Vidal Discusses Differences in Duration and AEs With Adjuvant CDK4/6i in Breast Cancer

EVENT REGION Florida, Georgia, Illinois, Tennessee, and Utah

PARTICIPANT LIST Ryan Carr, MD | Victor Gian, MD | Brian Hemphill, MD | Chandar Bhimani, MD | Gary Tian, MD | Carl Tahn, MD

Gregory Vidal, MD, PhD

Associate Professor

University of Tennessee

Health Sciences Center

Medical Oncologist

West Cancer Center

Memphis, TN

DISCUSSION QUESTIONS

• What are your reactions to the efficacy and safety data from the monarchE (NCT03155997) and NATALEE (NCT03701334) clinical trials of adjuvant CDK4/6 inhibitors?

Carr: I’m familiar with the data to a degree, and they have impressive improvement in invasive disease–free survival [IDFS] and other end points. I have a bias toward abemaciclib [Verzenio] in the metastatic setting because I have used it more often and find the diarrhea [adverse event; AE] a bit easier to deal with than some of the ECG [electrocardiogram] monitoring with ribociclib [Kisqali] because of the location of my clinic and our ability to do those things. It’s probably better to use longer CDK4/6 inhibition, so the one thing that may switch me over from abemaciclib to ribociclib is the ability to use it for a longer period of time in these high-risk patients.

Vidal: What if the IDFS is similar with 2 years rather than 3 years? Do you still think that holds true?

Carr: I think there has to be something to it in the very high-risk patients because you get late recurrences. We presented some data about the high-risk patients’ [disease] recurring earlier, but there are still some patients [whose disease recurs] much later. So, I think that the more CDK4/6 inhibition you can give them—that may be better. There is a point of diminishing returns; if you were going to do it for 5 years or 7 years, maybe at that point, it’s not as big of a deal. But I think the difference from 2 to 3 years might be meaningful in time.

Vidal: I hear your argument suggesting that if a patient has 10 lymph nodes that are positive, that patient probably has metastatic disease, and longer CDK4/6 inhibition might be beneficial. We’ll see more on that later once we start updating the NATALEE and monarchE datasets.

Gian: I have tried both fairly often. I have quite a few patients on both. I’ve not been able to keep people as well on abemaciclib. I think it’s a great drug. I would prefer a 2-year regimen of the CDK4/6 inhibitor over a 3-year regimen. I think that’s the preferable route to go, if possible, but I haven’t found tolerance to be great, especially [since] you’re talking about 2 years in the adjuvant setting. I’ve had to switch at least half my patients over to ribociclib because of the diarrhea.

Vidal: When you switch to ribociclib, [are] you still going for 3 years [of treatment]?

Gian: There’s no study to prove how I should do it, but that’s what I would do. As Dr Carr said, I would err on the side of longer therapy at that point. Abemaciclib may be a better drug because it is approved to be given by itself. Of the 2, you don’t give ribociclib as a single agent in the metastatic setting. You can give abemaciclib at the higher dose as a single agent, but I think the toxicity becomes excessive.

Vidal: I use abemaciclib a lot, and I’m usually able to manage [the AEs]. Don’t be discouraged about dose reduction…I’m usually able to get those patients’ diarrhea at least manageable at [a dosage of] 100 mg [From the Data¹].

Hemphill: I’m a fan of ribociclib. [It requires] a few ECGs and has what is almost certainly a class effect on the QTc interval and has a lower dose compared with metastatic disease. That makes a big difference. So far, I’ve gotten through much easier; 3 years does become a little more daunting compared with 2 years, but in a lot of these high-risk patients, we’re pushing the aromatase inhibitor [AI] to 10 years. That is going to have some incremental additional protection as well. With my patients receiving abemaciclib, many are requiring dose reductions. I have not been as big a fan of abemaciclib, but on the flip side, a lot of these patients have other medications, and it’s amazing how many drug interactions they have with ribociclib. We’re constantly invoking the wisdom of our specialty pharmacy to give me some idea about what is a severe vs moderate reaction. If there is a QTc interaction, a lot of that would have been [reported based on] the higher dose [of ribociclib].

Vidal: The adjuvant [trial] only called for 2 ECGs and not 3 as in the metastatic [setting]. Your point on drug-drug interaction is very important, and that’s one of the things about ribociclib, especially for those of us in the community, because the primary care physicians and endocrinologists who are not within our system can’t monitor what drugs [the patients] are on, and those patients are going out and getting new drugs added. If their primary care and other physicians are not aware of drug-drug interactions, you can potentially have issues with QTc prolongation. We should always remind our patients that when they’re starting new drugs, they need to let their primary care physician know that with ribociclib, there is a potential interaction that needs to be looked at.

Bhimani: I have noticed the patients who are older who have some cardiac history…some patients have a QTc interval of 455 or 460 milliseconds. I think the criteria are rigid. You don’t start it unless the QTc interval is [lower than] 450 milliseconds, is that right?

Vidal: Yes, that’s right.² You should follow it because of the medical/legal potential [issues] if you don’t. You can repeat [the ECG] if you find the offending event because the patient may be on drugs that are prolonging it. [Once] you remove that and it goes down, you could challenge [it]. But at 450 [milliseconds,] I wouldn’t start it unless I see these patients go below 450.

Tian: The patient populations in the 2 different trials are not entirely the same. Who was included in the NATALEE trial but not in the monarchE trial?

Vidal Any [stage] N0 patients are not in the monarchE trial. But in the NATALEE trial, even if you’re [stage] N0, not everybody meets the criteria. You have to be [stage] N0, grade 2, with some high-risk features, a large tumor [that is] genomic, high MammaPrint or Oncotype, with tumors greater than 3 cm. monarchE removed the [patients with stage] T4N0 [disease]; that’s a high-risk population. Those patients, although they could have been in monarchE, were excluded. Those patients are in NATALEE.

