Considerations for Selecting and Sequencing Therapy in HR+/HER2- mBC
In light of the second-line treatment armamentarium for patients with HR+/HER2- metastatic breast cancer, expert oncologists discuss the selection and sequencing of specific agents in this setting.
Transcript:
Joyce A. O’Shaughnessy, MD: Just a couple of questions, if you could say a word about selecting among CDK4/6 inhibitors in the first-line setting, but also, what do you tend to do from a practical standpoint? How do you sequence [the] therapy going to the patient in the second-line setting?… Pedram, what do you do both with regard to CDK choice and also sequencing?
Pedram Razavi, MD, PhD: So I think why we had the data in the beginning, and we saw that the progression-free survival [PFS] for all of these 3 CDK4/6 inhibitors in the first-line setting were very similar; we assume that these are all the same and they’re going to do the same thing, and that’s why we have the similar PFS. But now that we are getting more OS data from these large, randomized trials, it is becoming more obvious that these are not exactly the same drugs, and they have different efficacies and potentially even different mechanisms of actions and mechanisms of resistance beyond what they do with CDK4/6 [inhibitors]. So I think considering the overall survival benefit from ribociclib and also with abemaciclib, now more often I…for abemaciclib, but more often I offer the patients in the first line setting, one of the two. I discuss the [adverse] effects with the patients and often decide if the patient doesn’t have any contraindications for any of them. But [abemaciclib] has its own [adverse] effects. [With a] patient who has a colitis history [or] IBD [irritable bowel disease], history of something that makes me concerned that I might miss the abemaciclib-induced diarrhea, some of those underlying issues, I [am] more likely to offer that patient ribociclib or [if] the patient has cardiac issues or a medication that has QTc prolongation or has extensive liver involvement, the abnormal liver function tests might get worse on a liver toxicity on [ribociclib]. I might offer them [abemaciclib]. So we have to consider the clinical setting for the patients and know what are the potential other factors that change our decision. But overall, I’m more inclined to offer ribociclib in the first-line setting.
Joyce A. O’Shaughnessy, MD: I’ve really gone that way myself because of the evolving survival data. And, Komal, how do you decide what to do in the second-line setting upon progression on first-line CDK4/6 [inhibitors]?
Komal Jhaveri, MD, FACP: That’s where it gets the way more complex. That’s where we have so many things as a potential answer and so many things.... For example, if there are no alterations, as we were discussing [with] case No. 1 and there was nothing actionable detected, we certainly can rule out your alpelisib, which is only approved [with] PIK3 alteration. So we know that option is not appropriate. So then what would be considered, assuming based on the [phase 3 CAPitello-291] trial [NCT04305496], capivasertib gets approved, I think that would be a very strong dataset to apply if it gets approved in an all-comers setting. Because then our data that we have with everolimus, which is approved based on [the phase 3 BOLERO-2 trial; NCT0086365] predating the CDK4/6 approval, our data right now in the real-world datasets of maybe the…trial or retrospective dataset or other real-world datasets, it’s ranging about 4 to 5 months. And then capivasertib with 70% of the patients with prior CDK4/6 inhibitors is 7.3 months [of progression-free survival; PFS], which is similar to what we saw…with capivasertib if we had the PITK alteration. So that could be one potential strategy. Now [the MAINTAIN trial; NCT02632045] did affirm a little bit of our inclination about continuing CDK4/6 rechallenge after progression, especially if you swap both the endocrine therapy partner and the CDK4/6 inhibitor as was done in that study. It’s a phase 2 study…I’m happy to see those results. I just don’t know if that is necessarily ready for prime time for all patients in-clinic. The PFS is 5.2 months, so I’m really keeping my eye out for trials such as post-MONARCH, which are randomized phase 3 trials, looking at ribociclib plus fulvestrant upon progression on an AI-CDK4/6 [inhibitor] in the second-line setting. I’m looking for trials such as [the phase 3] EMBER-3 [trial; NCT04975308], which is looking at oral SERD [selective estrogen receptor degrader] imlunestrant plus abemaciclib in one of the arms in that study. So if imlunestrant alone [is] superior to standard-of-care endocrine therapy, we will then look at in imlunestrant versus imlunestrant-abemaciclib. So that would be an attractive trial to keep an eye on to see if that can push the needle forward. Meaning, can we hit that bar of 7 months, and then can we look at the toxicity profiles? If a patient has ESR1 mutation we said if they have a durable CDK4/6 inhibitor in the first line and then you have only an ESR1 alteration and you’re really not worried about the tumor biology necessarily beyond that, I think elacestrant alone is appropriate. And maybe you can think about combination drug therapies with additional toxicities potentially in the third line with a caveat that we don’t have data. We don’t know what fulvestrant plus [capivasertib], for example, or everolimus plus fulvestrant, for example, would do after elacestrant. We don’t know that. But that’s something that we have learned in breast cancer, even in HER2+ disease. T-DM1 [trastuzumab emtansine] got approved in the second-line setting…that’s where we were using that in until T-DXd [trastuzumab deruxtecan] replaced it. So I think this is what we would do. What we don’t know is if you have both P3CA alteration and ESR1 alteration, [if there is a] particular sequence, whether elacestrant first and say [capivasertib] and alpelisib or vice versa makes more sense in pushing down [chemotherapy] even further and maintaining the efficacy for the patient population. So we don’t have some answers, but at least this is how I think about it. Does this patient have primary endocrine resistance? Then we’re not necessarily thinking about a different therapy, we’re potentially thinking [chemotherapy] or even ADCs [antibody-drug conjugates] or relevant clinical trials in that space. Or if it’s only ESR1 alteration, maybe elacestrant alone. If it’s P3CA alteration and if [capivasertib] gets approved, I might tend to use [capivasertib] over alpelisib given less hypoglycemia and just diarrhea and rash, which I think we are probably in a better position to handle for more patients in some ways. So I’m a little biased there with that from the safety profile. And if they’re both, then I feel like I’m just going to discuss it with the patient and [look at] other characteristics such as tumor burden what liver metastases, how prolific that is, and what does the patient think about that. How will they want to perceive that information and how do we make that decision together, because we really don’t know how the sequence would play out in either way.
Transcript is AI-generated and edited for clarity and readability.
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