CKD4/6 Inhibition in HR+/HER2- BC: Trial Data With Abemaciclib and Ribociclib

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Hope S. Rugo, MD, FASCO: Then we use CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors. Of course, there are 3 of them available, and we have seen a lot of recent data about the use of CDK4/6 inhibitors both in the first- and second-line setting. One of the updates that we've heard about is MONARCH 3 using abemaciclib in the second-line setting with Fulvestrant. Of course, other second-line studies as well. Then at this meeting, we presented data from a matched adjusted indirect comparison, looking at quality of life between the MONARCH 3 and MONALEESA-2 data in the first-line setting. Mark, what's your take and summary on this data and where we are now up until where we came to this meeting?

Mark Pegram, MD: I thought this was an interesting paper because biostatisticians have always taught us not to do cross-trial comparisons, and yet they come up with this novel technique of matched adjusted indirect comparisons, MAICs. They can do just that using quality-of-life data. In this case, they use the EORTC QLQ-C30 [European Organization for Research and Treatment of Cancer quality of life] metric as well as the BR23 [EORTC-breast-cancer specific quality of life] questionnaires. Using this statistical method, they were able to compare the difference in adverse event/patient-reported outcomes with these metrics between the 2 trials that you mentioned. They could compare abemaciclib plus an AI [aromatase inhibitor] with ribociclib plus an AI and really get some interesting findings. Perhaps it's not surprising to any of you who use these agents and have experience with them that what they found comes as no surprise. The overall results tend to favor ribociclib, on balance. There was less anorexia, certainly less diarrhea with ribociclib, a little less fatigue, and improved arm symptoms compared with abemaciclib. Having used these drugs, none of this comes as any surprise. It's gratifying to see that the patient-reported outcomes match the investigator-reported data that's already been published and approved by the FDA [United States Food and Drug Administration] for both drugs. The overall metric they used was this time to sustained deterioration of all of these various symptoms on these questionnaires. I thought it met what I expected, having used these drugs personally, and I treated patients with them and heard my patients tell me about their experience. That's gratifying, and I thought the methods were very interesting and novel to allow this kind of cross-trial comparison where a head-to-head trial is simply not available.

Hope S. Rugo, MD, FASCO: MONARCH trials are kind of funny because they used the reverse numbers with MONARCH 2 for the second-line setting in MONARCH 3 for the first, whereas everybody else made their numbers go up through the progression. MONARCH 3, we're still waiting to hear. Survival data has shown a significant progression-free survival improvement, as have all 3 drugs. We've also heard some interesting data about ribociclib, and then recent updated data at ESMO [European Society for Medical Oncology] Breast Cancer 2022 meeting in May. The trials include pre- and perimenopausal women in the first-line setting, and then, of course, the second-line setting. They did a unique trial including the first and second-line group with fulvestrant, and then they have their first line trial, MONALEESA-2, in the postmenopausal women. We heard some updates that were quite interesting; some survival data at ESMO BC [Breast Cancer], and then we heard some data about dose adjustments in the first-line setting.

Mark Pegram, MD: Absolutely. I am happy to review the data from MONALEESA-3. Coming back to the numbers, it's more like MONALEESA-2.5, because it was a hybrid of first-line and second-line. The results from MONALEESA-3 overall demonstrated that there was an improvement in overall survival in patients who received ribociclib plus fulvestrant as compared with fulvestrant-placebo. At ESMO Breast, we saw the results of first-line. In the first-line setting, patients who got fulvestrant plus ribociclib had an overall survival of 67.6 months. That's more than 5 years—an overall survival we've never seen before—as compared with the control group, which was about 51 months. This corresponded to a hazard ratio of 0.67. Clear overall survival advantage seen with ribociclib plus fulvestrant in the first-line setting. Now, a question often comes up in clinic is we started 600 mg of ribociclib but if a patient has adverse events, should we dose reduce? If we dose reduce, would that compromise the efficacy? At ASCO [American Society of Clinical Oncology] 2022, we saw the results in terms of dose reductions and impact on survival. The bottom line was there was no impact. Even in patients who had a dose reduction, the outcomes are pretty much similar. This provides additional confidence that, for a patient who needs dose reduction, we should feel comfortable reducing the dose to 400 mg, and if needed, 200 mg as well.

Hope S. Rugo, MD, FASCO: It's interesting with ribociclib. Of course, you have the packaging dosing. Although you're paying for all the pills, you can take less without getting a new drug dose; it's fairly easy. In fact, in the poster discussion at ASCO 2022, someone asked, ‘Why don't you just start at a lower dose? Why start at a higher dose, after all?’ They had something like 66% of the people who dose reduced. I thought, well, then why not just start at the full dose because you can dose-reduce so easily? I don't know what your thought on that is.

Mark Pegram, MD: I fully agree, because that's how the trial was done, and we have the results related to that. Unless we have randomized data, 400 mg versus 600 mg, I would not start with 400. I would start with 600 mg, but if a patient has an adverse event, particularly neutropenia, I feel comfortable reducing to 400 mg.

Hope S. Rugo, MD, FASCO: There may be some pharmacogenomics that play a role there. Komal, you have a thought.

Komal Jhaveri, MD, FACP: I agree completely. There was a mention at the same discussion that perhaps there is a trial ongoing looking at the 400 mg versus 600 mg comparison. We know the adjuvant NATALEE trial is evaluating the 400-mg dose, but I agree with you. Not all patients get all adverse events, and it's something that we cannot predict for an individual patient. I see no harm in starting at the full dose because that patient might not need a dose reduction. We have the data, and we can easily dose reduce if we needed to.

Hope S. Rugo, MD, FASCO: These are really important points as we think about using these agents in our patients with metastatic breast cancer.

Transcript edited for clarity.