Studies Raise New Questions in HR-Positive, HER2-Negative Breast Cancer

Several studies presented at this year’s American Society of Clinical Oncology (ASCO) annual meeting highlighted emerging strategies for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, including early intervention for ESR1 mutations, oral selective estrogen receptor degraders (SERDs), and novel targeted combinations.

MedPage Today brought together three expert leaders in the field: Moderator Hope S. Rugo, MD, of the City of Hope Comprehensive Cancer Center in Duarte, California, is joined by William J. Gradishar, MD, of Northwestern University Feinberg School of Medicine in Chicago, and Paolo Tarantino, MD, PhD, of Dana-Farber Cancer Institute in Boston, for a virtual roundtable discussion. In this second of four exclusive episodes, the panel discusses the implications of SERENA-6, VIKTORIA-1, and evERA, and how an expanding list of treatment options may reshape sequencing decisions in metastatic disease.

Click here to watch the other videos from this series.

Following is a transcript of their remarks:

Rugo: Let’s go on and talk about another area that’s actually probably one of the biggest controversies right now in our treatment of hormone receptor-positive breast cancer.

The SERENA-6 trial, which went to an ODAC [Oncologic Drugs Advisory Committee] vote, which was actually kind of surprisingly negative, is a trial that looked at switching to an oral SERD with first appearance of an ESR1 mutation when a patient was on an AI [aromatase inhibitor] and CDK4/6 inhibitor. And the median time to having an ESR1 mutation show up was well over a year.

Patients had to be on for 6 months to just join the study and many of the patients joined at around the 18-month mark. The median time to actually having a positive test for the entire population being randomized was close to 2 years. They did show a significant improvement in progression-free survival [PFS]. They’ve shown an improvement in second progression-free survival [PFS2], although few patients received an oral SERD in the next-line therapy from the control arm.

But then they also showed that clearance of ctDNA was dramatically different between the two arms, I think, as you would expect because you’re staying on one treatment and you’re changing the other. But I think the question is whether or not that would motivate you to make a decision differently in terms of treatment.

At the same time, we also saw the second group of patients from VIKTORIA-1, which showed that the combination of gedatolisib, a PI3-kinase and mTOR combined inhibitor, given IV 3 out of every 4 weeks in combination with fulvestrant or with fulvestrant and palbociclib [Ibrance] was superior to alpelisib [Piqray] and fulvestrant in patients who had PIK3CA mutations. Very interesting results and I want to try and understand how do you put all of this into context?

We saw another updated trial from the evERA trial looking at patients who received giredestrant, another oral SERD, with everolimus compared to receiving fulvestrant or exemestane, mostly exemestane, with everolimus. And there we saw a significant benefit, a long PFS, somewhat similar to VIKTORIA-1 in patients who had ESR1 mutations.

So how do we put all this data together? How are we going to treat our patients with ER [estrogen receptor]-positive, HER2-negative disease? Paolo?

Tarantino: Good luck to us. Well, we are having many, many, many new options and I think that’s good. That’s of course good. Now we have to figure out for which patients do you use which option? And I think each one may fit a different patient better.

And so, for instance, I do wish we are going to have in practice camizestrant and the opportunity to switch upon ESR1 detection, but would I do that for every patient on first-line AI and CDK4/6? I would not. I don’t think that’s warranted across all patients. I think there’s especially some patients from which you’re worried either that they’re experiencing progressions but scans don’t reflect that, like patients with lobar tumors or patients that have painful bone metastasis for which the scans are not very good at predicting progression.

And then there’s patients from which you’re concerned that a progression may actually lead to poor outcomes. There are patients with visceral disease involvement. You don’t want patients to have increased organ dysfunction from progression. And so I think, for these patients, trying to detect molecular progression and act on that is clearly beneficial.

I think this update of SERENA-6 clearly shows a benefit in PFS, quality of life, ctDNA was very compelling. PFS2 is a little harder to interpret in this trial, but I don’t think it’s necessary. I think the benefit is there. We would love this strategy, as I believe we would love also gedatolisib.

Now I think it was extremely effective. When you think that the control arm in VIKTORIA-1, fulvestrant-alpelisib, a highly effective combo for this population of patients with PIK3CA mutation, doubling PFS versus that combo I think is remarkable. Now the issues are that side effects of gedatolisib are non-trivial. There is still a lot of stomatitis, 60% despite mouthwash, and it is intravenous. And so that’s kind of a switch compared to the oral medications and the evERA regimen, of course, which is also very compelling.

Now it was not tested against alpelisib. It was not focused on PIK3CA-mutant patients, but I think it will be very appealing for many patients, especially those without PIK3CA mutations.

So, many options. I predict that some patients may get camizestrant and switch and then afterwards evERA or could get VIKTORIA-1. I don’t think they’re exclusive. And so I think patients overall will do better with these options.

Rugo: I see a big world of real-world data in a few years after we have these drugs available. So, Bill, you have all these options available to you and what are you going to choose? How are you going to do this?

Gradishar: Well, it’s messy right now and I think the real-world data ultimately is going to inform. I mean, we have vepdegestrant [Veppanu] out there too. I mean, there are all these drugs and one of the key questions is whether there’s going to be … you know, we have the same question with ADCs [antibody-drug conjugates]. Is there a particular sequence that makes some sense? Or even more broadly, do we think that one of these drugs or this class of drugs will work after you’ve progressed through prior SERD? And we don’t know the answer to that.

I mean, on the surface, we might say no, but we might be surprised. As Paolo was saying, there are these doublets and triplets and maybe they’ll be able to overcome some of the resistance that we see when you treat with monotherapy. We just don’t know yet. And I think that’s going to really … It’s incumbent upon us to really capture that real-world data.

Rugo: Yeah. And it’s interesting because gedatolisib is moving rapidly into the first-line setting in both endocrine-resistant and sensitive disease. And if that turns out to be something people use and they make a sub-Q [subcutaneous] dosing available, then it may be that sort of our whole pattern changes. And the issue about oral SERDs will also come up because I think we all expect and hope to see giredestrant at least approved in high-risk early-stage disease and we don’t know whether that’s going to be better sequenced with CDK4/6 inhibitors or combined.

We saw that in the first-line non-ESR1-mutant population, giredestrant and palbociclib was about the same as an AI and palbociclib in persevERA. So hard to know what we’re going to be doing, but I guess I think that your guys’ approach is really very helpful. You take a unique population for SERENA-6 and then you really decide based on the individual patient and ESR1 mutations for the next-line therapy with these various options.

Gradishar: One of the issues too, just quickly, is what if we saw 4 to 6 months with sequential use of endocrine agents? That might be compelling enough to not pivot to chemo or an ADC if we could do that repetitively. We don’t know that yet, but we’ll see.

Rugo: Yeah, it’s interesting because I do think that as we treat more aggressively, we see more liver metastases in ER-positive disease when patients progress because we’ve treated them for longer before they have progressive disease and they tend to develop endocrine resistance.

So if we start moving all these drugs into the early-stage setting, it’s going to really change what we see in the metastatic setting, I think. But that’s probably, my guess, quite a number of years away from where we are now.

Please enable JavaScript to view the comments powered by Disqus.