Navigating Treatment Failure in CDK4/6 Therapy From The Pharmacist’s Perspective

Ryan Haumschild, PharmD, MS, MBA: Now let’s talk about the latest data around CDK4/6 [cyclin-dependent kinase 4 and 6] inhibitor use in the HR+/HER2- metastatic breast cancer patients. I want to start it off by talking about the pharmacist role. So many times we talk about how essential it is getting patients on the right therapy and keeping them there. But I also think the pharmacists are really essential in determining, if a patient is having a treatment failure? Is there any type of treatment resistance? Do we need to pivot in treatment as a whole? Dr Kettle, if you could kick us off, what is the pharmacist role determined treatment failure and treatment resistance in oncology therapies prior to CDK4/6 use?

Jacob K. Kettle, PharmD, BCOP: I think honestly, this historically has been an area where we have not traversed much in the pharmacy profession. I think we tend to be naturally lab driven and with a historically defining progression resistance; those things are going to be based on clinical exam, presentation of new symptoms, and particular radiographic evidence. Things we understand and utilize, but maybe not as predominantly as other members of our multidisciplinary team. I think what’s really exciting is just emerging data. We’ve started incorporating this—and this is outside of breast cancer—but into our precision oncology program, looking at minimal residual disease testing. How does that play a role in certain malignancies? [We’re looking at] circulating tumor DNA testing. From a big-picture level, I really do think we are moving into a space where we’re going to be able to do lab tests to confirm early on when patients have signs of progression, and how we incorporate that clinically. When does that determine when do we add different drugs? When do we not? I think we have a long way to go before we figure that out. But I think now [it’s] a good segue way from talking about adherence; I think from a pharmacist perspective, if we notice there are major adherence problems or the patient experienced the refill record, [if] those indicators don’t quite match, I think it’s really important at that point to engage with providers and [say] we may be heading into a problem here. [This is a benefit of] early identification. I’d be really interested to know if our other panelists have some additional insight on that question.

Rose DiMarco, PharmD, BCPS, BCOP: I can echo what Dr Kettle mentions. I’m one of the first people who says “I think something’s wrong.” Sometimes we’re getting a lot more contact with the patient than the physician is, or even nursing. Sometimes I know this patient is acting a little bit differently than they did before [and] I think we should take a look at something, even though it hasn’t been 3 months yet. I think we need to scan earlier. Sometimes a patient will start to tell me, “I just don’t feel like taking my med anymore.” It clues me in that something is going on. I just think that’s a unique role. I don’t think the physician is going to get the kind of real-life discussions that we have with our patients. I think it’s led to a lot of interventions. We’ve switched patients’ [medications] early because I’ve said something is wrong and I can’t tell what it is, but I think we need to look into it.

Jacob K. Kettle, PharmD, BCOP:Yeah, there’s a degree of intuition, and I call them pink flags. Sometimes we don’t have these big giant red flags that indicate there’s a problem, but you have an accumulation of a couple of different little pink flags that start to lead you toward those suspicions. Like you said, they’re not having adverse effects all of a sudden anymore. [Is it because] they stop taking their medicine, even though they didn’t tell you, or the refill history doesn’t look right, or their motivation for taking treatment has waned all of a sudden? I think all those things can be little subtle indicators; pharmacists play a real key role in picking up on those, even if it’s not the real overt signs and definition of progression, resistance, relapse, what have you. It’s picking up on those subtle clues and identifying those.

Ryan Haumschild, PharmD, MS, MBA: Well, thank you for that. As we build upon that, as we’re thinking about treatment, I think one of the other things that we think about a lot is overall survival, especially in our breast cancer patients. It is really kind of the hallmark indicator. As a patient meets with their provider, they’re thinking about outcomes. I’m sure they may have done their own research, but at the end of the day, it’s, “How am I going be able to live, and what’s going to improve my ability to survive my cancer diagnosis?” Dr Moore, I’d love for you to weigh in on this. When you’re having conversations with patients, as the pharmacist in clinic, describe the importance of overall survival, how it relates to clinical practice and your decision-making. Are there any real data around CDK4/6s that you can explain how that can impact overall survival as well?

Heather Moore, CPP, PharmD, BCOP: I think those are great points. When we think about selecting therapy for patients, a lot of what we’re looking at, especially in the metastatic setting, as you mentioned, is progression-free survival and overall survival. The reason that CDK4/6 inhibitors are first line is because we know that we have overall survival with these agents. Even prior, we had a trend toward overall survival when looking at the progression-free survival. If you’ve been aware of the data over the last year or two, we’ve seen a lot of controversy between abemaciclib, ribociclib as well as palbociclib in the overall survival space. We’ve seen overall survival that is statistically significant with drugs like ribociclib and abemaciclib. We haven’t seen that with palbociclib, and I think that really does impact and influence the physician’s choice when they’re deciding which agent is best for a patient. Because of the overall survival that we see with both of those agents, we are more inclined to use ribociclib or abemaciclib in clinic because we know that they have a statistically significant overall survival advantage vs maybe using an alternative agent like palbociclib. Now to those lines, you make a great point in thinking about the real-world setting. How does that translate? We’ve seen with a variety of studies that we do tend to still see the overall survival and progression-free survival advantage in the real-world setting for all of these agents, even though there has been a little bit of controversy. Thinking about that and going back to what we talked about earlier, I do think it’s really important that when we’re making a decision, yes, you want to think about the data side of things and efficacy, I think that’s always essential, but also thinking about the characteristics of your patient. Something that you mentioned earlier that I think is so important is thinking about the characteristics of your patient and then, how do you find the best drug for them? I’m always about making the drug fit the patient instead of making the patient fit the drug. For instance, if you have a patient with a history of arrhythmia, perhaps we don’t put them on ribociclib. If you have a patient who has a history of colitis or IBS [irritable bowel syndrome], and then maybe we don’t think about abemaciclib. Thinking about an older patient, multiple comorbidities, even though palbociclib doesn’t have that statistically significant overall survival, thinking about the data that we have and thinking about the PALOMA studies [NCT01740427 and NCT01942135], it’s still a very good drug. Thinking about choosing your decision of what you’re going to do, it’s still very reasonable to put that patient on palbociclib. I think, yes, think about overall survival and progression-free survival. All are very important. But also thinking about your patient who is in front of you and implementing the data that you have with your patient and making the right choice for them. I think [it’s] multifactorial, but of course it’s always going to be data driven.

Ryan Haumschild, PharmD, MS, MBA: Data driven, but I love how we’ve both brought it back to the patient. It’s really about shared decision making with the patient. Abemaciclib and ribociclib might have the clear overall survival benefit, but palbociclib’s been around. It has good data. Patients have tolerated it well. Many of us have seen patients do well on that treatment over time. We know there are different adverse effect profiles. It’s creating that treatment approach but individualizing it. I think that’s really the difference maker. You know, speaking of other treatments, we said that progression-free survival is data that we do have on all. That’s something that we use for decision-making.

Transcript is AI-generated and edited for clarity and readability.