Factors in Selecting 1L Therapy for Patients With HR+ Metastatic Breast Cancer


Expert perspectives on factors that aid in the selection of optimal first-line therapy for patients with HR+ metastatic breast cancer.

Aditya Bardia, MD, MPH:
Heather, do you think all 3 CDK4/6 inhibitors are the same? For this patient, what would be your preferred first-line treatment?

Heather McArthur, MD: That’s the million-dollar question. In the hazard ratios across studies—it didn’t matter if the drugs were administered in the first line vs later lines. It didn’t matter if patients were premenopausal or postmenopausal—that consistency was impressive. Palbociclib was first to market as the leader in this space. That had been my first-line approach, with an aromatase inhibitor [AI] based on the PALOMA-2 first-line data. It’s been turned on its head a little with recent updates, specifically the survival update from PALOMA-2 that Rich Finn provided that showed no difference in overall survival. That’s still a head-scratcher given the consistency and the hazard ratios for PFS [progression-free survival]. We’ll need some real-world data to further understand why those differences might exist.

MONALEESA-2, which was a study of postmenopausal women receiving letrozole plus or minus ribociclib, presented data at ASCO [American Society of Clinical Oncology Annual Meeting] that showed a survival advantage of 63.9 vs 51.4 months. That influenced my practice. I started increasingly using ribociclib in the first-line setting. We’re waiting for mature data from MONARCH 3, which is the AI abemaciclib first-line trial. This space is still somewhat fluid. I have patients on palbociclib who are clearly benefiting from that agent, so I continue to treat them with that drug. For the newly diagnosed metastatic patient you’re describing, I’d probably consider a ribociclib AI strategy. We could debate whether we’d continue a CDK4/6, or which CDK4/6 we’d give on progression on that regimen if at all. But that’s my first-line approach.

Aditya Bardia, MD, MPH: It’s good to have multiple agents. There are additional questions that we need to address from a research perspective. To finalize the recommendation for first-line therapy, let’s change the case. Instead of postmenopausal, let’s say this was a premenopausal patient or a patient with visceral crisis. Virginia, are there subgroups where you’d consider 1 CDK4/6 inhibitor over another or a subgroup where you won’t use a CD4/6 inhibitor?

Virginia Kaklamani, MD: With the premenopausal question, the answer comes from MONALEESA-7, which is the only trial that has a purely premenopausal patient population. That trial showed a survival benefit with ribociclib. I feel very confident and comfortable giving ribociclib as first-line therapy to my premenopausal patients.

Looking at other subgroups, such as the visceral crisis, this was always something that we oncologists were very careful with. We loved how CDK4/6 inhibitors compared with endocrine therapy. But we were always nervous about these patients with several liver metastases and potentially rapidly progressive disease. One of the highlights of SABCS [San Antonio Breast Cancer Symposium] was the RIGHT Choice trial. This was a trial of premenopausal women with aggressive HR [hormone receptor]–positive, HER2 [human epidermal growth factor receptor 2]–negative breast cancer who were in visceral crisis. The definition of visceral crisis was similar to what we use in clinic. I know it’s a clinical definition. It’s very hard to do trials like that.

These patients were randomized to treatment of physician’s choice, which was a doublet chemotherapeutic regimen: docetaxel-capecitabine, paclitaxel-gemcitabine, or capecitabine-vinorelbine. Besides capecitabine-vinorelbine, the other 2 are combinations that we use a lot in the United States. I use a doublet therapy. Interestingly, the ribociclib arm did significantly better than the combination chemotherapy arm. This was surprising. Median PFS was 24 vs 12 months—almost a doubling of median PFS. There were also fewer adverse events as expected with the use of a CDK4/6 inhibitor and fewer dose reductions and dose discontinuations. With that and with other data in premenopausal women looking at the CDK4/6 inhibitor vs chemotherapy, it’s clear that first-line therapy in an ER [estrogen receptor]–positive patient should be a CDK4/6 inhibitor with an endocrine therapy.

Aditya Bardia, MD, MPH: It’s been practice changing to have these data. Sara, you’ve been involved with development of several CDK 4/6 inhibitors. What’s your take on the different CDK 4/6 inhibitors? Are there real-world data that could guide help us in terms of choice of first-line CDK4/6 inhibitor?

Sara A. Hurvitz, MD: That’s a great question. It’s the million-dollar question because we don’t have any prospective head-to-head comparisons of the 3 agents. We’re stuck with the inappropriate cross-trial comparisons that we all do in terms of efficacy and safety. I was struck by the negative PALOMA-2 data in terms of overall survival. Although they surprised many of us, there were negative overall survival data PALOMA-3 and negative data in the adjuvant setting with PALLAS and PENELOPE-B. That has made me wonder if this agent isn’t as effective in the long term as the other 2. There are differences among the 3 agents, pharmacokinetically and pharmacodynamically, that might explain some of the differences emerging in long-term outcomes. We’ll need more data and a head-to-head comparison to know if 1 is better than the other.

I make my decision by looking at the adverse effect profile of each agent. Palbociclib may be the best tolerated in my experience. Abemaciclib has a fair amount of GI [gastrointestinal] toxicity, so I’m selective regarding patients I’ll use abemaciclib for. I also consider things like cardiac medications and medications that could interfere with ribociclib given the issue of QTC prolongation. It’s rare, but it needs to be thought about and considered proactively. Real-world data are interesting but have to be peppered with caveats because they’re retrospective, nonrandomized, and fraught with selection bias potential.

A poster from Spain was presented looking at patients who had received endocrine [therapy] with abemaciclib, ribociclib, or palbociclib from 2014 to 2021. They were followed for about 3 years, and they were looked at in terms of clinical characteristics and outcomes, like progression-free survival. There were fewer than 200 patients in this retrospective analysis: 29% received abemaciclib; 44%, palbociclib; and 27%, ribociclib. They were well balanced based on characteristics they looked at, and it seemed to indicate that abemaciclib was associated with a lower risk of progression compared with palbociclib or ribociclib. I don’t use data like these to tell me which agent to use in my individual practices because we have loads of phase 3 prospective data to inform our decision based on efficacy and safety. But this adds to the real-world evidence relating to tolerability.

Aditya Bardia, MD, MPH: It’s a complex decision. Overall survival is 1 piece of the equation, but there are other factors. Thanks for summarizing this very nicely.

Transcript edited for clarity.

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