Dr. Rachel Freedman and Dr. Sharon Giordano share the latest rapid guideline update from ASCO on the adjuvant use of the CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer. They share details on the impetus for the update, supporting evidence, and considerations of benefits and harms for individuals. Additionally, Drs. Freedman and Giordano discuss what these options mean for clinicians and patients, and outstanding questions regarding optimal adjuvant chemotherapy and targeted therapy for patients with early breast cancer. Read the full rapid update, "Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer – CDK4/6 Inhibitors: ASCO Rapid Guideline Update" at www.asco.org/breast-cancer-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00886 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Rachel Freedman from Dana Farber Cancer Institute and Dr. Sharon Giordano from MD Anderson Cancer Center, co-chairs on "Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer – CDK 4/6 Inhibitors: ASCO Rapid Guideline Update." Thank you for being here, Dr. Freedman and Dr. Giordano. Dr. Rachel Freedman: Hi. It's great to be here, thank you. Dr. Sharon Giordano: Yeah, thank you for having us. Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Freedman and Dr. Giordano, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content here. First, Dr. Freedman, what prompted this update to the "Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer Guideline", which was previously updated in 2021? Dr. Rachel Freedman: Yeah, at that time, we published guidelines which were part of an amendment to the previously published 2020 early breast cancer guidelines to include consideration of adjuvant CDK4/6 inhibitor use, because the first data for adjuvant abemaciclib became available from the monarchE trial, and because the FDA had acted to grant approval for the use of abemaciclib in those with node positive disease and a Ki-67 score of at least 20%. Our recommendation at that time was to apply abemaciclib in the greater context of the intention-to-treat population included on the monarchE study. But since that time, the FDA in 2023 expanded its approval for adjuvant abemaciclib for a broader population, removing that Ki-67 requirement that was a part of their initial approval. With this change, the recently published longer term data from the monarchE study and the recently published data from the NATALEE trial and adjuvant ribociclib study, we felt that it was time to update our guidelines to be more relevant to the most current data available. Brittany Harvey: I appreciate you providing that background information on the impetus for this latest update. So then, Dr. Giordano, based on this new data, what are the updated recommendations in the latest version of this guideline? Dr. Sharon Giordano: So we really have two updated recommendations and then two qualifying statements that go with the new recommendations. So the first recommendation focuses on the use of adjuvant abemaciclib, which, as Rachel noted, was included in our previous guideline. So this recommendation is that abemaciclib for two years plus endocrine therapy for five or more years may be offered to patients who meet the criteria of the intent-to-treat analysis in the monarchE study. These are patients with resected, hormone receptor-positive, HER2-negative, node-positive breast cancer at high risk of recurrence. The way the study defined the high risk of recurrence was having either four or more lymph nodes involved, axillary lymph nodes involved, or having one to three lymph nodes, plus other high risk features, which included having a grade three tumor the size of 5 cm or greater, or having a Ki-67 of more than 20%. And so, although the FDA has dropped the requirement for the Ki-67 testing, and the language is quite broad now, the panel recommends the use of abemaciclib, really in that subgroup of patients that would have been eligible for the original monarchE study. That's the first recommendation, kind of a long one, but that was the update. The second recommendation focuses on the use of adjuvant ribociclib, and this is based on the data from the phase three NATALEE trial that was recently published. This recommendation is that ribociclib for three years plus endocrine therapy, may be offered to patients with stage two or three breast cancer who would have met criteria for study entry and have a high risk of recurrence. I would note with this one, I think it's important to remember that the ribociclib that's used in the adjuvant setting is a different dosing. So it's 400 milligrams daily, three weeks on, one week off, as compared to the 600 milligrams we're using in the metastatic setting. That was the second new recommendation. As I previously mentioned, however, there were two qualifying statements. The first qualifying statement was really the panel wanted to make, because they felt that CDK4/6 therapy in the adjuvant setting may not provide meaningful clinical benefit to every single patient who would have been eligible for these two trials. The concern was especially around lower risk patients. So the early stage two breast cancer patients who were included in the NATALEE trial, and in that situation, the panel felt for some patients, the risks may outweigh the benefits. The challenge here really was that there was not a great way to pick a very specific subgroup of patient that would benefit or wouldn't benefit. So based on that, the panel really recommended taking a broad approach and considering the benefits of therapy, the risks, the costs, and of course, patient preference when making the decision about whether or not to offer these drugs in the adjuvant setting. Then the second qualifying statement was really around how to pick between the two drugs. What the panel stated was that for patients that met the criteria for both studies, they could have been in either monarchE or NATALEE, for those patients, that abemaciclib has longer follow up, has a deepening benefit over time, it's more convenient because it's two years versus three years, and it has FDA approval. So for patients, again, that would have met criteria for either study, the panel favored using abemaciclib, except if patients had some contraindication or intolerance. That is the update, both the recommendations and the qualifying statements in this updated guideline. Brittany Harvey: Understood. Thank you for reviewing both of those recommendations and the nuances between choosing between some of those options as detailed in the qualifying statements. So then, Dr. Freedman, I think Dr. Giordano has talked about this already a little bit, but what should clinicians know as they implement these new recommendations into practice? Dr. Rachel Freedman: Yeah, in the guidelines, as Sharon said, we've really tried to offer recommendations that balance the available efficacy data along with the toxicity data and even some mention of cost consideration, although we purposely can't address that in the guideline. And we just feel that all of these need to be considered in combination for the individual patient. And just like you heard, our panel felt that for those meeting criteria for both the monarchE and NATALEE trials, given all the reasons that Sharon explained, that abemaciclib may be the preferred agent for now, but we all look forward to the evolving data in this space. It's great to have another evidence-based option with ribociclib at this time, but we really acknowledge that longer term follow up will evolve these recommendations further. Brittany Harvey: Absolutely. As you mentioned, it's great to have another option in this space. So then, in your view, Dr. Giordano, how will these recommendations impact patients with early breast cancer? Dr. Sharon Giordano: I think that, overall, this is really good news for patients who are at high risk because there's now two new available therapies that they can use to help prevent recurrence. I will note, as we mentioned before, though, they do come with a price, both the cost of the drug and the additional side effects of having two or three years of an additional drug that they're taking. But having said that, I think it's always good to have new options for therapy, and we can discuss these options with the individual patients, weigh the risks and the benefits, and ultimately, we hope with longer follow up, it would be great to see if these drugs would actually improve overall survival, which is ultimately our biggest goal. Brittany Harvey: Definitely, those are key for shared decision making between patients and their clinicians. Then finally, looking forward, Dr. Freedman, what are the outstanding questions regarding the optimal adjuvant chemotherapy and targeted therapy for early breast cancer? Dr. Rachel Freedman: Well, there are a lot of outstanding questions wit
