or trials of a SERD with a CD4/6 inhibitor in the phase III setting.

Some of these trials are set to be reporting or at least meeting their accrual goals this year and each in the subsequent years. We are going to have this onslaught of data coming at us over the next 1 to 3 years from all of these trials. We’ll just have to see which of these actually get to the finish line and get approved. But we’ve been waiting for something new that’s not in a sense something that you partner with endocrine therapy but actually a new endocrine agent, for years.

Rugo: Yeah, I think that we have been. The SERD development process has been much slower, I think, than we had hoped in the beginning, mainly because some of the drugs caused more GI toxicity than we thought. Also, I think trying to find drugs that actually are effective in the face of fulvestrant resistance seem to be a really important factor in identifying the right agents for trials.

There is also the SERM, SARM [selective androgen receptor modulator], and SERCAs that are out there. A lot of interesting agents that are being studied in ESR-1 mutations, etc. Is there one particular, Jennifer, that you think is worth highlighting? Or we should look for all of these?

Litton: For me, I think the one that was in a poster discussion by Dr. Erika Hamilton. It was 83 patients heavily pretreated, H3B-6545. What I found really intriguing there is some of that early data showing that it’s not just the ESR mutation, but which one and where it is. It really heavily influenced — either really increasing response from like 30% to 60% versus no response or decreased response. I think it’s an early look into where the mutation is matters too. I found that one particularly intriguing.

Rugo: Yeah. I think it’s a fascinating idea that now we’re going to be able to not just look at a mutation, but maybe parse that treatment based on a mutation that might predict resistance to one endocrine therapy versus another. Hopefully in the next year we’ll see results from some of the phase III trials.

There are also other trials looking at SERDs and it’s important to keep this in mind when you’re thinking about your patients that are looking at SERDs with CDK4/6 inhibitors and combination, triplet therapy, as well as in the first-line and second-line setting, and then some of these newer agents are on the later-line setting. It’s worthwhile looking to see for your patients whether or not there are trials available that they might qualify for.

With that, I think we’ll close this particular section. Thank you very much for all of your thoughts. It’s amazing how much progress we’ve made in hormone receptor-positive disease, but we clearly still have a way to go. Thanks so much.

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    Greg Laub joined MedPage Today in 2005 as Production Manager and led the launch of the video department in 2007. He is currently responsible for the website’s video production. Follow

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