Optimizing Treatment for HR+/HER2- Metastatic Breast Cancer - Episode 5

Novel Treatment Modalities Under Investigation in HR+ Metastatic Breast Cancer

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After briefly addressing resistance to endocrine therapy, expert panelists broadly review novel treatment modalities in the setting of HR+ metastatic breast cancer.


Jules Cohen, MD: Dr Slamon, do you want to talk about resistance to endocrine therapy and mechanisms and strategies to overcome it?

Dennis J. Slamon, MD, PhD: One of the clear mechanisms that has come up is the PI3 kinase pathway being activated, either through mutational status, or there is preclinical evidence, but not clinical yet, that upregulation of a nonmutated variant also can participate in the resistance phenomena. There have been strategies that have tried to use triplet therapy, where you add the PI3 kinase inhibitor up front with CDK4/6, an endocrine blockade. It’s been sad to say that those have been very poorly tolerated by patients. It limited their availability in those trials, at least with the current suite, which have been stopped. We’ll see if that changes with some of the newer ones. Right now, that is certainly a pathway. ESR mutation status for hormonal blockade, specifically with AIs [aromatase inhibitors], is a mechanism. There are data showing that tracks also for CDK4/6, although there isn’t any clear biologic reason why that should be so, but that is according to clinical data. It would be good to see that explored more to see if that would be the case.

With the new class of SERDs [selective estrogen receptor degraders], in particular, some of the PROTAC [proteolysis targeting chimera] molecules, which target the proteosome inhibitors, are even better degraders of the estrogen receptor. That might be even more effective in this pathway. Time will tell, we’ll have to see what they do clinically. They’re being tested head-to-head, but the early data looked pretty impressive, some of which are being presented at San Antonio Breast Cancer Symposium this year.

Jules Cohen, MD: I believe the VERITAC trial is going to be presented tomorrow, which looks at ARV-471, which is one of the PROTACs. PROTAC, as I understand it, is sort of a bivalent molecule where one part of the molecule targets the estrogen receptor and the other targets the proteosome. It delivers the estrogen receptor right to the proteosome for degradation.

Dennis J. Slamon, MD, PhD: It gets it to the…ligase, which then takes it to the proteosome for degradation. You apparently get a much greater degree of illumination of the whole pathway by taking the receptor even more out of the picture.

Jules Cohen, MD:Dr Mortimer, do you want to speak about elacestrant or any of the other novel oral SERDS that look like they’re doing well and nearing FDA approval?

Joanne Mortimer, MD, FACP, FASCO: Elacestrant is an oral SERD. The data from the EMERALD trial was presented last year at the ASCO [American Society of Clinical Oncology] meeting and was incredibly exciting. EMERALD looked at elacestrant as a next-line therapy in patients with hormone receptor-positive breast cancer. This included patients who’d received fulvestrant, another SERD. It turned out that elacestrant had a significant improvement in progression-free survival. It looks like overall survival [OS], but they didn’t meet the statistical end point that was preplanned. Those data continue.

One of the other unique things about the EMERALD trial is they looked at elacestrant in patients who had ESR1 mutations. This was a very effective drug in patients with ESR1 mutations. I think some of the data that are being presented at this meeting look at the duration of prior CDK4/6 inhibitors in response to elacestrant. The longer you are on a CDK4/6 inhibitor, if I remember correctly, the greater your likelihood of responding. This sort of makes intuitive sense, that people who are hormonally sensitive tend to respond better to hormones and the longer the duration, the more likely they are to respond. Those data are to be presented here too. As for elacestrant, I don’t know where it is from a regulatory standpoint, but it’s clearly a very exciting drug. I presume it is soon to be approved.

Jules Cohen, MD:I think this analysis that looks at the length of time on CDK inhibitors is very exciting. Apparently, in patients with an ESR1 mutation, if they were able to be on the CDK inhibitor for at least 12 months, their progression-free survival on second-line elacestrant is something like 8 months, which is quite good and a lot better than the undifferentiated data for elacestrant. Dr Iyengar, do you want to talk about other novel strategies to treat ER-positive breast cancer, say the AKT inhibitors?

Neil M. Iyengar, MD: I think the phase 3 data testing capivasertib are exciting. We see activity with this AKT inhibitor in combination with endocrine therapy in the overall population, particularly in patients who have tumor mutations in the PI3 kinase, AKT, and related mutations in that pathway. I find those data to be particularly interesting because of the benefit in the overall population as well. We initially thought of AKT inhibitors as a strategy for those tumors that had mutations in the PI3 kinase pathway, PTEN loss, for example, or AKT mutations, but that activity in the overall population is encouraging. This gives us another molecular strategy in the metastatic setting. We now need our endocrine therapy partners to catch up with the molecular partners that are starting to become available. That’s yet another opportunity, in my opinion, for the oral SERDs to be combined with these molecular therapies. Those trials are ongoing.

Jules Cohen, MD: Dr Slamon, do you want to discuss antibody-drug conjugates [ADCs] and their accelerating role in ER-positive metastatic breast cancer?

Dennis J. Slamon, MD, PhD: The ADCs have moved from being not looked at closely to something that now is front and center. It looks like that has largely been accomplished with new strategies for linker payloads and linker payload combinations. The old ADCs suffered from the fact that they frequently came off the antibody before they got to the target and you had systemic effects. There were a lot of failures that biased everybody against it, using the older strategy for linkers and some of the payloads. With the newer strategies, it has come to the fore with what has been seen with the deruxtecan molecule and what we see with Trop-2, an ADC inhibitor. The data are pretty compelling. I think the strategies are going to continue to pay off as new surface proteins are identified.

In terms of the safety threshold, having clean expression in noninvolved tissue, nonmalignant tissue, is critical. Perhaps some of the earlier adverse effects that were seen with the HER2 blocking agents with the later generation medications were due to targeting normal tissue, where the 1-plus HER2 testing score, or low level, as we heard at San Antonio, drugs are effective. We have to remember normal tissues express that level as well, so we have to be very careful. In fact, in some of the early studies of HER2 expression, it is the normal bronchial epithelium that expresses among the highest levels, among normal tissues. That could explain some of the things that were seen on the phase 1 studies before it was fully appreciated that this drug could cause this class of toxicity. It’s something to watch, but I think ADCs are here. They’re here to stay. I think you’re going to see an expansion of this, and even better chemistry with linkers and payloads.

Transcript edited for clarity.