Komal Jhaveri, MD, FACP: Talking about adjuvant therapy, one of the exciting datasets that was presented was from the monarchE trial [NCT03155997], [which] we have approval for high-risk patients. So, 4 or more positive nodes or 1 to 3 positive nodes with either a tumor size of more than 5 cm or grade 3 tumor. We have abemaciclib. There was data presented from the phase 3 NATALEE trial [NCT03701334]; maybe share your impression about that dataset, Aditya.

Aditya Bardia, MD, MPH: The NATALEE trial was an adjuvant clinical trial looking at endocrine therapy plus ribociclib vs endocrine therapy for patients with medium or high-risk disease. There are 3 important features related to the NATALEE trial. The first, it included patients with medium risk which were not included in monarchE. It was defined as patients with stage II disease who had some other high-risk features like grade 3 or Ki-67 or high genomic risk and patients with stage III disease. The second was the dose of ribociclib; it was 400 mg as opposed to 600 mg that is used in the metastatic setting. The rationale was that with the lower dose, you’ll have less toxicity, especially in the adjuvant setting where compliance and tolerability is a critical issue. Third was the duration. The duration of ribociclib was 3 years as opposed to 2 years with abemaciclib in monarchE.

Overall, the trial met its primary end point. This was interim analysis, too; it showed improvement in invasive disease-free survival, a hazard ratio of 0.75, so 25% lower risk of progression or death. In terms of absolute disease-free survival improvement, there was 3% absolute disease-free survival improvement. It should be noted that only 20% of patients had completed 3 years of ribociclib. So, we do need additional follow-up patients. About 50% had completed 2 years of ribociclib. So, one way to look at this is we are seeing the data with 2 years of ribociclib rather than 3 years of ribociclib, so we can compare it more to monarchE in terms of the duration. We definitely need more follow-up to really see the benefit with 3 years of ribociclib and obviously follow-up for overall survival as well.

Komal Jhaveri, MD, FACP: ASCO [the American Society of Clinical Oncology Annual Meeting] is winding down today, and you’re going to go back to see your patients tomorrow in clinic, and you have a patient coming to you who said, “What do you think about getting the ribociclib?” Given that we saw activity stage II patients as well, how will you address that with your patient?

Aditya Bardia, MD, MPH: It’s a good question. It will be a patient-centered discussion. You present the data; you review the data that’s available. It’s not FDA-approved yet. We don’t have a label for the use of ribociclib. We don’t have ASCO guidelines or NCCN [National Comprehensive Cancer Center] guidelines endorsing that if we do have guidelines that endorse the use of ribociclib, and we saw this with olaparib, where before approval of adjuvant olaparib there was a rapid guideline update by ASCO supporting the use for olaparib. So if you have some evidence to back that up and some organization, I think it’s definitely reasonable to consider.

Komal Jhaveri, MD, FACP: Otherwise…I agree with you that I think it’s going to be a shared physician-patient decision-making process, given the efficacy that we have. It’s a 3% absolute benefit for a drug that is 3 years of duration. Right now, the data that we have is for 20% of the patients who completed the intended 3-year duration. The remaining are still ongoing, and we hopefully will get more follow-up data to be able to see that. What did you think about the dose and the discontinuation rates from the NATALEE study?

Aditya Bardia, MD, MPH: The discontinuation relatively was much lower as compared to some of the adjuvant trials, particularly PALLAS [NCT02513394], where there was a pretty high discontinuation rate. I think it speaks to the dose, the 400 mg. In the results that were presented, they also had a slide where they compared 400 [mg] historically to 600 [mg], and the rate of neutropenia was much lower. So I think that helps. There’s still a subset of patients who discontinued ribociclib, either based on physician decision or toxicity like LFT [liver function test] increase, which is [an adverse] effect we see with ribociclib.

Komal Jhaveri, MD, FACP: Based on this AMALEE trial [NCT03822468] that Aditya was talking us through with 400 mg and 600 mg that show less toxicity with 400 [mg], have you changed your practice in the metastatic setting and now with NATALEE confirming invasive disease-free survival benefit? Have you started initiating your patients at 400 [mg] instead of 600 [mg]? What do you do in the metastatic setting still?

Gregory Vidal, MD, PhD: Prior to this we really hadn’t had any data that showed survival difference for 400 [mg] to 600 [mg]. We had some ASCO data previously that really wasn’t positive. So no, I have not made any change. Am I going to make any change? Probably not without enough data or the completion of that data. I [must] add from the conversation we just had, I do think the extra year compared to abemaciclib is going to be important for that population. Those patients, we know there’s a high discontinuation rate for anti-estrogen therapies in the adjuvant setting, and an additional year is a conversation that we’re going to need to have. Then there’s a question of whether or not the data, once you have everybody treated for 3 years, is it going to be different? We see it now, do we need that extra year? So those are all sort of conversations we’re going to have. I think it was really smart on their part to have a lower dose for toxicity purposes. I still think we’re going to need to have those EKGs because those numbers hadn’t dropped as dramatically as I would’ve anticipated, but we’ll wait for the data.

Komal Jhaveri, MD, FACP: I agree. I think it was at least comforting to see that the grade 3 QTcF [interval] was not very high with the 400 [mg] dose, which is what we saw in the AMALEE study. I think the primary end point in AMALEE was overall response rate, and we did not see superiority for the 400-mg dose, but the secondary end point for QTcF was kind of met. If you look at the progression-free survival in the AMALEE trial from 400 [mg] to 600 [mg], it kind of looked comfortable. But I agree with you, I haven’t changed my practice. I think I’d still do 600 mg for my metastatic patients. I think it gives us comfort that we know, even with dose reductions, that efficacy is not impacted. So this data gives us comfort that, if for toxicity reasons we had to do a dose reduction, 400 [mg] is equally efficacious. So I think that was very, very helpful, and I think we’ll have to just wait and see how the FDA and the regulatory agencies review this data and what more might be required before we can start thinking about 2 options to discuss with a patient over 1.

Talking about disease-free survival and requirement for overall survival, what do you think about overall survival as an end point? How do you really think about disease-free survival? Is there any data that [shows] maybe one is better than the other, one is a good surrogate for the other?

Aditya Bardia, MD, MPH: No, ideally overall survival is the best end point. There’s no question, that is what matters to patients. As providers, that is what we want. The challenge is in a clinical trial setting that can take a very long period of time. If you think about an adjuvant trial, the median overall survival for a patient with metastatic disease at this time is about 7 [to] 7.5 years. That’s in the metastatic setting. Then, if you bring in the adjuvant setting as well, it’ll just take years to get that end point. That’s why disease-free survival is used as a surrogate marker. There’s evidence from a meta-analysis that were presented at ASCO 2023 that it’s a good surrogate marker for overall survival. So I think it’s very reasonable to consider disease-free survival in the adjuvant first-line metastatic setting but do follow patients for overall survival.

Transcript edited for clarity.

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