Because there are longer-term data with abemaciclib, and I’m more comfortable with abemaciclib, I give abemaciclib to patients who meet the criteria for monarchE, and the rest go to ribociclib…unless a patient cannot tolerate one or the other.

Tahn: Does [anyone] base it on dosing? Some patients are not able to keep in their head the idea of 3 weeks on, one week off [for ribociclib]. For those patients, I tend to want to put them on abemaciclib instead. And [they may be concerned with] how many times a day you have to take [abemaciclib].

Vidal: I think ribociclib has blister packs, so you know when you’re on and when you’re off. That’s very helpful. But I do have patients who say, “If I’m going to take it, I just want to know that I’ve taken it every day,” and that’s helpful. But on the other hand, I have patients who just want to take one drug a day, rather than twice a day. It can vary from patient to patient.

Gian: A lot of the patients are going to qualify for both, except for your node-negative patients who are high-risk who would qualify for ribociclib. What I would do is have the discussion [with the patient]. There are 2 different options, and I start a lot with abemaciclib because patients only want to take it for 2 years, not 3 years. [However,] I’m surprised not to hear [about] more people having problems with diarrhea.

Vidal: There are physicians who have a preference. If you [prefer] ribociclib, you talk all about abemaciclib’s diarrhea. If you [prefer] abemaciclib, [you feel] that diarrhea is easy to manage. As somebody who uses abemaciclib a lot, do [my patients] get diarrhea? Yes, but dose reduction is usually easy, and in those patients, diarrhea is well managed with dose reductions and other modifications.

Gian: I second that thought about the diarrhea with abemaciclib, and although it can be manageable, I find that a lot of the patients starting in the adjuvant setting, especially coming off of chemotherapy, tend to give up on it very early, and especially starting the standard dose. It’s hard to convince them. I’ve had several older patients say they’re done. That’s the challenge, when they don’t want to work through the diarrhea with dose reductions. They just quit in the first few months.

Vidal: I’ve had those patients, and I agree about those patients coming through chemotherapy, and what I’ve found is, if you give the plan upfront and set the expectation that this is what we’re doing next, those patients tend to have an easier transition. They know that’s what we’re doing next, rather than waiting and then saying, “I’m going to add this pill on, and then it might have these adverse events.”

There is a study that’s fully recruited [ADE-MI; NCT06169371] that is looking at starting low and titrating up and looking at tolerability and IDFS as a strategy for abemaciclib. For older patients, I usually start [them with a] lower [dose of] abemaciclib, if I’m going to give it to them.

For the dosage and administration of ribociclib, the indications are for hormone receptor–positive, HER2- negative, advanced metastatic breast cancer in combination with AI/endocrine therapy or fulvestrant in the metastatic setting or in the adjuvant setting, in combination with AI for patients with hormone receptor–positive stage II or greater breast cancer, excluding stage IV.² Dosage in the metastatic setting is 600 mg and that’s reduced to 400 mg in the adjuvant setting. In the metastatic setting, you have 2 dose reductions. In the adjuvant setting, you only have 1 dose reduction from 400 mg to 200 mg.

Abemaciclib comes in 4 doses; 200 mg is single-agent before chemotherapy.³ That study was done in the era when none of your patients had previously gotten abemaciclib. Abemaciclib had different dosing studied at 150 mg vs 400 mg for ribociclib, and there are 3 dose reductions in abemaciclib vs 1 dose reduction with ribociclib.

[There was an exploratory analysis of] dose intensity [for abemaciclib].⁴ This is very helpful to let you know that if you dose reduce your patients, they’re not losing the [IDFS] benefit. These are dose intensities of 0% to 66%, 66% to 93% or 93% and above. There is no statistically significant [difference] between those graphs. At 4 years, it is 87% vs 86% vs 83% [respectively] based on your dose intensity, with no significant difference [Table⁴].

The same thing [was studied] for ribociclib.⁵ The data were looking at dose intensity and dose reduction in terms of quartiles of 25%, 50%, and 75% dose intensity. Those graphs look very similar; there’s very little difference [in IDFS]. So, if you’re able to dose reduce, dose reduce for either drug.

DISCLOSURES: Vidal previously reported personal fees and other support from Genentech/Roche; Eli Lilly and Company; Pfizer, Inc; AstraZeneca; Daiichi Sankyo; and Merck; personal fees from Novartis; Biotheranostics, Inc; Stemline Therapeutics, Inc; ConcertAI; and Myriad Genetics, Inc; grants, personal fees, and other support from Gilead Sciences, Inc and Bristol Myers Squibb; other participants had no known relevant disclosures.

REFERENCES:

1. Johnston SRD, Toi M, O’Shaughnessy J, et al; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77- 90. doi:10.1016/S1470-2045(22)00694-5

2. Kisqali. Prescribing information. Novartis; 2025. Accessed March 26, 2025. https://tinyurl.com/2x32tzaw

3. Verzenio. Prescribing information. Eli Lilly and Company; 2021. Accessed March 26, 2025. https://tinyurl.com/jd9y97db

4. Goetz MP, Cicin I, Testa L, et al. Impact of dose reductions on adjuvant abemaciclib efficacy for patients with high-risk early breast cancer: analyses from the monarchE study. NPJ Breast Cancer. 2024;10(1):34. doi:10.1038/s41523-024-00639-1

5. Barrios CH, Harbeck N, Hortobagyi GN, et al. NATALEE update: safety and treatment (tx) duration of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2- early breast cancer (EBC). ESMO Open. 2024;9:103101. doi:10.1016/j.esmoop.2024.103101