 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?

 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.

 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.

 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.

 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.

 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.

 There may be some pharmacogenomics that play a role there. Komal, you have a thought.

 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.

 These are really important points as we think about using these agents in our patients with metastatic breast cancer.

Videos

Focusing on the frontline setting of HR+/HER2- breast cancer, panelists discuss clinical trial data with abemaciclib and ribociclib, respectively.

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

®: “Therapy Options in Hormone Receptor-Positive HER2 Negative Breast Cancer.” I'm Dr Hope Rugo, and I'm a breast medical oncologist at the University of California San Francisco's Comprehensive Cancer Center. I'm joined today by a panel of my colleagues who treat breast cancer. I'd like to welcome Dr Aditya Bardia, who's at Massachusetts General Hospital in Boston, Massachusetts; Dr Komal Jhaveri, who is at Memorial Sloan Kettering Cancer Center in New York City; Dr Mark Pegram from the Stanford Cancer Center at Stanford University in Palo Alto, California; and Dr Anne O'Dea from the University of Kansas Medical Center in Kansas City, Kansas. I think we have a nice geographic representation of experts in breast oncology in the United States. We're going to have an exciting discussion today talking about hormone and receptor-positive, HER2-negative breast cancer. Let's get started on our first topic. Komal will talk a little bit about outcomes in patients with hormone receptor-positive breast cancer and how this has changed over the last couple of decades.

 Thank you, Hope. We have come a very long way in the treatment of hormone receptor-positive disease. Certainly, when we even think about single-agent endocrine therapy, if we look at the current phase 3 trials in the first-line metastatic setting, we're seeing a difference in the overall survival. The gain that we've got in overall survival—it's nearly over 4 years even with single-agent endocrine therapy—but what has really been a big paradigm shift and a big revolutionary treatment paradigm now is the addition of CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors with an endocrine therapy. In more recent trials from CDK4/6, which have read out the overall survival gains, we're seeing that over 5 years. For example, in the MONALEESA-3 trial, which had 2 cohorts, including both first-line and second-line, the first line being the endocrine-sensitive patient population overall survival with the CDK4/6, and endocrine therapy was about 67 months. We're seeing progression-free survival gains with other targeted therapies—maybe alpelisib, which is the alpha-specific PI3K inhibitor in patients who harbor 

 mutations; maybe with everolimus if we can use that. At this 2022 ASCO [American Society of Clinical Oncology] annual meeting, we heard the results for the DESTINY-Breast04 trial, antibody-drug conjugate, which has activity beyond HER2-positive disease and what we now define as HER2-low breast cancers, the majority of which are hormone receptor-positive disease. They have also had a progression via overall survival benefit—a lot of great gains.

 It's an exciting time to hear about the advances we're making in this most common subset of breast cancer, the most common cancer worldwide in women. Maybe we've done a little bit better job at identifying our receptors, so that we can identify more about which patients are hormone receptor-positive. We heard today about additional testing looking at genomic signatures that might help further. Now we’ve heard about the CDK4/6 inhibitors from Komal. Of course, we're all using those, but, Anne, in your practice, how do you select and order therapy for a patient who has hormone receptor-positive, HER2-negative disease? We heard about how many options they have. How do you vary that based on menopausal status?

 For me the most important thing I'm looking at is disease-free interval for these women. We're also looking at those patients that progress while receiving their adjuvant endocrine therapy. Of course, those patients have a much different biology than patients that have a 6-year or 7-year disease-free interval. Then we're selecting a first-line therapeutic option for them. I think that's the primary thing, and then we're looking at the patient's performance status. We're looking at their comorbid medical conditions, what their goals are, and certainly, volume of disease is a consideration as well. If you have a patient that has perhaps a single, solitary bone metastasis, that is very different from a patient that has visceral metastases. Those are sort of the things that I think through when I'm having this type of a discussion with a patient.

 When you do think through those, do you always give a CDK4/6 inhibitor first-line? And then, how do you choose an AI [aromatase inhibitor]or fulvestrant as the partner?

 The overwhelming totality of data that was described that really supports use of first-line CDK4/6. It's really a very rare patient in whom I'm not using that in the first line; perhaps an elderly patient in a skilled nursing facility where it's very cumbersome for her to have laboratory monitoring, or something like. However, outside of a situation like that, I’m really using it in all my patients. Typically, in terms of deciding aromatase inhibitor or fulvestrant, I'm really looking at that disease-free interval so those patients that are progressing on their adjuvant-AI, we're certainly going with fulvestrant for patients who have that very long disease-free interval. We're usually using an aromatase inhibitor.

Expert perspectives on the evolving treatment paradigm for patients receiving frontline therapy for HR+/HER2- breast cancer.

Frontline Treatment Strategies for HR+/HER2- Breast Cancer

Data from the following clinical trials are discussed:

+ breast cancer identifies recurrent pathway alterations associated with anti-HER2 resistance and new therapeutic vulnerabilities

GS1-05: Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2- breast cancer: results from the phase 1 TROPION-PanTumor01 study

GS04-09: Quality-of-life results from OlympiA: a phase 3, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after neoadjuvant chemotherapy in patients with germline 

After discussing a few more key datasets from the SABCS 2021 Virtual Meeting, expert panelists discuss how they would approach treatment in several subsets of breast cancer. 

SABCS 2021: Novel Approaches to Breast Cancer Management 

PD4-02: Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis in 

+ breast cancer: Results from TBCRC049, a phase 2 nonrandomized study

PD4-04: Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated 

+ metastatic breast cancer with brain metastases (HER2CLIMB)

P1-18-26: Intracranial efficacy of tucatinib, palbociclib, and letrozole combination in patients with HR+/

P1-21-03: Efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of patients with 

+ breast cancer with or without brain metastases: a systematic review and meta-analysis

OT1-13-01: HER2CLIMB-04: phase 2 trial of tucatinib + trastuzumab deruxtecan in patients with 

+ locally advanced or metastatic breast cancer with and without brain metastases

Focusing on datasets from the SABCS 2021 Virtual Meeting, panelists consider novel approaches to the management of brain metastases in breast cancer.

SABCS 2021: Brain Metastases Updates in Breast Cancer 

GS3-01: Trastuzumab deruxtecan (T-DXd; DS-8201a) vs trastuzumab emtansine (T-DM1) in patients with 

–positive metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINYBreast03

GS3-02: Updated overall survival (OS) results from the phase 3 PHOEBE trial pyrotinib vs lapatinib in combination with capecitabine in patients with 

GS4-10: Neratinib + fulvestrant + trastuzumab for hormone receptor (HR)–positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: latest updates from the SUMMIT trial

P2-13-10: First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with 

+ metastatic breast cancer: results from a phase I study

P2-13-07: Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy for 

+ breast cancer: results from a phase 1 study

PD8-07: Evaluation of tucatinib + paclitaxel + pertuzumab + trastuzumab followed by AC (doxorubicin hydrochloride, cyclophosphamide) in high-risk HER2+ stage II/III breast cancer: results from the I-SPY2 trial

Expert panelists share their perspectives on metastatic breast cancer management datasets from the SABCS 2021 Virtual Meeting. 

Anne P. O’Dea, MD

Articles

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

Frontline Treatment Strategies for HR+/HER2- Breast Cancer

SABCS 2021: Novel Approaches to Breast Cancer Management

SABCS 2021: Brain Metastases Updates in Breast Cancer

SABCS 2021: Updates in Metastatic Breast Cancer