Dr. Aditya Bardia:
Welcome to the ASCO Post Roundtable Series on Novel Therapies for Advanced Breast Cancer. I'm Aditya Bardia, breast medical oncologist at Massachusetts General Hospital, Harvard Medical School. Joining me today are two of my colleagues. Dr. Tolaney?
Dr. Sara Tolaney:
Hi everyone, I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute. Thanks so much for having me.
Dr. Bardia:
And Dr. Wolff.
Dr. Antonio Wolff:
Good morning. My name is Antonio Wolff. I am a breast cancer medical oncologist at Johns Hopkins in Baltimore. Glad to be here.
Dr. Bardia:
Great. Today, we'll be discussing recent updates in the treatment of advanced breast cancer and integrating these new therapies in three patient scenarios. Our first installment will focus on treatment of hormone receptor–positive, HER2-negative metastatic breast cancer.
Let me start with a patient story. This is patient HB. HB is a 65-year-old female who was diagnosed with localized hormone receptor–positive, HER2-negative breast cancer in 2010. Received adjuvant exemestane for 5 years and then unfortunately, 6 years later, had disease recurrence in the bone. Had a bone biopsy which confirmed that the tumor was hormone receptive–positive, HER2-negative. She then started treatment with letrozole and a CDK4/6 inhibitor. It worked for about 2 years and then in 2023, the patient had disease progression with an increase in bone involvement as well as new liver lesions. The first question I'll ask Dr. Wolff is, which therapy would you consider next?
Dr. Wolff:
Aditya, thank you for the opportunity. This is a very common scenario and it is distressing to see disease recurring because I think this is a perfect example of what can happen. This is someone with disease recurrence in bone 11 years after initial diagnosis, 6 years after finishing adjuvant exemestane for 5 years, and she then started letrozole with CDK4/6 inhibitor. It's quite reassuring to see a long progression-free survival of about 2 years, although for the patient this is absolutely not long enough. But I think this is what we tend to see in patients who have disease. It does not appear to be immediately refractory to an aromatase inhibitor.
I think the immediate question here is, what should we do? Because we do have a couple of options. Should we simply change to a different SERD or to a different antiestrogen? An option could be a SERD such as fulvestrant, which it took a while for us to finally figure out how to use it because the initial studies of using without the loading, those were pretty unimpressive. But then we learned about the need to load up the patient with two injections of 500 mg, 2 weeks apart. We have questions about the possibility of keeping the patient still on the CDK4/6 inhibitor. I think we now have some evidence with the MAINTAIN study and switching from first line CDK4/6 inhibitor, usually palbociclib in those studies, now to moving the patient, for instance, to ribociclib. So, that's an option to consider.
We have more traditional options, which is actually a drug that I will admit for a while I was not knowing how to best use it, which would be everolimus. So, switching to another antiestrogen, whether it's injectable like fulvestrant or another aromatase inhibitor, but using everolimus and you can potentially avoid some of the toxicities by even reducing the dose upstart. I must say anecdotally, I have had very favorable experience with some of my patients with that strategy. The key issue here is what else can we know about this tumor and about the disease status? Because with these patients, as the tumor evolves, the tumors begin to develop somatic changes and this could certainly inform the decision about what to do next. Some patients may also have germline mutations that could influence therapy in the future. So, a couple of options. I would say for the most part, the first thing I would like to know is more information.
Dr. Bardia:
That's a great point. I think we need more information because that could guide treatment and there are treatment options, Antonio, as you nicely highlighted, which could include a continued CDK4/6 inhibitor, fulvestrant, everolimus. Sara, what would be your approach at this point?
Dr. Tolaney:
I think it's nice to have so many treatment options, but as Antonio pointed out, it's really important to have more information. At this point, I do think it's standard after someone has progressed on a CDK4/6 inhibitor to get a genomic analysis. Right now, I would typically get a ctDNA analysis simply because it's a little more practical to be able to get data back in a timely fashion. Here are the things that I would really want to know would be ESR1 mutation status. This patient's been on an AI in the metastatic setting for a couple of years now. We do know that about 30% to 50% of patients who progress on an AI in the metastatic setting will develop an ESR1 mutation and now we do have an agent that is approved for patients with ESR1-mutant, metastatic, ER-positive disease.
I think the other thing we're always looking for is PI3-kinase mutation status, where we know about 40% of patients with hormone receptor–positive breast cancer will have a PIK3CA mutation. This is usually a mutation that isn't an acquired mutation but more a mutation that's present at the primary status and then continues to be present. Every once in a while you get a small amount of acquired PIK3CA, but usually if you had gotten that mutational status at baseline, you would know that information. It sounds like this patient hasn't yet had genomic analysis. So, I think those are the key things that we're looking for right now to help us make a treatment decision.
