CDK4/6 inhibitors continue to serve as a cornerstone of care in the first line for both hormone receptor (HR)–positive, HER2-negative and HR-positive, HER2-positive metastatic breast cancer, particularly for patients with visceral crisis, according to Neelam V. Desai, MD.
“[We currently] use CDK4/6 inhibitors with endocrine therapy in the first line for patients with visceral crisis. Right now, the data is [strong] for ribociclib [Kisqali],” Desai explained during an interview with OncLive®. “If they’re not in visceral crisis, then you [can select between the 3 approved CDK 4/6 inhibitors] based on the [data from established studies]. Then, for patients with HR-positive, HER2-positive metastatic breast cancer, adding palbociclib [Ibrance] in the maintenance phase would be helpful.”
In the interview, Desai expanded on notable trials evaluating the 3 FDA-approved CDK4/6 inhibitors and highlighted important considerations when selecting a CDK4/6 inhibitor in clinical practice. She also detailed the role of palbociclib for the treatment of patients with HR-positive, HER2-positive metastatic breast cancer.
Desai is a medical oncologist and hematologist at the Atrium Health Levine Cancer Institute in Matthews, North Carolina.
OncLive: What are some notable clinical trials that have evaluated CDK4/6 inhibitors in breast cancer?
Desai: There [are several] pivotal trials for the 3 different CDK 4/6 inhibitors that are approved in metastatic HR-positive, HER2-negative breast cancer. These [include] the trials for palbociclib, [primarily] the [phase 3] PALOMA-2 trial [NCT01740427], the [phase 2] PARSIFAL trial [NCT02491983], and the [phase 2] Young-PEARL trial [NCT02592746]. [Furthermore, there are] the MONALEESA trials [evaluating] ribociclib, and [the phase 3] MONARCH 3 trial [NCT02246621] [evaluating] abemaciclib [Verzenio].
All of these trials show a consistent improvement in progression-free survival [PFS]. The ribociclib trials show a statistically significant improvement in overall survival [OS] as well. Although MONARCH 3 did not meet statistical significance [for its] OS end point, there was a 13.1-month benefit in OS, [which was] clinically meaningful.1 [Similarly, the] palbociclib trials failed to show any statistically significant improvement in OS. However, there has been some criticism about the collection of data [in these studies], which might have skewed the results. Some real-world studies [have shown an] improvement, both in terms of PFS and OS, with the use of palbociclib. All 3 of these drugs are approved in the metastatic setting.
What are some considerations when selecting CDK4/6 inhibitors in clinical practice?
I keep all 3 drugs as an option. We tend to use them in the first line, and if not the first line, the second line, if possible. I make a decision primarily based on [a patient’s] age and comorbidities, [treatment] tolerability, and my worry for what kind of [adverse] effects [AEs] they might [experience]. I do tend to prefer ribociclib and abemaciclib because of the OS benefit; however, I keep palbociclib as an option for my older patients. They have a lot of comorbidities, [so palbociclib is a good option if] I’m worried about their ability to tolerate abemaciclib because of diarrhea or fatigue concerns, or they have a lot of cardiac issues where combining ribociclib with their [other] medications might be challenging.
What is the role of palbociclib in HER2-positive metastatic breast cancer?
Data from the… [phase 3] PATINA trial [NCT02947685] were presented at the 2024 San Antonio Breast Cancer Symposium; that study [included] patients with HR-positive, HER2-positive, metastatic breast cancer. The current standard of care is to treat patients with induction taxane, trastuzumab [Herceptin], and pertuzumab [Perjeta]. After 6 to 8 cycles, the taxane is dropped, [trastuzumab and pertuzumab are] continued, and endocrine therapy is added for patients who have HR-positive disease. In this trial, at the juncture of maintenance therapy, patients were [randomly assigned] to [receive trastuzumab and pertuzumab], and endocrine therapy with or without palbociclib. This study showed that the addition of palbociclib led to a 15.2-month improvement in PFS.2 The OS data are [currently] not mature enough to comment on.
[Nevertheless,] the data are compelling. [I] certainly would consider adding palbociclib to maintenance [approaches] for patients who have HR-positive, HER2-positive metastatic disease. Generally, palbociclib is well tolerated. In this study, the addition of palbociclib to trastuzumab and pertuzumab [plus] endocrine therapy did not lead to too many issues in terms of AEs, and there were no new safety signals noted. This [combination] is certainly something that I would reach for [when treating] my patients.
Are there any biological differences in HR-positive/HER2-positive breast cancer compared with HER2-negative disease that could influence how patients respond to CDK4/6 inhibitors?
There is a lot of crosstalk in the receptor signaling. It would be important to see what long-term data continue to show, because the HR signaling is important. However, the HER2 receptor part is where we often worry about progression. Therefore, putting the brakes on both sides is important. We usually tend not to place as much emphasis on the endocrine therapy part in HER2-positive disease. There are [attempts] to bring that to the forefront, and hopefully we’ll continue to show long-term benefit.
What were the results from the RIGHT Choice trial evaluating ribociclib plus endocrine therapy?
The RIGHT Choice trial [evaluated] first-line ribociclib and endocrine therapy in patients with HR-positive, HER2-negative metastatic disease, or at visceral crisis, where we traditionally treat them with chemotherapy. The trial looked at treating them with ribociclib and endocrine therapy and compared that with a doublet chemotherapy regimen and showed that ribociclib and endocrine therapy led to improvement in PFS with fewer AEs.
References
- Goetz MP, Toi M, Huober J, et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol. 2024;35(8):718-727. doi:10.1016/j.annonc.2024.04.013
- Metzger O, Mandrekar S, DeMichele A, et al. AFT-38 PATINA: a randomized, open-label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy vs. anti-HER2 therapy + endocrine therapy after induction treatment for hormone receptor-positive (HR+)/HER2-positive metastatic breast cancer. Presented at: San Antonia Breast Cancer Conference; December 10-13, 2024; San Antonio, TX. GS2-12