Emergence of CDK4/6 Inhibitors in mBC Treatment Pathway

Ryan Haumschild, PharmD, MS, MBA: For a viewing audience, it’s helpful for them to know how the treatment landscape has evolved over the years. There are more treatments, but historically there haven’t been as many options outside of chemotherapy. Dr Moore, I know you’ve been practicing [as] a breast cancer specialist here and for a number of years, and you’ve seen a lot of changes in the space. Can you review the chemotherapy regimens that have been conventionally used in these patients [with] HR+/HER2– metastatic breast cancer? On top of that, what are some of the potential benefits or drawbacks with some of these chemotherapy regimens?

Heather Moore, PharmD, CPP, BCOP : First and foremost, we’re thinking about our patients [with] hormone receptor–positive [disease]. Our goal is to avoid chemotherapy in those patients. And what we know is that we have a target. They’re hormonally driven. So what has typically been the standard is thinking about a monotherapy endocrine backbone. So thinking about things like tamoxifen or aromatase inhibitors. And we find that sometimes in community settings, there are providers that will start patients on chemotherapy. And we have a lot of data now to support that. Even if patients are in a potential visceral crisis, [findings from] studies [such as] the RIGHT Choice study have shown that we can use CDK4/6 inhibitors in instances [such as] that vs starting with chemotherapy alone. Of course, we have to be mindful [when] thinking about hepatic dysfunction and what that looks like and making the right choice for the patient. But…for patients that may be in visceral crisis or have a high disease burden, there are times when we do have to give chemotherapy, and in those instances, we’re generally going to give something [such as] small doses of weekly paclitaxel. Sometimes you may consider doing a doublet if they have more extensive disease. But when we think about what goes along with chemotherapy, it’s like some of the things that you mentioned. So having concerns from an adverse effect perspective, but having to come into clinic, to go into the infusion room, to have IV [intravenous] infusions every week vs having the ability to be at home, be on an oral medication. So it [affects] their quality of life at home, their family members, how they’re interacting with society vs the ability to take an oral targeted therapy. So we’ve really moved from chemotherapy into targeting the endocrine pathway but taking it a step further: how we can do that to target [disease in] patients with certain mutations.

Ryan Haumschild, PharmD, MS, MBA: Chemotherapy is still utilized. But you’re right. We want to use the most appropriate therapy. The good news is we’ve gotten more targeted therapy, therapy that might have more reduced adverse effects and be more tolerable so that these patients have a better durability of response over time. And you hinted at it. We’re talking about the CDK4/6 [inhibitors] and other treatments, and that’s becoming a mainstay of treatment across a number of different providers and consensus guidelines. Dr Kettle, I’d love for you to weigh in. What is the role of the CDK4/6 pathway and metastatic breast cancer? And while you’re answering that and talking about the CDK4/6 use, what are the 3 approved FDA agents for [management of] HR+/HER2– breast cancer?

Jacob K. Kettle, PharmD, BCOP: I’ll answer the second question first, because that part’s a lot easier and more definitive. So we…have 3 approved agents: abemaciclib, ribociclib, and palbociclib. There are…lots of overlap [among] the 3 of them. And we’ll talk about this more momentarily…. But there are some unique defining features between the 2. So there [are] nuances that characterize differences between them: dosing regimen, adverse effect profile…indications, data…. [Those] are some slight differences we will highlight in a moment. But when we talk about the cyclin-dependent kinase pathway, that’s what CDK stands for, this gets way over my head quickly, and I’m not afraid to admit that. But these are pathways that drive cell cycle replication. And if we inhibit cyclin-dependent kinase, what we do is cause the cells to enter into a phase of arrest. We arrest that cell cycle process, and that’s what we’re doing. In fact, on the cancer, this becomes manifest when you look at the neutropenia adverse effects of these drugs; you can see that you don’t need growth factor to support these patients when they [develop neutropenia] on these drugs. What these drugs do, [with] inhibition of CDK, you cause affected cells to enter into an arrest, a freeze, and when you remove the drug, those cells finish their job of replicating and dividing. So when you look at the neutropenic adverse effect of these drugs, you’ll see that neutropenia [is] typically mild. That may develop as soon as you remove the drug that resolves [it]. And that’s what these drugs do: freeze the cell cycle. And that’s effective.... There’s still hope that we find some other roles, because an upregulation of these cyclin-independent kinase processes is seen in many different types of cancer. Breast cancer tends to be a place where this lands. That makes sense. When you think of this as an arrest of processes, you pair this with other agents. Again, we’ll talk about the hormone-targeting agents in breast cancer. But the idea is if we can slow the process of the cell [and] introduce some other agents, we can reduce the development and propagation of cancer cells, particularly if they’re metastatic. And that’s the goal. That’s probably why we tend to see the efficacy of these drugs land in slower-growing malignant tumors. Again, I’m talking way above my cerebral level, but that’s part of why we see these drugs mostly propagate [in] slower-growing malignant tumors [such as] hormone-positive breast cancer as opposed to more aggressive malignant tumors.

Ryan Haumschild, PharmD, MS, MBA: Thank you for that overview. And you’re right, I do think CDK4/6 has a huge role in breast cancer, especially in this patient population in the frontline setting and even the second-line setting.

Transcript is AI generated and edited for clarity and readability.