Dr. Bardia:
Now, that's a good point in both, we're consistent on this in terms of the need for more information and to get genotyping. So, that's exactly what was done. The patient had plasma-based genotyping and ctDNA analysis revealed both PIK3CA and ESR1 mutations. Both were detectable in blood. Sara, now that we have the information, how would you choose the next therapy?
Dr. Tolaney:
It's a case that's going to be a little controversial here, which is good because I think it does go to show how we do have choices and there certainly isn't a right or wrong answer. I think the challenge here is that one, the patient has an ESR1 mutation. So, we know elacestrant could be an option. I think the challenge with elacestrant is we did see a very steep drop-off in the curves in the EMERALD trial where there are a lot of patients who progressed on initial restaging, but yet then there were some patients who continued to have benefit. In fact, a very interesting subgroup analysis of EMERALD had shown that patients who had been on their upfront CDK4/6 inhibitor for over 12 months could have a PFS as long as 8 months in the ESR1-mutant patients, whereas the median PFS in someone with an ESR1 mutation with elacestrant was just under 4 months.
I think maybe it's a way to help us select patients who are actually going to gain quite a bit of benefit from elacestrant. This patient did have a time on their AI/CDK longer than 12 months. So, would fit that category of someone who may have a nice response to elacestrant as monotherapy. On the flip side, they have a PI3-kinase mutation and the challenge is we do know that patients with PIK3CA mutations often are a little bit more resistant to endocrine monotherapy. We don't yet have data from EMERALD looking at outcomes for elacestrant monotherapy in the PIK3CA-mutant patients. Hopefully, we will see those data soon. So, that always makes me a little anxious truthfully because I do know that PFS is a little bit shorter, for example, with SERD therapy in general like with fulvestrant, when given as monotherapy here.
But we do have an agent that targets the PI3-kinase mutation, alpelisib, and we do have data from the BYLieve study that had looked at the combination of fulvestrant alpelisib in patients with the PI3-kinase mutation and in patients who had progressed on prior CDK4/6 inhibition. In general, the PFS was around 7 or so months, but when they looked at the subgroup in BYLieve that had both an ESR1 mutation and a PI3-kinase mutation just like this particular patient in a post-CDK setting, the PFS was a little over 5 months, which truthfully is a little longer than what we've seen in EMERALD. So, I do tend to err on the side of using a PI3-kinase inhibitor in this setting.
But my challenge is that it's a tough drug. Alpelisib is associated with hyperglycemia, rash, a lot of dose holds, some dose discontinuations. So, I would have to think about this particular patient a bit more to understand what risk they have for developing hyperglycemia and making sure they're looking at BMI, baseline fasting glucose, things like that to understand tolerability of this agent in this case. I think it would be a decision and one could think about these options potentially sequentially as well. So, it's not that you have to give necessarily just one choice. Again, they could potentially get these agents one after another. I will say I'm hoping we will see approval of capivasertib soon too because that could be another nice option for this patient with a little, probably better tolerability.
Dr. Wolff:
Sara, let me ask you one question about, great discussion, thank you for all that you said, the issue of toxicity I think all of us were alluding to. We are all dealing with the fact that these drugs were approved on the basis of MTD, maximum tolerated dose, and not what we would like to have, which is the minimum effective dose, MED. For a lot of these drugs, I have taken a detect of potentially starting at a lower dose and assessing tolerability at the beginning. Have you done that to alpelisib? Because I agree with you, with full doses, it's not an easy drug to use.
Dr. Tolaney:
Yeah, truthfully, I actually have not done that. I do do that with some other agents. Sometimes everolimus, for example, I'll start a little lower. With alpelisib, I've traditionally tried to use other agents to help mitigate toxicity like using the antihistamine starting the day before treatment. Now, we have data from METALLICA for using metformin starting a week prior to initiation of alpelisib. So, those are some strategies I have taken on, but actually I haven't. Have you tried starting low with alpelisib and how has that gone for you?
Dr. Wolff:
Anecdotally, the answer is yes. Usually, dropping the dose by a little, one dose level. I'm still seeing issues. It's not as if you are getting rid of the toxicities. I don't have a good answer. I haven't seen a formal case series reported to potentially guide us.
Dr. Bardia (12:35):
It's an interesting point and sometimes with abemaciclib as well, we start with a lower dose, especially in the adjuvant setting, and bring it up. So, it's an interesting concept about minimal effective dose rather than the highest tolerated dose.
Continuing on the topic of other therapies, are there upcoming therapies you're excited about, I'll start with Sara first and then Antonio, over the next 2 to 4 years? Say, we do this in 2024, what are the therapies that we might see or you're excited about?
Dr. Tolaney:
This space post-CDK4/6 inhibition is I think rapidly evolving. Antonio brought up that we could think about changing to CDK4/6 inhibition, but truthfully, we don't yet have phase III data for doing that. We're all awaiting post-MONARCH for example to understand. I think truthfully, genomics are going to play a big role in how we approach patients in this post-CDK4/6 setting.
Right now, we talked about just ESR1 and PI3K, but in truth, I think there's going to be a lot of other things we're going to need to think about to select patients for treatments. We alluded to the fact that we hopefully will have capivasertib available. We'll see what the approval is, but if it were in a biomarker enriched population, then we'd have to think about AKT mutations, P10, as well as PIK3CA for that particular agent. So, I think that's an exciting agent moving along.
There's also multiple other drugs, multiple oral SERDs, not just elacestrant in development here, other novel endocrine therapies, PROTACs, SERMs. So, we're going to see a lot of novel antiestrogen agents move into this space, which will be very exciting because it'll be interesting to understand how these drugs can function as monotherapy as opposed to SERD-targeted therapy combinations, which I think will be very attractive in a post-CDK setting.
I think beyond that, there are also novel targeted therapies that are moving into this space, things like CDK2 inhibition, novel CDK4 inhibitors, as well as CDK7 inhibitors. There are all these cell cycle agents that are moving into this space as well. So, I think, again, lots of novel combinations to be had. Certainly, of course, there are also the ADCs that are trying to inch their way a little bit earlier in the field. We'll see all of this change, I think, quite rapidly over the next year or two.
Dr. Bardia:
That's great. It looks like Antonio will lead another ASCO guideline updates next year and maybe biomarkers as well. So, your final thoughts related to the future in upcoming therapies and biomarkers?
Dr. Wolff:
Sara gave a great summary of all that is coming down the pipe, and I think recently, we saw the interesting and exciting news of the potential for using also checkpoint inhibitors in patients with HR-positive disease. But we know that even for all of these therapies, it's not going to be for everyone. We haven't seen the official data yet from checkpoint inhibitors, but we have preliminary data in the neoadjuvant setting from groups suggesting that patients with high genomic risk may be a particular group of patients that could benefit from these types of initiatives.
I think the biggest challenge is, I don't know whether it's going to be guidelines. First and foremost, we need data, which is actually how to better select the right treatment for the right patient at the right time? Because again, we have always thought of HR-positive disease as a better phenotype because these patients have a longer natural history. But it's almost as if the most common subtype of breast cancer is now becoming... I don't know if we can call it an orphan phenotype? It's just getting too confusing and there are too many options.
A lot of these patients, after CDK4/6 inhibitors, they are not doing well. They are really having rapid disease progression despite the advances with CDK4/6 inhibitors. So, the biomarkers are going to be so critical and from a quality of life standpoint, figuring out which patients we can do a little bit more by perhaps doing a little bit less and minimizing toxicity from some of the combinations from some of the drugs as full doses, because sometimes we're surprised. We all have had examples. We go back to an old-fashioned antiestrogen after progression on some of these drugs and sometimes we still see responses again.
So, whether we can reset the estrogen receptor, we just don't understand enough. I think we just need to be humble and remind ourselves that sometimes we may be able to get along from a quality of life standpoint with a little bit less therapy and with diseases that may sometimes be more indolent. I don't envy the oncologists in the community, especially those who are seeing so many different diseases, not just breast cancer, to try to keep up with what is happening.
Dr. Bardia:
That was fantastic. Thank you so much for the nice summary. Both Sara and Antonio, thanks for summarizing future directions in terms of what we can expect.
I'll finish with key clinical takeaways. To summarize, endocrine therapies, the mainstay of management for patients with hormone receptor–positive breast cancer. At this time, first-line therapy would include endocrine plus a CDK4/6 inhibitor, given that we've seen improvement in overall survival. In the post-CDK4/6 inhibitor setting, in the second-line setting, we would strongly recommend genotyping to evaluate for actionable alterations.
For a patient with PIK3CA-mutant hormone receptor–positive breast cancer, alpelisib plus fulvestrant is the standard of care. For patients with ESR1-mutant breast cancer, elacestrant is a potential option. These therapies can be used sequentially in the metastatic breast cancer setting. There are several oral SERDs in clinical development, which both alone and in combination with other targeted therapies like PI3-kinase or AKT inhibitor will likely change how we practice in the upcoming years.
This brings us to the end of the case. Please see the other segments for further discussion about the latest data in metastatic breast cancer or visit ascopost.com. Thank you so much for joining today.
